Current Medical Diagnosis & Treatment 2015

32

Viral & Rickettsial Infections

Wayne X. Shandera, MD
J. Daniel Kelly, MD

VIRAL DISEASES

HUMAN HERPESVIRUSES

  1. Herpesviruses 1 & 2

 ESSENTIALS OF DIAGNOSIS

 Spectrum of illness from stomatitis and urogenital lesions to facial nerve paralysis (Bell palsy) and encephalitis.

 Variable intervals between exposure and clinical disease, since HSV causes both primary (often subclinical) and reactivation disease.

 General Considerations

Herpesviruses 1 and 2 affect primarily the oral and genital areas, respectively. Asymptomatic shedding of either virus is common, especially following primary infection or symptomatic recurrences, and may be responsible for transmission. Asymptomatic HSV-2–infected individuals shed the virus less frequently than those with symptomatic infection. Disease is typically a manifestation of reactivation. Total and subclinical shedding of HSV-2 virus decrease after the first year of initial infection, although viral shedding continues for years thereafter. Higher than expected rates of HSV-2 lesions occur among women in the postpartum period and also among women who have sex with women.

Although HSV-2 is the most common cause of genital ulcers in the developed world, HSV-1 is increasingly recognized as causing primary urogenital infections. HSV-2 seropositivity increases the risk of HIV acquisition (it is threefold higher among persons who are HSV-2-seropositive than among those who are HSV-2 seronegative), and reactivates more frequently in advanced HIV infection. HIV replication is increased by interaction with HSV proteins. Suppression of HSV-2 decreases HIV-1 plasma levels and genital tract shedding of HIV, which can contribute to a reduction in sexual transmission of HIV-1.

 Clinical Findings

  1. Symptoms and Signs
  2. Mucocutaneous disease—SeeChapter 6for HSV-1 mucocutaneous disease involving the mouth and oral cavity (“herpes labialis” or “gingivostomatitis;” the latter largely in children). Digital lesions(whitlows) (Figure 32–1) are an occupational hazard in medicine and dentistry. Contact sports (eg, wrestling) are associated with outbreaks of skin infections (“herpes gladiatorum”). Asymptomatic shedding of HSV-1 is frequent, with most infected individuals shedding virus at least once a month.

 Figure 32–1. Herpetic whitlow. (Reproduced, with permission, from Richard P. Usatine, MD.)

Vesicles form moist ulcers after several days and epithelialize over 1–2 weeks if untreated. Primary infection is usually more severe than recurrences but may be asymptomatic. Recurrences often involve fewer lesions, tend to be labial, heal faster, and are induced by stress, fever, infection, sunlight, chemotherapy (eg, fludarabine, azathioprine) or other undetermined factors.

HSV-2 lesions largely involve the genital tract, with the virus remaining latent in the presacral ganglia (see Chapter 6). Occasionally, lesions arise in the perianal region or on the buttocks and upper thighs. Dysuria, cervicitis, and urinary retention may occur in women. Most HSV-2 infected persons in the United States are unaware that they are infected. Current epidemiologic studies show that HSV-1 is a more common cause of both genital and oral lesions than HSV-2 in young women in the United States.

Proctitis and sacral lesions in HIV-infected persons with CD4 cytopenia may present with extensive, ulcerating, weeping lesions. Large ulcerations and atypical lesions suggest drug-resistant isolates (see below).

  1. Ocular disease—HSV can cause keratitis, blepharitis, and keratoconjunctivitis. Keratitis is usually unilateral and is often associated with impaired visual acuity. Lesions limited to the epithelium usually heal without affecting vision, whereas stromal involvement can cause uveitis, scarring, and eventually blindness. Recurrences of ocular disease are frequent. HSV is the second most common cause, after VZV, of acute retinal necrosis.
  2. Neonatal and congenital infection—Both herpesviruses can infect the fetus and induce congenitalmalformations (organomegaly, bleeding, and CNS abnormalities). Maternal infection during the third trimester is associated with the highest risk of neonatal transmission, but about 70% of these infections are asymptomatic or unrecognized. Neonatal transmission during delivery, however, is more common than intrauterine infection. Invasive fetal monitoring and vacuum or forceps delivery increase the risk of herpesvirus transmission.
  3. Central nervous system disease—Herpes simplex encephalitis is predominantly caused by HSV-1 and presents with nonspecific symptoms: a flu-like prodrome, followed by headache, fever, behavioral and speech disturbances, and focal or generalized seizures. The temporal lobe is often involved. Untreated disease and presentation with coma carry a high mortality rate, with many survivors suffering neurologic sequelae.

Both HSV-1 and HSV-2 are increasingly recognized as a cause of mild, nonspecific neurologic symptoms and are also associated with benign recurrent lymphocytic (Mollaret) meningitis. Primary HSV-2 infection in women often presents as aseptic meningitis. Recurrent meningitis from HSV-2 occurs in both younger and older individuals.

  1. Disseminated infection—Disseminated HSV infection occurs in the setting of immunosuppression, either primary or iatrogenic, or rarely with pregnancy. In disseminated disease, skin lesions are not always present. Disseminated skin lesions are a particular complication in patients with atopic eczema (eczema herpeticum) and burns. Pneumonia can occur regardless of immune status.
  2. Bell palsy—HSV-1 is a cause of Bell palsy.
  3. Esophagitis and proctitis—HSV-1 can cause esophagitis in immunocompromised patients, particularly those with AIDS. The lesions are smaller and deeper than those observed in patients with CMV esophagitis or with other herpesvirus known to cause esophagitis in immunocompromised hosts. HSV-1 may also activate mononuclear cells in the pathogenesis of achalasia. Proctitis occurs mainly in men who have sex with men.
  4. Erythema multiforme—Herpes simplex viruses remain, along with certain drugs, a leading cause of erythema multiforme minor (“herpes-associated erythema multiforme”) and of the more severe condition Stevens–Johnson syndrome/toxic epidermal necrolysis (see alsoChapter 6).
  5. Other—HSV is the cause of approximately 1% of cases of acute liver failure, particularly in pregnant women and immunosuppressed patients. The mortality of such rare fulminant hepatitis is nearly 75%. An HSV lower respiratory tract infection of unknown clinical significance is common in mechanically ventilated patients. Evidence suggests that this finding is usually an indicator rather than the cause of a poor clinical condition. HSV-1 pneumonia is associated with high morbidity in patients with solid tumors. HSV-1 is reported to be a cause of perinephric abscess, febrile neutropenia, chronic urticaria, and esophagitis and enteritis in systemic lupus erythematosus. HSV is also associated withHelicobacter pylori–negative upper gastrointestinal tract ulcers.
  6. Laboratory Findings
  7. Mucocutaneous disease—SeeChapter 6.
  8. Ocular disease—Herpes keratitis is diagnosed by branching (dendritic) ulcers that stain with fluorescein. The extent of epithelial injury in herpes keratitis correlates well with polymerase chain reaction (PCR) positivity.
  9. Encephalitis and recurrent meningitis—Cerebrospinal fluid pleocytosis is common, with a similar increase in the number of red cells. HSV DNA PCR of the cerebrospinal fluid is a rapid, sensitive, and specific tool for early diagnosis and can be included in a multiple rapid array panel. Antibodies to HSV in cerebrospinal fluid can confirm the diagnosis but appear late in disease. Viral culture shows a sensitivity of only 10%. MRI scanning is often a useful adjunct showing increased signal in the temporal and frontal lobes. Temporal lobe seizure foci may be shown on electroencephalograms (EEGs).
  10. Esophagitis and proctitis—Esophagitis is diagnosed by endoscopic biopsy and cultures. Proctitis may be diagnosed by rectal swab for PCR or culture, or both, with complicated cases requiring biopsy.
  11. Pneumonia—Pneumonia is diagnosed by clinical, pathologic, and radiographic findings. The CT findings include diffuse or multifocal areas of ground-glass attenuation or consolidative changes or both and are best confirmed using high-resolution CT techniques.

 Treatment & Prophylaxis

Medications that inhibit replication of HSV-1 and HSV-2 include trifluridine and vidarabine (both for keratitis), acyclovir and related compounds, foscarnet, and cidofovir (Table 32–1).

Table 32–1. Agents for viral infections.1

  1. Mucocutaneous Disease

See Chapter 6.

  1. Keratitis

For the treatment of acute epithelial keratitis, topical antiviral agents (ophthalmic trifluridine, vidarabine, acyclovir, and ganciclovir) are all nearly equivalent in efficacy and are recommended. Combination of topical antiviral agents with interferon or debridement (or both) hastens healing. Intravenous acyclovir is used for acute retinal necrosis. Oral famciclovir is a reasonable alternative, especially in patients unable to tolerate intravenous therapy and when acyclovir resistance is present. The usage of topical corticosteroids may exacerbate the infection, although systemic corticosteroids may help with selected cases of stromal infection. Long-term treatment (> 1 year) with acyclovir at a dosage of 800 mg/d orally decreases recurrence rates of keratitis, conjunctivitis or blepharitis due to HSV.

  1. Neonatal Disease

Intravenous acyclovir (20 mg/kg every 8 hours for 14–21 days) is effective for the treatment of disseminated lesions in neonatal disease. Counseling with serologic screening should be offered to pregnant mothers. The use of maternal antenatal suppressive therapy with acyclovir (typically, 400 mg three times daily) beginning at 36 weeks gestation decreases the presence of detectable HSV, the rates of recurrence at delivery, and the need for cesarean delivery. Cesarean delivery is recommended for pregnant women with active genital lesions or typical prodromal symptoms.

  1. Encephalitis and CNS Meningitis

Because of the need for rapid treatment to decrease mortality and neurologic sequelae, intravenous acyclovir (10 mg/kg every 8 hours for 10 days or more, adjusting for kidney dysfunction) should be started in those patients with suspected HSV encephalitis, stopping only if another diagnosis is established. If the PCR of cerebrospinal fluid is negative but clinical suspicion remains high, treatment should be continued for 10 days because the false-negative rate for PCR can be as high as 25% (especially in children) and acyclovir is relatively nontoxic. Data from the California Encephalitis project suggest that anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a more common entity than viral encephalitis especially in children (see West Nile virus encephalitis below).

Long-term neurologic sequelae of HSV encephalitis are common and late pediatric relapse is recognized. Acyclovir resistance in a case of herpes simplex encephalitis is reported. Aseptic meningitis may also require a course of intravenous acyclovir or valacyclovir.

  1. Disseminated Disease

Disseminated disease responds best to parenteral acyclovir when treatment is initiated early.

  1. Bell Palsy

Prednisolone, 25 mg orally twice daily for 10 days started within 72 h of onset, significantly increases the rate of recovery. Data on antiherpes antiviral agents are equivocal; according to one study, valacyclovir (but not acyclovir), 1 g orally daily for 5 days, plus corticosteroid therapy may be beneficial if started within 7 days of symptom onset. In patients with severe or complete facial paralysis, such antiviral therapy is often administered but without a firm proof of efficacy.

  1. Esophagitis and Proctitis

Patients with esophagitis should receive either intravenous acyclovir (5–10 mg/kg every 8 hours) or oral acyclovir (400 mg five times daily) through resolution of symptoms, typically 3–5 days; however, longer treatment may be necessary for immunosuppressed patients. Maintenance therapy for AIDS patients is also with acyclovir (400 mg three to five times daily). Proctitis is treated with similar dosages and usually responds within 5 days.

  1. Erythema Multiforme

Suppressive therapy with oral acyclovir (400 mg twice a day for 6 months) decreases the recurrence rate of HSV-associated erythema multiforme. Valacyclovir (500 mg twice a day) may be effective in cases unresponsive to acyclovir.

 Prevention

Besides antiviral suppressive therapy, prevention also requires counseling and the use of condom barrier precautions during sexual activity. Disclosure to sexual partners of HSV-seropositive status is associated with about a 50% reduction in the HSV-2 acquisition. Male circumcision is associated with a lower incidence of acquiring HSV-2 infection.

Preventing spread to hospital staff and other patients from cases with mucocutaneous, disseminated, or genital disease requires isolation and the usage of handwashing and gloving–gowning precautions. Staff with active lesions (eg, whitlows) should not have contact with patients. Asymptomatic transmission occurs, especially with HSV-2. The only effective vaccine to date is an HSV-2 subunit vaccine that protects against genital HSV-1 but not HSV-2 in women.

Belshe RB et al; Herpevac Trial for Women. Efficacy results of a trial of a herpes simplex vaccine. N Engl J Med. 2012 Jan 5;366(1):34–43. [PMID: 22216840]

Bernstein DI et al. Epidemiology, clinical presentation, and antibody response to primary infection with herpes simplex virus type 1 and type 2 in young women. Clin Infect Dis. 2013 Feb;56(3):344–51. [PMID: 23087395]

Cunningham A et al. Current management and recommendations for access to antiviral therapy of herpes labialis. J Clin Virol. 2012 Jan;53(1):6–11. [PMID: 21889905]

Leveque N et al. Rapid virological diagnosis of central nervous system infections by use of a multiplex reverse transcription-PCR DNA microarray. J Clin Microbiol. 2011 Nov;49(11):3874–9. [PMID: 21918017]

Tronstein E et al. Genital shedding of herpes simplex virus among symptomatic and asymptomatic persons with HSV-2 infection. JAMA. 2011 Apr 13;305(14):1441–9. [PMID: 21486697]

  1. Varicella (Chickenpox) & Herpes Zoster (Shingles)

 ESSENTIALS OF DIAGNOSIS

 Varicella rash: pruritic, centrifugal, papular, changing to vesicular (“dewdrops on a rose petal”), pustular, and finally crusting.

 Zoster rash: tingling, pain, eruption of vesicles in a dermatomal distribution, evolving to pustules and then crusting.

 General Considerations

Varicella zoster virus (VZV), or HHV-3, disease manifestations include chickenpox (varicella) and shingles (herpes zoster). Chickenpox generally presents during childhood; has an incubation period of 10–20 days (average 2 weeks); and is highly contagious, spreading by inhalation of infective droplets or contact with lesions.

The incidence and severity of herpes zoster (“shingles”), which affects up to 25% of persons during their lifetime, increases with age due to an age-related decline in immunity against VZV. More than half of all patients in whom herpes zoster develops are older than 60 years, and the incidence of herpes zoster reaches 10 cases per 1000 patient-years by age 80 (by which time 50% are infected with VZV). The annual incidence in the United States of 1 million cases is increasing as the population ages. Populations at increased risk for varicella-zoster–related diseases include immunosuppressed persons and persons receiving biologic agents (ie, tumor necrosis factor [TNF] inhibitors).

 Clinical Findings

  1. Varicella
  2. Symptoms and signs—Fever and malaise are mild in children and more marked in adults. The pruritic rash begins prominently on the face, scalp, and trunk, and later involves the extremities (Table 32–2). Maculopapules change in a few hours to vesicles that become pustular and eventually form crusts (Figures 32–2 and 32–3). New lesions may erupt for 1–5 days, so that different stages of the eruption are usually present simultaneously. The crusts slough in 7–14 days. The vesicles and pustules are superficial and elliptical, with slightly serrated borders. Pitted scars are frequent. Although the disease is often mild, complications (such as secondary bacterial infection, pneumonitis, and encephalitis) occur in about 1% of cases and often lead to hospitalization.

Table 32–2. Diagnostic features of some acute exanthems.

 Figure 32–2. Primary varicella (chickenpox) skin lesions. (Public Health Image Library, CDC.)

 Figure 32–3. Chickenpox (varicella) with classic “dew drop on rose petal” appearance. (Reproduced, with permission, from Richard P. Usatine, MD.)

After the primary infection, the virus remains dormant in cranial nerves sensory ganglia and spinal dorsal root ganglia. Latent VZV will reactivate as herpes zoster in about 10–30% of persons (see below). Varicella is more severe in older patients and immunocompromised persons. In the latter, atypical presentations, including widespread dissemination in the absence of skin lesions, are often described.

There is a small increased risk of Guillain-Barré syndrome for at least 2 months after an acute herpes zoster attack.

  1. Laboratory findings—Diagnosis is usually made clinically, with confirmation by direct immunofluorescent antibody staining or PCR of scrapings from lesions. Multinucleated giant cells are usually apparent on a Tzanck smear or Calcofluor stain of material from the vesicle bases. Leukopenia and subclinical transaminase elevation are often present and thrombocytopenia occasionally occurs.

A varicella skin test and interferon-gamma enzyme-linked immunospot (ELISPOT) can screen for VZV susceptibility.

  1. Herpes Zoster

Herpes zoster (“shingles”) usually occurs among adults, but cases are reported among infants and children. Skin lesions resemble those of chickenpox. Pain is often severe and commonly precedes the appearance of rash. Lesions follow a dermatomal distribution, with thoracic and lumbar roots being the most common. In most cases, a single unilateral dermatome is involved, but occasionally, neighboring and distant areas are involved. Lesions on the tip of the nose, inner corner of the eye, and root and side of the nose (Hutchinson sign) indicate involvement of the trigeminal nerve (herpes zoster ophthalmicus). Facial palsy, lesions of the external ear with or without tympanic membrane involvement, vertigo and tinnitus, or deafness signify geniculate ganglion involvement (Ramsay Hunt syndrome or herpes zoster oticus). Shingles is a particularly common and serious complication among immunosuppressed patients. Contact with patients who have varicella does not appear to be a risk factor for zoster.

 Complications

  1. Varicella

Secondary bacterial skin superinfections, particularly with group A streptococcus and Staphylococcus aureus, are the most common complications. Cellulitis, erysipelas, and scarlet fever are described. Bullous impetigo and necrotizing fasciitis are less often seen. Other associations with varicella include epiglottitis, necrotizing pneumonia, osteomyelitis, septic arthritis, epidural abscess, meningitis, endocarditis, and purpura fulminans. Toxic shock syndrome can also develop.

Interstitial VZV pneumonia is more common in adults (especially smokers, HIV-infected patients, and pregnant women) and may result in acute respiratory distress syndrome (ARDS). After healing, numerous densely calcified lesions are seen throughout the lung fields on chest radiographs.

Historically, neurologic complications developed in about 1 in 2000 children. Currently, cerebellar ataxia occurs at a frequency of 1:4000 in the young. A limited course and complete recovery are the rule. Encephalitis is similarly infrequent, occurs mostly in adults, and is characterized by delirium, seizures, and focal neurologic signs. The rates for both mortality and long-term neurologic sequelae are about 10%. Ischemic strokes in the wake of acute VZV infection present at a mean of 4 months after rashes and may be due to an associated vasculitis. Multifocal encephalitis, ventriculitis, myeloradiculitis, arterial aneurysm formation, and arteritis are also described in immunosuppressed, especially HIV-infected, patients.

Clinical hepatitis is uncommon and mostly presents in the immunosuppressed patient but can be fulminant and fatal. Reye syndrome (fatty liver with encephalopathy) also complicates varicella (and other viral infections, especially influenza B virus), usually in childhood, and is associated with aspirin therapy (see Influenza, below).

When contracted during the first or second trimesters of pregnancy, varicella carries a very small risk of congenital malformations, including cicatricial lesions of an extremity, growth retardation, microphthalmia, cataracts, chorioretinitis, deafness, and cerebrocortical atrophy. If varicella develops around the time of delivery, the newborn is at risk for disseminated disease.

  1. Herpes Zoster

Postherpetic neuralgia occurs in 60–70% of patients who have herpes zoster and are older than 60 years. The pain can be prolonged and debilitating. Risk factors for postherpetic neuralgia include advanced age, female sex, the presence of a prodrome, and severity of rash or pain but not family history.

Other complications include the following: (1) bacterial skin superinfections; (2) herpes zoster ophthalmicus, which occurs with involvement of the trigeminal nerve and is a sight-threatening complication (especially when it involves the iris), and is a marker for stroke over the ensuing year (Hutchinson sign is a marker of ocular involvement in the HIV-positive population); (3) rarely, unilateral ophthalmoplegia; (4) involvement of the geniculate ganglion of cranial nerve VII as well as cranial nerves V, VIII, IX, and X; (5) aseptic meningitis; (6) peripheral motor neuropathy; (7) transverse myelitis; (8) encephalitis; (9) acute cerebellitis; (10) stroke; (11) vasculopathy; (12) acute retinal necrosis; (13) progressive outer retinal necrosis (largely among HIV infected persons); and (14) sacral meningoradiculitis (Elsberg syndrome). VZV is a major cause of Bell palsy in patients who are HSV seronegative.

Diagnosis of neurologic complications requires the detection of VZV DNA or anti-VZV IgG in cerebrospinal fluid or the detection of VZV DNA in tissue. Zoster sine herpete (pain without rash) can also be associated with most of the above complications.

 Treatment

  1. General Measures

In general, patients with varicella should be isolated until primary crusts have disappeared and kept at bed rest until afebrile. The skin is kept clean. Pruritus can be relieved with antihistamines, calamine lotion, and colloidal oatmeal baths. Fever can be treated with acetaminophen (not aspirin). Fingernails can be closely cropped to avoid skin excoriation and infection.

  1. Antiviral Therapy
  2. Varicella—Acyclovir, 20 mg/kg (up to 800 mg per dose) orally four times daily for 5 days, should be given within the first 24 hours after the onset of varicella rash and should be considered for patients older than 12 years, secondary household contacts (disease tends to be more severe disease in secondary cases), patients with chronic cutaneous and cardiopulmonary diseases, and children receiving long-term therapy with salicylates (to decrease the risk of Reye syndrome). Experience with valacyclovir and famciclovir in these settings is scant.

In immunocompromised patients, in pregnant women during the third trimester, and in patients with extracutaneous disease (encephalitis, pneumonitis), antiviral therapy with high-dose acyclovir (30 mg/kg/d in three divided doses intravenously for at least 7 days) should be started once the diagnosis is suspected. Corticosteroids may be useful in the presence of pneumonia. Prolonged prophylactic acyclovir is important to prevent VZV reactivation in profoundly immunosuppressed patients.

  1. Herpes zoster—For uncomplicated herpes zoster, valacyclovir or famciclovir is preferable to acyclovir due to dosing convenience and higher drug levels in the body. Therapy should start within the first 72 hours of the onset of the lesions and be continued for 7 days or until the lesions crust over.There is no role for corticosteroids. Antiviral therapy reduces the duration of a herpetic lesion and associated episode of acute pain but does not decrease the risk of postherpetic neuralgia.

Intravenous acyclovir is used for extradermatomal complications of zoster. Adjunctive therapy may be considered in retinal disease (foscarnet) and acute herpes zoster (sorivudine, a topical antiviral). In cases of prolonged or repeated acyclovir use, immunosuppressed patients may require a switch to foscarnet due to the development of acyclovir-resistant VZV infections. The Ramsay Hunt syndrome is more resistant to antiviral therapy.

  1. Treatment of Postherpetic Neuralgia

Once established, postherpetic neuralgia may respond to gabapentin or lidocaine patches. Tricyclic antidepressants, opioids, and capsaicin cream are also widely used and effective. The epidural injection of corticosteroids and local anesthetics appears to modestly reduce herpetic pain at 1 month but is not effective for prevention of long-term postherpetic neuralgia. There is reported success using transcutaneous electrical nerve stimulation.

 Prognosis

The total duration of varicella from onset of symptoms to disappearance of crusts rarely exceeds 2 weeks. Fatalities are rare except in immunosuppressed patients.

Herpes zoster resolves in 2–6 weeks. Antibodies persist longer and at higher levels than with primary varicella. Eye involvement with herpes zoster necessitates periodic future examinations.

 Prevention

Health care workers should be screened for varicella and vaccinated if seronegative. Patients with active varicella or herpes zoster are promptly separated from seronegative patients. For patients with varicella, airborne and contact isolation is recommended, whereas for those with zoster, contact precautions are sufficient. For immunosuppressed patients with zoster, precautions should be the same as if the patient had varicella. Exposed serosusceptible patients should be placed in isolation and exposed serosusceptible employees should stay away from work between days 10 and 21 after exposure. Health care workers with zoster should receive antiviral agents during the first 72 hours of disease and withdraw from work until lesions are crusted. Postexposure prophylaxis should be evaluated (see below).

  1. Varicella
  2. Vaccination—Universal childhood vaccination against varicella is effective. The varicella vaccine (Varilrix) is safe and over 98.1% effective when given after 13 months of age. A single antigen live attenuated vaccine (VARIVAX) or a quadrivalent measles, mumps, rubella, and varicella vaccine (ProQuad) are available. The first dose should be administered at 12–15 months of age and the second at 4–6 years. Aspirin should be avoided for at least 6 weeks because of the risk of Reye syndrome. This vaccine is safe, well tolerated, but the quadrivalent vaccine is associated with a small risk of febrile seizures 5–12 days after vaccination among infants aged 12–23 months. Rashes, when secondary to the varicella vaccine, appear 15–42 days after vaccination. Rare cases of zoster among children who received the varicella vaccine are attributable to delayed vaccination (after age 5), severe asthma, and developmental disorders. Such complications appear to occur less often among American children of African ancestry.

For serosusceptible individuals older than 13 years, two doses of varicella vaccine (single antigen) administered 4–8 weeks apart are recommended. For those who received a single dose in the past, a catch-up second dose is advised, especially in the epidemic setting (where it is effective when it can be given during the first 5 days postexposure). Household contacts of immunocompromised patients should adhere to these recommendations. Susceptible pregnant women need to receive the first dose of vaccine before discharge after delivery and the second dose 4–8 weeks later. The quadrivalent vaccine MMRV can be used for the second doses of MMR and varicella in patients aged 15 months to 12 years and for the first dose in patients aged 48 months or older. The vaccine, administered as two doses 3 months apart, should also be considered for HIV-infected adolescents and adults with CD4 T lymphocyte counts ≥ 200 cells/mcL. The vaccine may also be given to patients with impaired humoral immunity, to patients receiving corticosteroids, and to patients with juvenile rheumatoid arthritis who receive methotrexate. Patients receiving high doses of corticosteroids for over 2 weeks may be vaccinated a month after discontinuation of the therapy. Patients with leukemia, lymphoma, or other malignancies whose disease is in remission and who have not undergone chemotherapy for at least 3 months may be vaccinated. Kidney and liver transplant patients should be vaccinated if they are susceptible to varicella.

The incidence of varicella in the United States is significantly reduced with the varicella vaccine. Meanwhile, the varicella vaccine has not been found to affect the incidence of herpes zoster.

  1. Postexposure—Postexposure vaccination is recommended for unvaccinated persons without other evidence of immunity. Varicella-zoster immune globulin (VZIG) (in short supply with production stopped in 2004) or VariZIG (a lyophilized product available under expanded access since December 2007) should be considered for susceptible exposed patients (and given for up to 10 days in new FDA regulations) who cannot receive the vaccine, including immunosuppressed patients, neonates from mothers with varicella around the time of delivery, exposed premature infants born from serosusceptible mothers at > 28 weeks of gestation, neonates born at < 28 weeks of gestation regardless of maternal serostatus, and pregnant women. No controlled studies have evaluated the use of acyclovir in this setting. VZIG is given by intramuscular injection in a dosage of 12.5 units/kg up to a maximum of 625 units, with a repeat identical dose in 3 weeks if a high-risk patient remains exposed. VZIG has no place in therapy of established disease; however, VariZIG reduces the severity of varicella in high-risk children or adults (ie, those with impaired immunity, pregnant women, and infants exposed peripartum) if given within 4 days of exposure.

Further information may be obtained by calling the Centers for Disease Control and Prevention’s Immunization Information Hotline (800-232-2522).

  1. Herpes Zoster

A live attenuated VZV vaccine (ZOSTAVAX, 19,400 plaque forming units [pfu] of Oka/Merck strain) consists of varicella virus at a concentration at least 14 times that found in VARIVAX. This vaccine should be offered to persons 60 years and older because it reduces the incidence of herpes zoster and postherpetic neuralgia by 51% and 67%, respectively. Even if the person has had a prior episode of herpes zoster, the vaccine has efficacy and can be administered. A second dose of the zoster vaccine is not recommended because it does not boost VZV specific immunity beyond the levels achieved by the first dose. The attenuated VZV vaccine is safe but only moderately immunogenic among HIV-infected persons with a CD4 count of at least 200 cells/mcL.

Concurrent administration of the live attenuated VZV vaccine with 23-valent pneumococcal polysaccharide vaccine is safe. If a varicella vaccine is mistakenly administered to an adult instead of a zoster vaccine, the dose should be considered invalid and the patient should be administered a dose of zoster vaccine at the same visit. On the other hand, the zoster vaccine cannot be used in children in place of varicella vaccine; if the vaccine is accidentally given to a child, the event should be reported to the CDC.

Centers for Disease Control and Prevention (CDC). FDA approval of an extended period for administering VariZIG for postexposure prophylaxis of varicella. MMWR Morb Mortal Wkly Rep. 2012 Mar 30;61(12):212. [PMID: 22456121]

Cohen JI. Clinical practice: herpes zoster. N Engl J Med. 2013 Jul 18;369(3):255–63. [PMID: 23863052]

Hales CM et al. Examination of links between herpes zoster incidence and childhood varicella vaccination. Ann Intern Med. 2013 Dec 3;159(11):739–45. [PMID: 24297190]

Morrison VA et al; Shingles Prevention Study Group. Safety of zoster vaccine in elderly adults following documented herpes zoster. J Infect Dis. 2013 Aug 15;208(4):559–63. [PMID: 23633406]

Tseng HF et al. Herpes zoster vaccine in older adults and the risk of subsequent herpes zoster disease. JAMA. 2011 Jan 12;305(2):160–6. [PMID: 21224457]

  1. Epstein–Barr Virus & Infectious Mononucleosis

 ESSENTIALS OF DIAGNOSIS

 Malaise, fever, and sore throat, sometimes with exudates.

 Palatal petechiae, lymphadenopathy, splenomegaly, and, occasionally, a maculopapular rash.

 Positive heterophil agglutination test (Monospot).

 Atypical large lymphocytes in blood smear; lymphocytosis.

 Complications: hepatitis, myocarditis, neuropathy, encephalitis, airway obstruction secondary to lymph node enlargement, hemolytic anemia, thrombocytopenia.

 General Considerations

Epstein-Barr virus (EBV, or human herpes virus-4 [HHV-4]) is one of the most ubiquitous human viruses, infecting > 95% of the adult population worldwide and persisting for the lifetime of the host. Infectious mononucleosis is a common manifestation of EBV and may occur at any age. In the United States, EBV infection usually develops in persons between the ages of 10 and 35 years, sporadically or epidemically. In the developing world, infectious mononucleosis occurs at younger ages and tends to be less symptomatic. Rare cases in the elderly occur usually without the full symptomatology. EBV is largely transmitted by saliva but can also be recovered from genital secretions. Saliva may remain infectious during convalescence, for 6 months or longer after symptom onset. The incubation period lasts several weeks (30–50 days).

 Clinical Findings

  1. Symptoms and Signs

The protean manifestations of infectious mononucleosis reflect the dissemination of the virus in the oral cavity and through peripheral blood lymphocytes and cell-free plasma. Fever, sore throat, fatigue, malaise, anorexia, and myalgia typically occur in the early phase of the illness. Physical findings include lymphadenopathy (discrete, nonsuppurative, slightly painful, especially along the posterior cervical chain), transient bilateral upper lid edema (Hoagland sign), and splenomegaly (in up to 50% of patients). A maculopapular or occasionally petechial rash occurs in < 15% of patients unless ampicillin is given (in which case rash is seen in > 90%). Conjunctival hemorrhage (Figure 32–4), exudative pharyngitis, uvular edema, tonsillitis, or gingivitis may occur and soft palatal petechiae may be noted.

 Figure 32–4. Conjunctival hemorrhage of the eye due to infectious mononucleosis. (From Dr. Thomas F. Sellers, Emory University, Public Health Image Library, CDC.)

Other manifestations include hepatitis, interstitial pneumonitis, cholestasis, gastritis, acute interstitial nephritis, nervous system involvement in 1–5% (mononeuropathies and occasionally aseptic meningitis, encephalitis, cerebellitis, peripheral and optic neuritis, transverse myelitis, or Guillain-Barré syndrome), kidney disease (mostly interstitial nephritis), pneumonia, pleural involvement, and myocarditis. Vaginal ulcers are rare but may be present. Airway obstruction from lymph node enlargement, pericarditis, life-threatening thrombocytopenia, severe CNS complications, and massive splenomegaly are all considered indications for hospitalization or close observation.

  1. Laboratory Findings

An initial phase of granulocytopenia is followed within 1 week by lymphocytic leukocytosis (> 50% of all leukocytes) with atypical lymphocytes (larger than normal mature lymphocytes, staining more darkly, and showing vacuolated, foamy cytoplasm and dark nuclear chromatin) comprising > 10% of the leukocyte count. Hemolytic anemia, with anti-i antibodies, occurs occasionally as does thrombocytopenia (at times marked).

Diagnosis is made on the basis of characteristic manifestations and serologic evidence of infection (the heterophil sheep cell agglutination [HA] antibody tests or the correlated mononucleosis spot test [Monospot]). These tests usually become positive within 4 weeks after onset of illness and are specific but often not sensitive in early illness. Heterophil antibodies may be absent in young children and in as many as 20% adults. During acute illness, there is a rise and fall in immunoglobulin M (IgM) antibody to EB virus capsid antigen (VCA) and a rise in IgG antibody to VCA, which persists for life. Antibodies (IgG) to EBV nuclear antigen (EBNA) appear after 4 weeks of onset and also persist. Absence of IgG and IgM VCA or the presence of IgG EBNA should make one reconsider the diagnosis of acute EBV infection.

PCR for EBV DNA is useful in the evaluation of malignancies associated with EBV. For instance, detection of EBV DNA in cerebrospinal fluid shows a sensitivity of 90% and specificity of nearly 100% for the diagnosis of primary CNS lymphoma in patients with AIDS, and monitoring of quantitative EBV DNA levels (a “viral load”) in blood may be useful in early detection of posttransplant lymphoproliferative disorder in high-risk patients. PCR analysis may also be helpful in monitoring disease and treatment response in primary CNS lymphoma and posttransplant lymphoproliferative disorder patients. Antibodies against ZEBRA (a replication protein) are produced in early infection and assays for these antibodies are commercially available.

 Differential Diagnosis

CMV infection, toxoplasmosis, acute HIV infection, secondary syphilis, HHV-6, rubella, and drug hypersensitivity reactions may be indistinguishable from infectious mononucleosis due to EBV, but exudative pharyngitis is usually absent and the heterophil antibody tests are negative. With acute HIV infection, rash and mucocutaneous ulceration are common but atypical lymphocytosis is much less common. Heterophil-negative infectious mononucleosis with nonsignificant lymphocytosis (especially if rash or mucocutaneous ulcers are present) should prompt investigation for acute HIV infection. Heterophil-negative infectious mononucleosis with atypical lymphocytosis can be caused by CMV, toxoplasmosis and, on occasion, EBV itself. Mycoplasma infection may also present as pharyngitis, though lower respiratory symptoms usually predominate. A hypersensitivity syndrome induced by carbamazepine or phenytoin may mimic infectious mononucleosis.

The differential diagnosis of acute exudative pharyngitis includes gonococcal and streptococcal infections, and infections with adenovirus and herpes simplex. Head and neck soft tissue infections (pharyngeal and tonsillar abscesses) may occasionally be mistaken as the lymphadenopathy of mononucleosis.

 Complications

Secondary bacterial pharyngitis can occur and is often streptococcal. Splenic rupture (0.5–1%) is a rare but dramatic complication, and a history of preceding trauma can be elicited in 50% of the cases. Acalculous cholecystitis, fulminant hepatitis with massive necrosis, pericarditis and myocarditis are also infrequent complications. Neurologic involvement—including transverse myelitis, encephalitis, and Guillain-Barré syndrome—is infrequent.

 Treatment

  1. General Measures

Over 95% of patients with acute EBV-associated infectious mononucleosis recover without specific antiviral therapy. Treatment is symptomatic with acetaminophen or other nonsteroidal anti-inflammatory drugs and warm saline throat irrigations or gargles three or four times daily. Acyclovir decreases viral shedding but shows no clinical benefit. Corticosteroid therapy, although widespread, is not recommended in uncomplicated cases; its use is reserved for impending airway obstruction from enlarged lymph nodes, hemolytic anemia, and severe thrombocytopenia. The value of corticosteroid therapy in impending splenic rupture, pericarditis, myocarditis, and nervous system involvement is less well defined. If a throat culture grows beta-hemolytic streptococci, a 10-day course of penicillin or erythromycin is indicated. Ampicillin and amoxicillin are avoided because of the frequent association with rash.

  1. Treatment of Complications

Hepatitis, myocarditis, and encephalitis are treated symptomatically. Rupture of the spleen requires splenectomy and is most often caused by deep palpation of the spleen or vigorous activity. Patients should avoid contact or collision sports for at least 4 weeks to decrease the risk of splenic rupture (even if splenomegaly is not detected by physical examination, which can be insensitive).

 Prognosis & Prevention

In uncomplicated cases, fever disappears in 10 days and lymphadenopathy and splenomegaly in 4 weeks. The debility sometimes lingers for 2–3 months.

Death is uncommon and is usually due to splenic rupture, hypersplenic phenomena (severe hemolytic anemia, thrombocytopenic purpura), or encephalitis.

Several vaccines including viral-like proteins are under development but none is marketed. Handwashing after contact and avoidance of close personal contact with active cases is prudent.

  1. Other Epstein–Barr Virus Syndromes

EBV viral antigens are found in > 90% of patients with endemic (African) Burkitt lymphoma and nasopharyngeal carcinoma (among whom quantified EBV DNA can be used to follow disease). Risk factors for Burkitt lymphoma include a history of malaria (which may decrease resistance to EBV infection) while risk factors for nasopharyngeal carcinoma include long-term heavy cigarette smoking and seropositive EBV serologies (VCA and deoxyribonuclease [DNase]). VCA-IgA in peripheral blood is a sensitive and specific predictor for nasopharyngeal carcinoma in endemic areas.

Chronic EBV infection is associated with aberrant cellular immunity (a low frequency of EBV-specific CD8 cells), an X-linked lymphoproliferative syndrome (Duncan disease), lymphomatoid granulomatosis, and a fatal T cell lymphoproliferative disorder in children.

EBV is an important cause of hemophagocytic lymphohistiocytosis among immunodeficient patients, B-cell lymphomas (such as primary CNS lymphoma in HIV-infected individuals), and posttransplant lymphoproliferative disorders. Posttransplant lymphoproliferative states are commonly associated with EBV, especially in children. EBV-naïve patients who receive a donor organ from an EBV-infected donor are at the highest-risk for the development of posttransplant lymphoproliferative disorder. Decreasing the iatrogenic immunosuppression, given to reduce graft rejection, is the initial step in managing such patients, while rituximab (CD20 monoclonal antibody) is effective in treating more than two-thirds of cases. The efficacy of rituximab therapy can be often assessed by monitoring levels of EBV DNA load in the blood and, if indicated, CNS. Infusion of EBV-specific cytotoxic T cell lymphocytes (adoptive cell therapy) is also used but with a less established role.

Age is a major determinant of the type of tumor associated with EBV. T and NK cell lymphoma caused by chronic active EBV infections are more frequent in childhood while peripheral T cell lymphomas and diffuse large B cell lymphomas are more common in the elderly due to waning immunity. EBV is also associated with leiomyomas in children with AIDS and with nasal T cell lymphomas.

 When to Admit

  • Acute meningitis, encephalitis, or acute Guillain-Barré syndrome.
  • Severe thrombocytopenia; significant hemolysis.
  • Potential splenic rupture.
  • Airway obstruction from severe adenitis.
  • Pericarditis.
  • Abdominal findings mimicking an acute abdomen.

Kelly MJ et al. Epstein-Barr virus coinfection in cerebrospinal fluid is associated with increased mortality in Malawian adults with bacterial meningitis. J Infect Dis. 2012 Jan 1;205(1):106–10. [PMID: 22075766]

Pembrey L et al. Seroprevalence of cytomegalovirus, Epstein Barr virus and varicella zoster virus among pregnant women in Bradford: a cohort study. PLoS One. 2013 Nov 27;8(11):e81881. [PMID: 24312372]

Sanz J et al. EBV-associated post-transplant lymphoproliferative disorder after umbilical cord blood transplantation in adults with hematological diseases. Bone Marrow Transplant. 2014 Mar;49(3):397–402. [PMID: 24292521]

Styczynski J et al. Response to rituximab-based therapy and risk factor analysis in Epstein Barr virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Clin Infect Dis. 2013 Sep;57(6):794–802. [PMID: 23771985]

  1. Cytomegalovirus Disease

 ESSENTIALS OF DIAGNOSIS

 Mononucleosis-like syndrome.

 Frequent pathogen seen in transplant populations.

 Diverse clinical syndromes in HIV (retinitis, esophagitis, pneumonia, encephalitis).

 Major pathogen to consider in neonates in the differential of maternally transmitted agents.

 General Considerations

Most cytomegalovirus (CMV) infections are asymptomatic. After primary infection, the virus remains latent in most body cells. Seroprevalence in adults of Western developed countries is about 60–80% but is higher in developing countries. CMV seroprevalence increases with age and among people who are employed in child day care centers, and fall into low socioeconomic status; in addition, seroprevalence increases with the number of sexual partners and a history of prior sexually transmitted infections. The virus can be isolated from a variety of tissues under nonpathogenic conditions. Transmission occurs through sexual contact, breastfeeding, blood products, or transplantation; it may also occur person-to-person (eg, day care centers) or be congenital. Serious disease occurs primarily in immunocompromised persons.

There are three recognizable clinical syndromes: (1) perinatal disease and CMV inclusion disease; (2) diseases in immunocompetent persons; and (3) diseases in immunocompromised persons.Congenital CMV infection is the most common congenital infection in developed countries (between 0.2% and 2% of all live births, with higher rates in underdeveloped areas and among lower socioeconomic groups). Transmission is much higher from mothers with primary disease than those with reactivation (40% vs 0.2–1.8%). About 10% of infected newborns will be symptomatic with CMV inclusion disease.

In immunocompetent persons, acute CMV infection is the most common cause of the mononucleosis-like syndrome with negative heterophil antibodies. CMV appears to play a role in critically ill immunocompetent adults wherein it is reactivated and associated with prolonged hospitalization and death. Other syndromes associated with CMV and whose role in pathogenesis requires further elucidation include inflammatory bowel disease, atherosclerosis, cognitive decline, and breast cancer.

In immunocompromised persons, tissue and bone marrow transplant patients are mainly at risk for a year after allograft transplantation (but especially during the first 100 days afterward) and in particular when graft-versus-host disease or CMV seropositivity, or both, are present in the donor and recipient. Depending on the serostatus of the donor and recipient, disease may present as primary infection or reactivation. The risk of CMV disease is proportionate to the intensity of immunosuppression. CMV itself is immunosuppressive. CMV may contribute to transplanted organ dysfunction, which often mimics organ rejection. CMV disease in HIV-infected patients (retinitis, serious gastrointestinal disease) occurs most prominently when the CD4 count is < 50 cells/mcL. Highly active antiretroviral therapy (HAART) reduces the frequency of retinitis and may reverse active disease. CMV retinitis may also develop after solid organ or bone marrow transplantation. CMV retinitis associated with intravitreal delivery of corticosteroids (injections or implants) or systemic anti-TNF antibodies is also described. Occasionally, CMV retinitis presents in immunocompetent persons. Serious gastrointestinal CMV disease also occurs after organ transplantation, cancer chemotherapy, or corticosteroid therapy. CMV may exist alongside other pathogens, such as Cryptosporidium, in up to 15% of patients with AIDS cholangiopathy. CMV pneumonitis occurs in transplant recipients (mainly bone marrow and lung) with a mortality rate up to 60–80%, and less often in AIDS patients. CMV pneumonitis in hematologic malignancies (eg, lymphoma) is increasingly reported. Neurologic CMV in patients with advanced AIDS is usually associated with disseminated CMV infection.

 Clinical Findings

  1. Symptoms and Signs
  2. Perinatal disease and CMV inclusion disease—CMV inclusion disease in infected newborns is characterized by jaundice, hepatosplenomegaly, thrombocytopenia, purpura, microcephaly, periventricular CNS calcifications, mental retardation, and motor disability. Hearing loss develops in > 50% of infants who are symptomatic at birth. Most infected neonates are asymptomatic, but neurologic deficits may ensue later in life, including hearing loss in 15% and mental retardation in 10–20%. Perinatal infection acquired through breastfeeding or blood products typically shows a benign clinical course.
  3. Disease in immunocompetent persons—Acute acquired CMV infection is characterized by fever, malaise, myalgias, arthralgias, and splenomegaly. Exudative pharyngitis or cervical lymphadenopathies are uncommon, but cutaneous rashes (including the typical maculopapular rash after exposure to ampicillin) are common. The mean duration of symptoms is 7–8 weeks. Complications include mucosal gastrointestinal damage, encephalitis, severe hepatitis, thrombocytopenia (on occasion, refractory), the Guillain-Barré syndrome, pericarditis, and myocarditis. The risk of Guillain-Barre syndrome developing after primary CMV infection is estimated to be 0.6–2.2 cases per 1000 primary infection, similar to that seen withCampylobacter jejuniinfection. The mononucleosis-like syndrome due to CMV can also occur postsplenectomy, often years later and associated with a protracted fever, marked lymphocytosis, and impaired anti-CMV IgM response.
  4. Disease in immunocompromised persons—Distinguishing between CMV infection (with evidence of CMV replication) and CMV disease (evidence for systemic symptoms or organ invasion) is important. In addition to patients infected with HIV, those who have undergone transplantation (solid organ or hematopoietic stem cell) show a wide spectrum of disease including gastrointestinal (eg, acute cholecystitis), renal, and CNS disease, as outlined above. CMV viral loads correlate with prognosis after transplantation.
  5. CMV RETINITISA funduscopic examination reveals neovascular, proliferative lesions (“pizza-pie” retinopathy). Immune restoration with HAART is associated with CMV vitritis and cystoid macular edema. Infants with CMV retinitis tend to have more macular than peripheral disease.
  6. GASTROINTESTINAL AND HEPATOBILIARY CMVEsophagitis presents with odynophagia. Gastritis can occasionally cause bleeding, and small bowel disease may mimic inflammatory bowel disease or may present as ulceration or perforation. Colonic CMV disease causes diarrhea, hematochezia, abdominal pain, fever, and weight loss and may mimic inflammatory bowel disease. CMV hepatitis commonly complicates liver transplantation and appears to be increased in those with hepatitis B or hepatitis C viral infection.
  7. RESPIRATORY CMVCMV pneumonitis is characterized by cough, dyspnea, and relatively little sputum production.
  8. NEUROLOGIC CMVNeurologic syndromes associated with CMV include polyradiculopathy, transverse myelitis, ventriculoencephalitis (suspected with ependymitis), and focal encephalitis. These manifestations are more prominent in patients with advanced AIDS in whom the encephalitis has a subacute onset.
  9. Laboratory Findings
  10. Mothers and newborns—Pregnant women should be tested for IgM CMV antibodies every 3 months if an assay during the first trimester is seropositive. Congenital CMV disease is confirmed by presence of the virus in amniotic fluid or an IgM assay from fetal blood. Amniocentesis is less reliable before 21 weeks of gestation (due to inadequate fetal urinary development and release into the amniotic fluid), but amniocentesis is attendant with greater risk when performed after 21 weeks of gestation. PCR assays of dried blood samples from newborns and micro-enzyme-linked immunosorbent assay (ELISA) on urine, saliva, or blood specimens obtained during the first 3 weeks of life are used to diagnose congenital CMV infection.
  11. Immunocompetent persons—The acute mononucleosis-like syndrome is characterized by initial leukopenia; within 1 week, it is followed by absolute lymphocytosis with atypical lymphocytes. Abnormal liver function tests are common in the first 2 weeks of the disease (often 2 weeks after the fever). Detection of CMV specific IgM or a fourfold increase of specific IgG levels support the diagnosis of acute infection.
  12. Immunocompromised persons—CMV retinitis is diagnosed on the basis of the characteristic ophthalmoscopic findings. In HIV-infected patients, negative CMV serologies lower the possibility of the diagnosis but do not eliminate it. Cultures alone are of little use in diagnosing AIDS-related CMV infections, since viral shedding of CMV is common. PCR analysis should be used to diagnose CNS infection since cultures are not specific for disease.

Detection of CMV by quantitative DNA PCR is used in posttransplant patients for guidance on both treatment and prevention and should be interpreted in the context of clinical and pathologic findings. Conversion of CMV viral loads to international units has standardized detection assays and replaced CMV antigenemia tests in many settings. The PCR is sensitive in predicting clinical disease.

Rapid shell-vial cultures detect early CMV antigens with fluorescent antibodies in 24–48 hours. Shell-vial cultures are more useful on bronchoalveolar lavage fluid than in routine blood monitoring. CMV colitis can occur in the absence of a detectable viremia.

A variety of false-positive immunologic assays occur in the setting of acute CMV infections, including positive rheumatoid factor, direct Coombs test, cryoglobulins, and speckled antinuclear antibody.

  1. Imaging

The chest radiographic findings of CMV pneumonitis are consistent with interstitial pneumonia.

  1. Biopsy

Tissue confirmation is especially useful in diagnosing CMV pneumonitis and CMV gastrointestinal disease; the diagnosis of colonic CMV disease is made by mucosal biopsy showing characteristic CMV histopathologic findings of intranuclear (“owl’s eye”) and intracytoplasmic inclusions. In situations where histopathologic or immunohistochemical findings are not seen but CMV colitis is suspected, CMV DNA PCR can be used to identify additional cases.

 Treatment

Sight-threatening CMV retinitis (lesions close to the fovea or optic nerve head) is treated with ganciclovir induction therapy (5 mg/kg intravenously every 12 hours for 14–21 days) followed by maintenance therapy at lower doses (5 mg/kg intravenously daily). Sustained-release ganciclovir intraocular implants (always accompanied by systemic valganciclovir) are another option. In less severe retinal disease, valganciclovir (900 mg orally twice daily for 14–21 days followed by 900 mg/d maintenance) is preferred. Due to potential toxicities, foscarnet, cidofovir, and fomivirsen are usually reserved for CMV infections that are resistant to ganciclovir. Combinations of ganciclovir and foscarnet are shown to be safe and effective in treating clinically resistant CMV retinitis. The role of HAART in reducing the need for CMV antiviral agents is essential. Other forms of CMV disease in AIDS are managed initially with intravenous ganciclovir and subsequently with oral valganciclovir; alternative agents (listed above) are used when resistance evolves.

The treatment of other systemic CMV infection (colitis, encephalitis, pneumonia) involves the use of the main antiviral agents used in CMV retinitis. The length of therapy depends on the state of immunosuppression, and secondary prophylaxis is typically maintained until immune restoration with two CD4 T-cell counts > 100 cells/mcL is present for at least 6 months. Prolonged prophylaxis may be necessary in other immunosuppressed patients, such as those receiving TNF inhibitors.

For non-severe, posttransplant CMV disease, oral valganciclovir (900 mg twice daily) or intravenous ganciclovir (5 mg/kg every 12 hours) are the recommended first-line agents. Valganciclovir has been shown to be noninferior to intravenous ganciclovir-based therapy in solid organ transplant patients and is associated with less clinical resistance than ganciclovir. For severe CMV disease, intravenous ganciclovir remains the treatment of choice. Dosage adjustments of all medications are needed for kidney dysfunction. Reduction of immunosuppression should be attempted when possible (especially for muromonab, azathioprine, or mycophenolate mofetil). Treatment should be continued for at least 2 weeks until viral eradication is achieved. Two consecutive negative samples of CMV quantitative analysis testing or antigenemia based assay ensure viral clearance. Other agents that may be useful in resistant CMV infections include leflunomide, sirolimus-based therapy, and artesunate. Adoptive immunotherapy is also under study.

In pregnant women with primary CMV infection, passive immunization with hyperimmune globulin appears preliminarily to be effective in both treatment and prevention of fetal infection, but controlled clinical trials are lacking. While CMV immunoglobulin is also used in the treatment of CMV pneumonia in stem cell transplant recipients, its efficacy is not completely established.

 Prevention

Recombinant human CMV vaccine studies are under development. A CMV glycoprotein B with MF59 adjuvant vaccine showed efficacy of 50% in preventing congenital disease, and CMV glycoprotein B with pp95 DNA adjuvant vaccine also showed signs of clinical benefit in hematopoietic stem cell transplant recipients. These studies inform the development of next generation vaccine candidates.

HAART is effective in preventing CMV infections in HIV-infected patients. Use of leukocyte-depleted blood products effectively reduces the incidence of CMV disease in patients who have undergone transplantation. Prophylactic and preemptive strategies (eg, antiviral agents only when antigen detection or PCR assays show evidence of active CMV replication) are effective in preventing disease in the early transplantation period but are associated with a risk of a late-onset form of the disease after the prophylaxis is discontinued. The appropriate management of transplant patients is based on the serostatus of the donor and the recipient. All effective anti-CMV agents can serve as prophylactic agents for CMV-seropositive transplants or for CMV-seronegative recipients of CMV-positive organ transplants. The dose for valganciclovir prophylaxis is 450 mg orally twice daily. CMV immune globulin may also be useful in reducing the incidence of bronchiolitis obliterans in the bone marrow transplant population and is used in some centers as part of the prophylaxis in kidney, liver, and lung transplantation patients. CMV immune globulin as prophylaxis is not recommended in hematopoietic stem cell transplant recipients.

Withdrawal of infected children from day care centers, reduction of patient contact by health care workers, screening for women of childbearing age, or restrictions to breastfeeding are not recommended because the virus is ubiquitous, although women who are CMV negative should reconsider taking employment in child day care centers.

 When to Refer

  • Neonatal infections consistent with CMV inclusion disease.
  • AIDS patients with retinitis, esophagitis, colitis, hepatobiliary disease, or encephalitis.
  • Organ and hematopoietic stem cell transplants with suspected reactivation CMV.

 When to Admit

  • Risk of colonic perforation.
  • Evaluation of unexplained, advancing encephalopathy.
  • Biopsy of tissues in the differential diagnosis of transplant rejection vs infection.
  • Initiation of treatment with intravenous anti-CMV agents.

Johnson J et al. Prevention of maternal and congenital cytomegalovirus infection. Clin Obstet Gynecol. 2012 Jun;55(2):521–30. [PMID: 22510635]

Lilja AE et al. The next generation recombinant human cytomegalovirus vaccine candidates-beyond gB. Vaccine. 2012 Nov 19;30(49):6980–90. [PMID: 23041121]

Mannonen L et al. Comparison of two quantitative real-time CMV-PCR tests calibrated against the 1st WHO international standard for viral load monitoring of renal transplant patients. J Med Virol. 2014 Apr;86(4):576–84. [PMID: 24026892]

Mills AM et al. A comparison of CMV detection in gastrointestinal mucosal biopsies using immunohistochemistry and PCR performed on formalin-fixed, paraffin-embedded tissue. Am J Surg Pathol. 2013 Jul;37(7):995–1000. [PMID: 23648457]

  1. Human Herpesviruses 6, 7, & 8

HHV-6 is a B cell lymphotropic virus that is the principal cause of exanthema subitum (roseola infantum, sixth disease). Primary HHV-6 infection occurs most commonly in children under 2 years of age and is a major cause of infantile febrile seizures. HHV-6 is also associated with encephalitis (symptoms may include insomnia, seizures, and hallucinations) and with acute liver failure. Primary infection in immunocompetent adults is rare and can produce a mononucleosis-like illness. Reactivation of HHV-6 in immunocompetent adults is rare and can present as encephalitis. Imaging studies in HHV-6 encephalitis typically show lesions in the hippocampus, amygdala, and limbic structures.

Infection during pregnancy and congenital transmission is recognized. Most cases of reactivation, however, occur in immunocompromised persons. Reactivation is associated with graft rejection, graft-versus-host disease, and bone marrow suppression in transplant patients and with encephalitis and pneumonitis in AIDS patients and in recipients of hematopoietic cell transplants (but the absence of an HHV-6 association with survival in such patients suggests that for now surveillance for the virus is not needed). HHV-6 is on occasion also associated with drug-induced hypersensitivity syndromes. HHV-6 may cause fulminant hepatic failure and acute decompensation of chronic liver disease in children. Purpura fulminans and corneal inflammation are reported with HHV-6 infection. Two variants (A and B) of HHV-6 have been identified. HHV-6B is the predominant strain found in both normal and immunocompromised persons. Ganciclovir, cidofovir, and foscarnet (but not acyclovir) appear to be clinically active against HHV-6.

HHV-7 is a T cell lymphotropic virus that is associated with roseola (serologically), seizures and, rarely, encephalitis. Pregnant women are often infected. Infection with HHV-7 is synergistic with CMV in kidney transplant recipients.

HHV-8 is associated with Kaposi sarcoma, multicentric Castleman disease, and primary effusion (body cavity) lymphoma. HHV-8 infection is endemic in Africa; transmission seems to be primarily horizontal in childhood from intrafamilial contacts and continues through adulthood possibly by nonsexual routes. See Chapter 31 for pathogenesis and management.

Ablashi D et al. Classification of HHV-6A and HHV-6B as distinct viruses. Arch Virol. 2013 Nov 6. [Epub ahead of print] [PMID: 24193951]

Betts BC et al. Human herpesvirus 6 infection after hematopoietic cell transplantation: is routine surveillance necessary? Biol Blood Marrow Transplant. 2011 Oct;17(10):1562–8. [PMID: 21549850]

Husain Z et al. DRESS syndrome: part I. Clinical perspectives. J Am Acad Dermatol. 2013 May;68(5):693.e1–14. [PMID: 23602182]

Mbondji-Wonje C et al. Seroprevalence of human herpesvirus-8 in HIV-1 infected and uninfected individuals in Cameroon. Viruses. 2013 Sep 19;5(9):2253–9. [PMID: 24056671]

Ogata M et al. Human herpesvirus 6 (HHV-6) reactivation and HHV-6 encephalitis after allogeneic hematopoietic cell transplantation: a multicenter, prospective study. Clin Infect Dis. 2013 Sep;57(5):671–81. [PMID: 23723198]

MAJOR VACCINE-PREVENTABLE VIRAL INFECTIONS1

  1. Measles

 ESSENTIALS OF DIAGNOSIS

 Exposure 10–14 days before onset in an unvaccinated patient.

 Prodrome of fever, coryza, cough, conjunctivitis, malaise, irritability, photophobia, Koplik spots.

 Rash: brick red, irregular, maculopapular; onset 3–4 days after onset of prodrome; begins on the face and proceeds “downward and outward,” affecting the palms and soles last.

 Leukopenia.

 General Considerations

Measles is a reportable acute systemic paramyxoviral infection transmitted by inhalation of infective droplets. It is a major worldwide cause of pediatric morbidity and mortality, although vaccination programs successfully reduced this number. Between 2001 and 2012, a median of 60 measles cases were reported to the CDC yearly among a yearly median of 4 outbreaks. In 2013 (through August 31) a total of 159 cases were reported to the CDC with the largest case numbers from New York, Texas, North Carolina, and California and with most of these attributed to 3 outbreaks among members of groups with philosophical or religious reasons for not vaccinating. All but 2 of the cases in 2013 were import-associated, although actual cases among immigrants was 42 (with 21 of these from the WHO European Region). A major outbreak in France between 2005 and 2012 was associated with over 22,000 cases and 10 deaths, with over 80% of cases occurring among the unvaccinated and with the highest incidence among infants younger than 1 year.

Illness confers permanent immunity. It is highly contagious and communicability is greatest during the preeruptive and catarrhal stages but continues as long as the rash remains. Despite high community vaccination coverage, rising rates of intentional undervaccination lead to sporadic outbreaks among clusters of intentionally undervaccinated children and can undermine measles elimination programs. Therefore, laboratory testing and confirmation of suspected measles infection is especially important in countries that report the elimination of measles. Sporadic outbreaks of the disease in adults, adolescents, and unvaccinated preschool children in dense urban areas, and sporting event participants emphasize the need for specific recommendations concerning prevention (see below).

In the United States, measles was declared eliminated in 2000 and except for sporadic outbreaks this success is maintained due to a high MMR vaccination coverage. Recent increases in outbreaks and importations are a reminder of measles endemicity in the rest of the world and how undervaccinated individuals pose a risk to themselves and their communities.

 Clinical Findings

  1. Symptoms and Signs

Fever is often as high as 40–40.6°C. It persists through the prodrome and early rash (about 5–7 days) (Table 32–2). Malaise may be marked. Coryza (nasal obstruction, sneezing, and sore throat) resembles that seen with upper respiratory infections. Cough is persistent and nonproductive. Conjunctivitis manifests as redness, swelling, photophobia, and discharge. These symptoms intensify over 2–4 days before onset of the rash and peak on the first day of the rash.

Koplik spots (small, irregular, and red with whitish center on the mucous membranes) are pathognomonic of measles. They appear about 2 days before the rash and last 1–4 days as tiny “table salt crystals” in the buccal mucosa opposite the molars and vaginal membranes. The rash usually appears on the face and behind the ears 4 days after the onset of symptoms. The initial lesions are pinhead-sized papules that coalesce to form a brick red, irregular, blotchy maculopapular rash. In severe cases, the rash coalesces to form a nearly uniform erythema in some areas. The rash next appears on the trunk, followed by the extremities, including the palms (25–50% of those infected) and soles. The rash lasts for 3–7 days and fades in the same manner it appeared. Hyperpigmentation remains in fair-skinned individuals and severe cases. Slight desquamation may follow.

Other findings in measles include pharyngeal erythema, tonsillar yellowish exudate, coating of the tongue in the center with a red tip and margins, moderate generalized lymphadenopathy and, at times, splenomegaly.

Atypical measles is a syndrome occurring in adults who received inactivated measles vaccine (1963–1968) or who received live measles vaccine before age 12 months and as a result developed hypersensitivity rather than protective immunity. Infection later in life with wild measles virus can lead to a potentially fatal illness with high fever; unusual rashes (papular, hemorrhagic), most prominent on the extremities, without Koplik spots; headache; arthralgias; hepatitis; a high rate of pneumonitis, and sometimes pleural effusions. Atypical measles cases show unusually high hemagglutinin-inhibition titers. Measles may be distinctive in HIV-infected individuals, with higher rates of pneumonitis, higher mortality, prolonged viral shedding, and higher vaccine failure rates. Measles during pregnancy is not known to cause congenital abnormalities of the fetus. It is, however, associated with spontaneous abortion and premature delivery and can cause severe disease in the mother. Although measles does not always develop in the offspring of mothers with the disease, it can be severe when it does. It is recommended that infants born to such mothers be passively immunized with immunoglobulin at birth.

  1. Laboratory Findings

Leukopenia is usually present unless secondary bacterial complications exist. A lymphocyte count under 2000/mcL is a poor prognostic sign. Thrombocytopenia is common. Proteinuria is often observed. Although technically difficult, virus can be cultured from nasopharyngeal washings and from blood. Detection of IgM measles antibodies with ELISA or a fourfold rise in serum hemagglutination inhibition antibody supports the diagnosis. Fluorescent antibody staining of respiratory or urinary epithelial cells can also confirm the diagnosis.

IgM assays can be falsely negative the first few days of infection and falsely positive in the presence of rheumatoid factor or with acute rubella, erythrovirus (parvovirus) B19, or HHV-6 infection. White reverse transcriptase-PCR techniques, typically available in research settings, can help establish a diagnosis. The virologic clearance of measles can take months, leading to false-positive results.

 Differential Diagnosis

Measles is usually diagnosed clinically but may be mistaken for other exanthematous infections (see Table 32–2). Frequent difficulty in establishing a diagnosis suggests that measles may be more prevalent than is recognized.

 Complications

  1. Central Nervous System

Postinfectious encephalomyelitis occurs in about 0.05–0.1% of cases. Higher rates of encephalitis occur in adolescents and adults than in school-aged children. Its onset is usually 3–7 days after the rash. Vomiting, convulsions, coma, and diverse, severe neurologic symptoms and signs may develop. Treatment is symptomatic and supportive. Virus is usually not found in the CNS, though demyelination is prominent. There is an appreciable mortality (10–20%) and morbidity (33% of survivors are left with neurologic deficit).

A similar form, “inclusion body encephalitis,” occurs months after exposure. This complication is reported to occur after measles vaccination in patients with inadequate cellular immunity but is associated with isolation of the measles virus.

Subacute sclerosing panencephalitis (SSPE) is a very late CNS complication (5–15 years after infection; the measles virus acts as a “slow virus” to produce degenerative CNS disease years after the initial infection. SSPE is rare (1:100,000 cases of measles) and occurs more often when measles develops early in life among males who live in rural environments. SSPE very rarely develops in adults.

Measles virus can opportunistically invade the CNS. An acute progressive encephalitis (subacute measles encephalitis), characterized by seizures, neurologic deficits, and stupor progressing to death, can occur among immunosuppressed patients. Treatment is supportive, withholding immunosuppressive chemotherapy when feasible. Interferon and ribavirin are variably successful.

  1. Respiratory Tract Disease

Early in the course of the disease, bronchopneumonia or bronchiolitis due to the measles virus may occur in up to 5% of patients and result in serious respiratory difficulties. Bronchiectasis may occur in up to a quarter of nonvaccinated children. Pneumonia occurring with or without an evanescent rash is seen in atypical measles.

  1. Secondary Bacterial Infections

Immediately following measles, secondary bacterial infection, particularly cervical adenitis, otitis media (the most common complication), and pneumonia, occurs in about 15% of patients.

  1. Immune Reactivity

Measles produces temporary anergy to cell-mediated skin tests.

  1. Gastroenteritis

Diarrhea and protein-losing enteropathy (prodromal rectal Koplik spots may be seen) are significant complications among malnourished children.

  1. Other Complications

Other complications include conjunctivitis, keratitis, and otosclerosis.

 Treatment

  1. General Measures

The patient should be isolated for the week following onset of rash and kept at bed rest until afebrile. Treatment is symptomatic including antipyretics and fluids as needed. Vitamin A, 200,000 units/d orally for 2 days (the benefit being maintenance of gastrointestinal and respiratory epithelial mucosa) reduces pediatric morbidity (diarrhea, night blindness, xerophthalmia) and measles-associated mortality for infants between 6 months and 5 years of age, although high-dose vitamin A exposure increases the severity and risk of antibiotic failure in non-measles pneumonia. Measles virus is susceptible to ribavirin in vitro and has been used in selected severe cases of pneumonitis (35 mg/kg/d intravenously in three divided doses for 2 days, followed by 20 mg/kg/d intravenously in three divided doses for 5 days) and was deemed effective in containing a measles outbreak in a pediatric oncology unit in India.

  1. Treatment of Complications

Secondary bacterial infections, including pneumonia, are treated with appropriate antibacterial antibiotics. Post-measles encephalitis, including SSPE, can be managed only symptomatically.

Repeated studies fail to show an association between vaccination and autism. The prevalence of asthma-like diseases in childhood appears to be reduced among vaccinated children. Some data implicate the measles virus in the pathogenesis of rheumatoid arthritis.

 Prognosis

Between 2000 and 2008, measles mortality rate declined by 78%. In the last decade, the case-fatality rate in the United States stayed around 3 per 1000 reported cases, with deaths principally due to encephalitis (15% mortality rate) and secondary bacterial pneumonia. Deaths in the developing world are mainly related to diarrhea and protein-losing enteropathy.

 Prevention

In the United States, children receive their first vaccine dose at 12–15 months and a second at age 4–6 years, prior to entry into school. Combination measles-mumps-rubella-varicella vaccines (MMRV) can be used in place of the traditional measles, mumps, and rubella (MMR) vaccine. The median coverage with two doses of MMR vaccine nationally is 91% among children 19–35 months of age; however, there is considerable geographic disparity in this value (in the US Virgin Islands the coverage is only 63.7% and in West Virginia and Washington it is 84.6% and 84.8% respectively). The clustering of unvaccinated individuals also increases the likelihood of an outbreak. Susceptibility to measles is 2.4-fold higher if the vaccine is given prior to 15 months, suggesting that administration before that age may not be optimal for measles eradication. The evidence is not convincing that routine anthelmintic treatment affects the immune response to childhood vaccination.

American students beyond high school and medical staff starting employment require documentation of the above vaccination schedule or must show serologic evidence of immunity if they were born after 1956. For individuals born before 1957, herd immunity is assumed. Health care workers, immigrants, and refugees should be screened and vaccinated if necessary regardless of date of birth. International travelers (if immunocompetent and born after 1956) to the developing world and teachers should receive booster doses of vaccination.

At 6 months of age, more than 99% of infants of vaccinated women and 95% of infants of naturally immune women lose maternal antibodies. Therefore, in outbreaks that include infants less than 1 year of age, initial vaccination may be given at 6 months, with repeat at 15 months. When outbreaks take place in day care centers, K–12 institutions, or colleges and universities, revaccination is probably indicated for all, in particular for students and their siblings born after 1956 who do not have documentation of immunity as defined above. Susceptible personnel who were exposed should be isolated from patient contact between the fifth and the twenty-first day after exposure regardless of whether they were vaccinated or given immune globulin. If measles develops in these persons, they should be isolated from patient contact until 7 days after the rash develops.

When susceptible individuals are exposed to measles, live virus vaccine can prevent disease if given within 5 days of exposure. In addition, immune globulin (0.25 mL/kg [0.11 mL/lb] body weight) can be injected intramuscularly for prevention or modification of clinical illness if given within 6 days after exposure. This must be followed by active immunization with live measles vaccine 3 months later. In the developing world, the use of a second vaccine dose is an important aspect of achieving control of measles in the community.

Pregnant women and immunosuppressed persons should not receive this vaccine. Exception to this contraindication is asymptomatic HIV-infected patients, including children, who have not shown adverse effects from measles vaccination. In asymptomatic HIV-infected children, vaccination improves survival after measles, and HAART therapy is associated with an improved vaccine response. Repeat vaccination may be necessary in HIV-infected children after immune restoration. Immune globulin should be administered within 6 days of exposure for postexposure prophylaxis in any high-risk person exposed to measles. Such high-risk persons include children with malignancy and patients with AIDS who are at risk for developing severe or fatal disease.

Severe allergic reactions including anaphylaxis to the MMR vaccine are rare, though fever and rash appear to occur slightly more often among female recipients. Quadrivalent MMRV vaccine is associated with an increased risk of seizures that appears to be age-related; the risk is highest when MMRV is given to infants under 15 months of age. Future vaccines for a variety of infectious agents may utilize measles vectors, thereby augmenting immunity to measles. Rare cases of post-immunization encephalitis represent a form of acute disseminated encephalomyelitis (which can occur after many other vaccines including rabies, DPT, smallpox, and hepatitis B virus vaccinations).

 When to Refer

  • Any suspect cases should be reported to public health authorities.
  • HIV infection.
  • Pregnancy.

 When to Admit

  • Meningitis, encephalitis, or myelitis.
  • Severe pneumonia.
  • Diarrhea that significantly compromises fluid or electrolyte status.

Centers for Disease Control and Prevention (CDC). Measles—United States, 2011. MMWR Morb Mortal Wkly Rep. 2012 Apr 20;61:253–7. [PMID: 22513526]

De Serres G et al. Higher risk of measles when the first dose of a 2-dose schedule of measles vaccine is given at 12–14 months versus 15 months of age. Clin Infect Dis. 2012 Aug;55(3):394–402. [PMID: 22543023]

Lievano F et al. Measles, mumps, and rubella virus vaccine (M-M-R”II): a review of 32 years of clinical and postmarketing experience. Vaccine. 2012 Nov 6;30(48):6918–26. [PMID: 22959986]

McLean HQ et al; Centers for Disease Control and Prevention. Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2013 Jun 14;62(RR-04):1–34. [PMID: 23760231]

Roy Moulik N et al. Measles outbreak in a pediatric oncology unit and the role of ribavirin in prevention of complications and containment of the outbreak. Pediatr Blood Cancer. 2013 Oct;60(10):E122–4. [PMID: 23629813]

Sever AE et al. Measles elimination in the Americas: a comparison between countries with a one-dose and two-dose routine vaccination schedule. J Infect Dis. 2011 Sep;204(Suppl 2):S748–55. [PMID: 21954277]

  1. Mumps

 ESSENTIALS OF DIAGNOSIS

 Exposure 14–21 days before onset.

 Painful, swollen salivary glands, usually parotid.

 Frequent involvement of testes, pancreas, and meninges in unvaccinated individuals.

 General Considerations

Mumps is a paramyxoviral disease spread by respiratory droplets. Children are the age group most affected, although in some outbreaks, patients are in the late second or early third decades of life. Mumps can spread rapidly in congregate settings, such as colleges and schools. The incidence is highest in spring. The incubation period is 14–21 days (average, 18 days). Infectivity occurs via saliva and urine and precedes the symptoms by about 1 day and is maximal for 3 days, although it may last a week. Up to one-third of affected individuals have subclinical infection. The most recent outbreaks in the United States were in Guam during 2009 and 2010 and among Orthodox Jewish children during 2009 and 2010 in New York.

 Clinical Findings

  1. Symptoms and Signs

Mumps is more serious in adults than in children. Parotid tenderness and overlying facial edema (Figure 32–5) are the most common physical findings and typically develop within 48 hours of the prodromal symptoms. Usually, one parotid gland enlarges before the other, but unilateral parotitis alone occurs in 25% of patients. The orifice of Stensen duct may be red and swollen. Trismus may result from parotitis. The parotid glands return to normal within a week. Involvement of other salivary glands (submaxillary and sublingual) occurs in 10% of cases.

 Figure 32–5. Mumps. (Public Health Image Library, CDC.)

Fever and malaise are variable but often minimal in young children. High fever accompanies meningitis or orchitis. Neck stiffness, headache, and lethargy suggest meningitis. Testicular swelling and tenderness (unilateral in 75% of cases) denote orchitis; the testes are the most common extrasalivary site of disease in adults. Orchitis develops 7–10 days after the onset of parotitis in about 25–40% of postpubertal men but occurred in only 7% of males above age 12 in the Orthodox Jewish outbreaks in New York mentioned above. Sterility is rare. Acute hormonal disturbances are prevalent, including decreased levels of testosterone and inhibin B with low or normal levels of gonadotropins in up to 35% cases with mumps orchitis. Upper abdominal pain, nausea, and vomiting suggest pancreatitis. Mumps is the leading cause of pancreatitis in children. Lower abdominal pain and ovarian enlargement suggest oophoritis (which occurs in 5% of postpubertal women, usually unilateral); it is a difficult diagnosis to establish.

  1. Laboratory Findings

Mild leukopenia with relative lymphocytosis may be present. Serum amylasemia usually reflects salivary gland involvement rather than pancreatitis. Lymphocytic pleocytosis and hypoglychorrhachia of the cerebrospinal fluid in meningitis may be asymptomatic. Mild kidney function abnormalities are found in up to 60% of patients.

Characteristic clinical picture is usually sufficient for diagnosis. An elevated serum IgM is considered diagnostic and a repeat test 2–3 weeks after the onset of symptoms is recommended if the first assay is negative due to a delay in IgM rise, especially in vaccinated persons. A fourfold rise in complement-fixing antibodies to mumps virus in paired serum IgG also confirms infection. Confirmatory diagnosis of mumps is also made by isolating the virus preferably from a swab of the duct of the parotid or other affected salivary gland. The virus can also be isolated from cerebrospinal fluid early in the course of aseptic meningitis. Isolation from urine is no longer advised. Nucleic acid amplification techniques are more sensitive than viral cultures but their availability is limited. In the above New York outbreak, for example, a real time reverse transcriptase PCR (RT-PCR) available through CDC increased the diagnostic yield 14% when samples were collected within the first 2 days of the outbreak (while IgM assays were more sensitive 3 days or more into the outbreak).

 Differential Diagnosis

Swelling of the parotid gland may be due to calculi in the parotid ducts, tumors, or cysts, or to a reaction to iodides. Other causes include starch ingestion, sarcoidosis, cirrhosis, diabetes, bulimia, pilocarpine usage, and Sjögren syndrome. Parotitis may be produced by pyogenic organisms (eg, S aureus, gram-negative organisms), particularly in debilitated individuals with poor oral intake, drug reaction (phenothiazines, propylthiouracil), and other viruses (influenza A, parainfluenza, EBV infection, coxsackieviruses, adenoviruses, HHV-6). Swelling of the parotid gland must be differentiated from inflammation of the lymph nodes located more posteriorly and inferiorly than the parotid gland.

 Complications

Other manifestations of the disease are less common and usually follow parotitis but may precede it or occur without salivary gland involvement. Such manifestations include meningitis (30%), priapism or testicular infarction from orchitis, thyroiditis, neuritis, hepatitis, myocarditis, thrombocytopenia, migratory arthralgias (infrequently among adults and even rarer in children), and nephritis. Mumps is also been associated with cases of endocardial fibroelastosis and a hemophagocytosis syndrome. Rare neurologic complications include encephalitis, Guillain-Barré syndrome, cerebellar ataxia, facial palsy, and transverse myelitis. Encephalitis is associated with cerebral edema, serious neurologic manifestations, and sometimes death. Deafness from eighth nerve neuritis develops in about 0.1%; it is typically unilateral, severe, and permanent.

 Treatment

  1. General Measures

The patient should be isolated until swelling subsides (about 9 days from onset) and kept on bed rest while febrile. Treatment is symptomatic. Topical compresses may relieve parotid discomfort. Some clinicians advocate intravenous immunoglobulin (IVIG) for complicated disease (eg, thrombocytopenia) although its definitive role is unproven.

  1. Management of Complications
  2. Aseptic meningitis—The treatment is symptomatic. The management of encephalitis requires attention to cerebral edema, the airway, and vital functions.
  3. Epididymo-orchitis—The scrotum should be supported with a suspensor or toweling “bridge” and ice bags applied. Incision of the tunica may be necessary in severe cases. Pain can be relieved with opioids, or by injecting the spermatic cord at the external inguinal ring with 10–20 mL of 1% procaine solution. The merit of hydrocortisone sodium succinate (100 mg intravenously, followed by 20 mg orally every 6 hours for 2 or 3 days) in reducing inflammation is not firmly established. Interferon alfa-2b may be useful in preventing testicular atrophy.
  4. Pancreatitis—Symptomatic treatment should be provided, with emphasis on parenteral hydration.

 Prognosis

The entire course of mumps rarely exceeds 2 weeks. Rare fatalities are usually due to encephalitis.

 Prevention

Mumps live virus vaccine is safe and effective (there is some variability among vaccines, the Jeryl Lynn strain being highly effective, the Urabe intermediate, the Rubini less so) with long lasting immunity. It is recommended for routine immunization for children over age 1 year, either alone or in combination with other virus vaccines (eg, in the MMR vaccine or as a quadrivalent vaccine with varicella). A second dose is recommended for children (ages 4–6 years) before starting school. (In outbreaks from Canada and Scotland, cases disproportionately included those who received only one dose of the vaccine.) Two doses of the vaccine should also be considered for high-risk individuals (eg, health care workers) born before 1957 and without evidence of immunity. The use of a third dose of mumps vaccine in the above New York summer camp outbreak showed efficacy with decreased attack rates among sixth through twelfth graders, and there were few adverse effects noted to date other than infrequent injection site reactions.

There are no known cases of long-term sequelae associated with mumps vaccination and the currently used mumps strain (Jeryl Lynn) shows the lowest associated incidence of post vaccine aseptic meningitis (from 1 in 150,000 to 1 in 1.8 million). This vaccine is less effective in epidemic settings. Reactions are reviewed in the measles section. It should not be given to pregnant women or to immunocompromised individuals, though the vaccine is given to asymptomatic HIV-infected individuals without adverse sequelae and should be given when the individuals show immune restoration with HAART. In the developed world, persons in whom mumps develops are less likely to have received a second vaccine dose. The mumps skin tests are less reliable than serum neutralization titers in determining immunity.

 When to Refer

Any suspect cases should be reported to public health authorities.

 When to Admit

  • Trismus; meningitis, encephalitis; myocarditis.
  • Severe abdominal pain or vomiting suggesting pancreatitis.
  • Severe testicular pain; priapism.
  • Severe thrombocytopenia.

Barskey AE et al. Mumps outbreak in Orthodox Jewish communities in the United States. N Engl J Med. 2012 Nov;367(18):1704–13. [PMID: 23113481]

Deeks SL et al. An assessment of mumps vaccine effectiveness by dose during an outbreak in Canada. CMAJ. 2011 Jun 14;183(9):1014–20. [PMID: 21576295]

Ogbuanu IU et al. Impact of a third dose of measles-mumps-rubella vaccine on a mumps outbreak. Pediatrics. 2012 Dec;130(6):e1567–74. [PMID: 23129075]

  1. Poliomyelitis

 ESSENTIALS OF DIAGNOSIS

 Incubation period 9–12 days from exposure.

 Muscle weakness, headache, stiff neck, fever, nausea and vomiting, sore throat.

 Lower motor neuron lesion (flaccid paralysis) with decreased deep tendon reflexes and muscle wasting.

 Cerebrospinal fluid shows lymphocytic pleocytosis but rarely > 500/mcL.

 General Considerations

Poliomyelitis virus, an enterovirus, is present in throat washings and stools (excretion may last for weeks after infection). It is highly contagious through fecal–oral route, especially during the first week of infection. While by 2012, because of global vaccination efforts, indigenous transmission of wild poliovirus (WPV) types 1 and 3 were eliminated from all but three countries (Afghanistan, Nigeria, and Pakistan), data in 2012 described five cases from Chad and data through October 29, 2013 report a large number of cases secondary to the three above endemic nation cases from Somalia (180) with additional cases from Kenya (14), the Syrian Arab Republic (10), Ethiopia (7), and Cameroon (1). India has not reported a polio case since January 2011 and is considered polio free since February of 2012. The last case of WPV type 2 was in 1999, although a case was reported in 2011 of a woman with combined variable immunodeficiency who acquired type 2 poliomyelitis in Minnesota nearly 12 years after her child was given the oral vaccination.

While the177 cases were reported in 2012 represented a downward trend in the global tally of poliomyelitis cases, the preliminary reports for 2013 show an increase to 322, with 100 of these from the nonendemic countries listed above. All 2013 cases were WVP type 1 and only 19 of those in 2012 were WVP type 3 (one recombinant WPV types 1 and 3). A smoldering outbreak (largely in the Horn of Africa) was responsible for 6 of the 223 cases in 2012.

 Clinical Findings

  1. Symptoms and Signs

At least 95% of infections are asymptomatic, but in those who become ill, manifestations include abortive poliomyelitis (minor illness), nonparalytic poliomyelitis, and paralytic poliomyelitis.

  1. Abortive poliomyelitis (minor illness)—Such minor illness occurs in 4–8% of infections and the symptoms are fever, headache, vomiting, diarrhea, constipation, and sore throat lasting 2–3 days. This entity is suspected clinically only during an epidemic.
  2. Nonparalytic poliomyelitis—In addition to the above symptoms, signs of meningeal irritation and muscle spasm occur in the absence of frank paralysis. This disease is indistinguishable from aseptic meningitis caused by other viruses.
  3. Paralytic poliomyelitis—Paralytic poliomyelitis represents 0.1% of all poliomyelitis cases (the incidence is higher when infections are acquired later in life). Paralysis may occur at any time during the febrile period. Tremors, muscle weakness, constipation, and ileus may appear. Paralytic poliomyelitis is divided into two forms, which may coexist: (1)spinal poliomyelitis,with involvement of the muscles innervated by the spinal nerves, and (2) bulbar poliomyelitis, with weakness of the muscles supplied by the cranial nerves (especially nerves IX and X) and of the respiratory and vasomotor centers.

In spinal poliomyelitis, paralysis of the shoulder girdle often precedes intercostal and diaphragmatic paralysis, which leads to diminish chest expansion and decreased vital capacity. The paralysis occurs over 2–3 days, is flaccid, has an asymmetric distribution, and affects the proximal muscles of the lower extremities more frequently. Sensory loss is very rare.

In bulbar poliomyelitis, symptoms include diplopia (uncommonly), facial weakness, dysphagia, dysphonia, nasal voice, weakness of the sternocleidomastoid and trapezius muscles, difficulty in chewing, inability to swallow or expel saliva, and regurgitation of fluids through the nose. The most life-threatening aspect of bulbar poliomyelitis is respiratory paralysis. Lethargy or coma may be due to hypoxia, most often from hypoventilation. Vasomotor disturbances in blood pressure and heart rate may occur. Convulsions are rare. Bulbar poliomyelitis is more common in adults. Bulbar and spinal disease can coexist (bulbospinal poliomyelitis).

  1. Laboratory Findings

The peripheral white blood cell count may be normal or mildly elevated. Cerebrospinal fluid findings include the following: (1) normal or slightly increased pressure and protein, (2) glucose is not decreased, and (3) white blood cells usually number < 500/mcL and are principally lymphocytes after the first 24 hours. Cerebrospinal fluid is normal in 5% of patients. The virus may be recovered from throat washings (early) and stools (early and late) and PCR of washings, stool, or cerebrospinal fluid can also facilitate diagnosis. Neutralizing and complement-fixing antibodies appear during the first or second week of illness. Serologic testing cannot distinguish between wild type and vaccine-related virus infections.

 Differential Diagnosis

Nonparalytic poliomyelitis is similar to other forms of enteroviral meningitis; the distinction is made serologically. Acute flaccid paralysis is the term used in the developing world for the variety of neurologic illnesses that both include and mimic poliomyelitis. Acute flaccid paralysis due to poliomyelitis is distinguished by the greater frequency of fever and asymmetric neurologic signs. Acute inflammatory polyneuritis (Guillain-Barré syndrome), Japanese B virus encephalitis, West Nile virus infection, and tick paralysis may resemble poliomyelitis. In Guillain-Barré syndrome (see Chapter 24), the weakness is more symmetric and ascending in most cases, but the Miller Fisher variant is quite similar to bulbar polio. Paresthesias are uncommon in poliomyelitis but common in Guillain-Barré syndrome. The cerebrospinal fluid usually has high protein content but normal cell count in Guillain-Barré syndrome.

 Complications

Urinary tract infection, atelectasis, pneumonia, myocarditis, paralytic ileus, gastric dilation, and pulmonary edema may occur. Respiratory failure may be a result of paralysis of respiratory muscles, airway obstruction from involvement of cranial nerve nuclei, or lesions of the respiratory center.

 Treatment

In the acute phase of paralytic poliomyelitis patients should be hospitalized. Strict bed rest in the first few days of illness reduces the rate of paralysis. Comfortable but rotating positions should be maintained in a “polio bed”: firm mattress, footboard, sponge rubber pads or rolls, sandbags, and light splints. Intensive physiotherapy may help recover some motor function with paralysis. Fecal impaction and urinary retention (especially with paraplegia) are managed appropriately. In cases of respiratory weakness or paralysis, intensive care is needed. Attention to psychological disorders in long-standing disease is also important. The antiviral pleconaril shows no clear benefit in cases of polio meningoencephalitis.

 Prognosis

During the febrile period, paralysis may develop or progress. Mild weakness of small muscles is more likely to regress than severe weakness of large muscles. Bulbar poliomyelitis carries a mortality rate of up to 50%. Long-term sequelae include pain, weakness, fatigue, and obesity, factors often worsened by age and comorbidities. When new muscle weakness and pain develop and progress slowly years after recovery from acute paralytic poliomyelitis, the entity is called postpoliomyelitis syndrome. Risk factors for the syndrome include female gender, respiratory symptoms during the acute polio syndrome, and the need for orthoses and aids during the rehabilitation phase. The syndrome presents with signs of chronic and new denervation, is associated with increasing dysfunction of surviving motor neurons, and is not infectious in origin; patients do not shed the virus. Immune modulators, such as prednisone, interferon, and IVIG, do not show any clear benefits in the treatment of post poliomyelitis syndrome.

 Prevention

Given the epidemiologic distribution of poliomyelitis and the continued concern about vaccine-associated disease (estimated in 1:750,000 recipients) with the trivalent oral live poliovirus vaccine (OPV), the inactive (Salk) parenteral vaccination is currently used in the United States for all four recommended doses (at ages 2 months, 4 months, 6–18 months, and at 4–6 years). Inactivated vaccine is also routinely used elsewhere in the developed world. Oral vaccines are limited to usage for outbreak control, travel to endemic areas within the ensuing month, and protection of children whose parents do not comply with the recommended number of immunizations. The advantages of oral vaccination are the ease of administration, low cost, effective local gastrointestinal and circulating immunity, herd immunity, and decreased viral shedding in stool samples.

Routine immunization of adults in the United States is no longer recommended because of the low incidence of the disease. Exceptions include adults not vaccinated within the prior decade who are exposed to poliomyelitis or who plan to travel to endemic areas (mentioned above). Vaccination should also be considered for adults engaged in high-risk activities (eg, laboratory workers handling stools). Such adults should be given inactivated poliomyelitis vaccine (Salk) as should immunodeficient or immunosuppressed individuals and members of their households.

In the developing world, three doses of OPV seem sufficient for adequate immunization and the interval between doses should probably be > 1 month (because of interference from enteric pathogens). Intramuscular injections should be routinely avoided during the month following oral poliomyelitis vaccination to prevent provocation paralysis. Clinical studies suggest that rotavirus and OPV can be given concomitantly. Ancillary useful control measures (“supplementary immunization activities”) in polio-endemic countries include national immunization days (mass campaigns in which all children are vaccinated twice, 4–6 weeks apart, regardless of vaccine history); cross-border vaccination activities; surveillance for acute flaccid paralysis, an indicator for poliomyelitis; and aggressive outbreak responses as well as intensified immunization activities in countries impacted by armed conflicts.

VDPV cases with the oral Sabin vaccination are due to mutations leading to neurovirulence. Such cases serve as a reminder of the need to maintain high levels of immunization coverage even in the absence of overt disease. An immunogenic monovalent type 1 oral vaccine (several times more effective than the trivalent oral vaccine) is successfully used in India, Egypt, and Nigeria. Cost and administrative considerations along with a need for effective herd immunity remain major reasons the oral Sabin is still administered. Current research on developing improved inactivated polio vaccine (IPV) will be crucial for the final eradication of poliomyelitis. There is no epidemiologic evidence to implicate poliomyelitis vaccination as a cause for recurrent worsening wheezing or eczema in childhood.

 When to Refer

  • Neurologic compromise.
  • Any suspicious cases should be referred to public health authorities.

Bertolasi L et al. Risk factors for post-polio syndrome among an Italian population: a case-control study. Neurol Sci. 2012 Dec;33(6):1271–5. [PMID: 22246456]

Centers for Disease Control and Prevention (CDC). Assessing the risks for poliovirus outbreaks in polio-free countries—Africa, 2012–2013. MMWR Morb Mortal Wkly Rep. 2013 Sep 20;62(37):768–72. [PMID: 24048153]

Hird TR et al. Systematic review of mucosal immunity induced by oral and inactivated poliovirus vaccines against virus shedding following oral poliovirus challenge. PLoS Pathog. 2012;8(4):e1002599. [PMID: 22532797]

Liao G et al. Safety and immunogenicity of inactivated poliovirus vaccine made from Sabin strains: a phase II, randomized, positive-controlled trial. J Infect Dis. 2012 Jan 15;205(2):237–43. [PMID: 22158682]

World Health Organization; Global Polio Eradication Initiative. Data and monitoring: polio this week. http://www.polioeradication.org/Dataandmonitoring/Poliothisweek.aspx

  1. Rubella

 ESSENTIALS OF DIAGNOSIS

 Exposure 14–21 days before onset.

 Arthralgia, particularly in young women.

 No prodrome in children, mild prodrome in adults; mild symptoms (fever, malaise, coryza) coinciding with eruption.

 Posterior cervical and postauricular lymphadenopathy 5–10 days before rash.

 Fine maculopapular rash of 3 days duration; face to trunk to extremities.

 Leukopenia, thrombocytopenia.

 General Considerations

Rubella is a systemic disease caused by a togavirus transmitted by inhalation of infective droplets. It is moderately communicable. One attack usually confers permanent immunity but reinfection is possible, albeit rarely. The incubation period is 14–21 days (average, 16 days). The disease is transmissible from 1 week before the rash appears until 15 days afterward.

The clinical picture of rubella is difficult to distinguish from other viral illnesses such as infectious mononucleosis, measles, echovirus infections, and coxsackievirus infections; however, arthritis is more prominent in rubella. Surveillance of female military recruits suggests that serologic protection, largely vaccine derived, against rubella, measles, and mumps is inadequate. The rubella case load decreased from 670,894 cases in 2000 to 121,344 cases in 2009 with reports of disease from 167 nations. A major outbreak occurred in Japan in early 2013 with over 5442 cases through May 1—77% in males (vaccine programs between 1976 and 1989 targeted only girls) and 10 cases of congenital rubella syndrome. Rubella-containing vaccine is available in 130 nations. In the United States, rubella was last endemic in 2001. The principal importance of rubella lies in its devastating effects on the fetus in utero, producing teratogenic effects and a continuing congenital infection (congenital rubella syndrome). The control of rubella is so successful that the number of cases worldwide of reported congenital rubella syndrome in 2008 was only 165 with over one-third of these from the Eastern Mediterranean region. In the United States, congenital rubella syndrome among the native-born population last occurred in 2004, although periodic cases have occurred among women who emigrated from Africa including three in 2012.

 Clinical Findings

  1. Symptoms and Signs

While fetal rubella can be devastating, postnatally acquired rubella is usually innocuous and asymptomatic in up to 50% of cases. In the postnatally acquired infection, fever and malaise, usually mild, accompanied by tender suboccipital adenitis, may precede the eruption by 1 week. Mild coryza may be present. Polyarticular arthritis occurs in about 25% of adult cases and involves the fingers, wrists, and knees. Rarely does chronic arthritis develop. The polyarthritis usually subsides within 7 days but may persist for weeks. Early posterior cervical and postauricular lymphadenopathy is very common. Erythema of the palate and throat, sometimes patchy, may be noted.

A fine, pink maculopapular rash appears on the face, trunk, and extremities in rapid progression (2–3 days) and fades quickly, usually lasting 1 day in each area (Table 32–2). Rubella without rash may be at least as common as the exanthematous disease. When rubella is suspected because of disease in the community, the diagnosis requires serologic confirmation.

  1. Laboratory Findings

Leukopenia may be present early and may be followed by an increase in plasma cells. The definitive diagnosis of acute rubella infection is based on elevated IgM antibody, fourfold or greater rise in IgG antibody titers, or isolation of the virus. False-positive IgM antibodies, however, are associated with Epstein-Barr virus, CMV, erythrovirus (parvovirus), and rheumatoid factor. Detection of antibodies against rubella in other body fluids, such as urine and saliva, are promising diagnostic aids. An interferon-gamma-ELISPOT can provide valuable additional information in seronegative individuals. PCR techniques are also available.

 Complications

  1. Exposure During Pregnancy

When a pregnant woman is exposed to a possible case of rubella, an immediate hemagglutination-inhibiting rubella antibody level should be obtained to document immunity, since fetal infection during the first trimester leads to congenital rubella in at least 80% of fetuses.

Positive tests for IgG antibodies alone indicate past infection or vaccination. High-avidity anti-rubella IgG assays may distinguish past infection from vaccination. If no antibodies are found, clinical observation and serologic follow-up are essential. An isolated IgM-positive test needs to be interpreted with caution because it does not necessarily imply acute infection. Confirmation of rubella in the expectant mother raises the question of therapeutic abortion, an alternative to be considered in light of personal, religious, legal, and other factors.

The immune status of the mother needs to be evaluated because titers fall to seronegativity in about 10% by 12 years after vaccination.

  1. Congenital Rubella

An infant acquiring the infection in utero may be normal at birth but probably—50% in a series of nearly 70 pregnant women with rubella in Mexico—will have a wide variety of manifestations, including early-onset cataracts and glaucoma, microphthalmia, hearing deficits, psychomotor retardation, congenital heart defects (patent ductus arteriosus, branch pulmonary artery stenosis), organomegaly, and maculopapular rash. In general, the younger the fetus when infected, the more severe the illness. Deafness is the primary complication in the second trimester. Viral excretion in the throat and urine persists for many months despite high antibody levels. A specific test for IgM rubella antibody is useful for diagnosis in the newborn. A confirmatory diagnosis is made by isolation of the virus or PCR detection of viral RNA in tissues. Treatment is directed toward the many anomalies.

  1. Postinfectious Encephalopathy

In 1:6000 cases, postinfectious encephalopathy develops 1–6 days after the rash; the virus cannot always be isolated. The mortality rate is 20%, but residual deficits are rare among the recovered. The mechanism is unknown.

Other unusual complications of rubella include hemorrhagic manifestations due to thrombocytopenia and vascular damage, duodenal stenosis, and mild hepatitis.

 Treatment

Acetaminophen provides symptomatic relief for acute rubella. Encephalitis and non–life-threatening thrombocytopenia should be treated symptomatically.

 Prognosis

Rubella is a mild illness and rarely lasts more than 3–4 days. Congenital rubella, on the other hand, has a high mortality rate, and the associated congenital defects are largely permanent.

 Prevention

Live attenuated rubella virus vaccine should be given to all infants and a second dose should be given to children of school age. It is important that girls in particular are immune to rubella prior to the menarche. When women are immunized, they should not be pregnant, and the absence of antibodies should be established. (In the United States, about 80% of 20-year-old women are immune to rubella.) Postpartum administration to susceptible female hospital employees is recommended. It is recommended that women not become pregnant for at least 3 months after vaccine administration. Nonetheless, there are no reports of congenital rubella syndrome after rubella immunization, and inadvertent immunization of a pregnant woman is not considered an indication for therapeutic abortion. Arthritis is more marked after rubella vaccination than in native disease and appears to be immunologically mediated. A flare of juvenile rheumatoid arthritis after rubella vaccination is reported. The association between chronic arthropathies and rubella vaccination is controversial. Anaphylactoid reactions following vaccination are rare, and a self-limited thrombotic thrombocytopenic purpura is a reported but very rare (2.6 per 100,000 doses) complication.

MMR may be given in conjunction with DPT or varicella boosters as adequate serologic responses are documented. The administration of two or more doses appears to overcome an immunogenetic risk for vaccine failure in some vaccinees. Immunogenicity is similar with intramuscular and intracutaneous infection, for MMR and varicella vaccinations. Children with biliary atresia in particular show impaired responses to MMR and varicella vaccinations, although children with juvenile rheumatoid arthritis show intact responses to MMR boosters. Preliminary data suggests that vaccination may be safe for patients receiving immunosuppressive therapy in the setting of solid organ, bone marrow, or stem cell transplantation. Immigrants, especially the HIV-positive, should be vaccinated if CD4 counts show immune restoration.

Geographic areas with high birth rates and transmission rates of rubella may require baseline societal coverage rates for rubella higher than the conventional 80% often used.

 When to Refer

  • Pregnancy.
  • Meningitis/encephalitis.
  • Significant vaccination reactions.
  • Any suspect cases should be reported to public health authorities.

Castillo-Solórzano C et al. Elimination of rubella and congenital rubella syndrome in the Americas. J Infect Dis. 2011 Sep 1;204(Suppl 2):S571–8. [PMID: 21954249]

Centers for Disease Control and Prevention (CDC). Nationwide rubella epidemic—Japan, 2013. MMWR Morb Mortal Wkly Rep. 2013 Jun 14;62(23):457–62. Erratum in: MMWR Morb Mortal Wkly Rep. 2013 Jul 12;62(27):558. [PMID: 23760185]

Centers for Disease Control and Prevention (CDC). Three cases of congenital rubella syndrome in the postelimination era—Maryland, Alabama, and Illinois, 2012. MMWR Morb Mortal Wkly Rep. 2013 Mar 29;62(12):226–9. [PMID: 23535689]

Reef SE et al. Evidence used to support the achievement and maintenance of elimination of rubella and congenital rubella syndrome in the United States. J Infect Dis. 2011 Sep 1;204(Suppl 2):S593–7. [PMID: 21954252]

OTHER NEUROTROPIC VIRUSES

  1. Rabies

 ESSENTIALS OF DIAGNOSIS

 History of animal bite.

 Paresthesia, hydrophobia, rage alternating with calm.

 Convulsions, paralysis, thick tenacious saliva.

 General Considerations

Rabies is a viral (rhabdovirus) encephalitis transmitted by infected saliva that gains entry into the body by an animal bite or an open wound. Worldwide, 17.4 million cases of animal bites are reported every year, and it is estimated that between 26,000 and 61,000 deaths annually are attributable to rabies. Most of these cases occur in rural areas of Africa and Asia, with India accounting for 36% of the global deaths. In developing countries, more than 90% of human cases and 99% of human deaths from rabies are secondary to bites from infected dogs. Rabies among travelers to rabies-endemic areas is usually associated with animal injuries (including dogs in North Africa and India, cats in the Middle East, and non-human primates in sub-Saharan Africa and Asia), with most travel-associated cases occurring within 10 days of arrival.

In the United States, domestically acquired rabies cases are rare (approximately 92% of cases are associated with wildlife) but probably underreported. Reports largely from the East Coast show an increase in rabies among cats, with about 1% of tested cats showing rabies seropositivity. In 2012, 1 case of rabies was reported in United States citizens, and surveillance for animal rabies showed 62 cases among 49 states and Puerto Rico. Wildlife reservoirs, each species having its own rabies variant(s), follow a unique geographic distribution in the United States: raccoons in the East Coast; skunks in the Midwest, Southwest, and California; and foxes in the Southwest and in Alaska. Hawaii is the only rabies-free state to date. Bats were the second most reported rabid animals after raccoons during 2012. Raccoons, bats, and skunks account for 84% of the rabid animals found in the United States; other rabid animals include foxes, cats, cattle, and dogs. Rodents and lagomorphs (eg, rabbits) are unlikely to spread rabies because they cannot survive the disease long enough to transmit it (woodchucks and groundhogs are exceptions). Wildlife epizootics present a constant public health threat in addition to the danger of reintroducing rabies to domestic animals. Vaccination is the key to rabies in small animals and rabies transmission to human beings.

The virus gains entry into the salivary glands of dogs 5–7 days before their death from rabies, thus limiting their period of infectivity. Less common routes of transmission include contamination of mucous membranes with saliva or brain tissue, aerosol transmission, and corneal transplantation. Transmission through solid organ and vascular segment transplantation from donors with unrecognized infection is also reported.

The incubation period may range from 10 days to many years but is usually 3–7 weeks depending in part on the distance of the wound from the CNS. The virus travels in the nerves to the brain, multiplies there, and then migrates along the efferent nerves to the salivary glands. Rabies virus infection forms cytoplasmic inclusion bodies similar to Negri bodies. These Negri body-like structures are thought to be the sites of viral transcription and replication.

 Clinical Findings

  1. Symptoms and Signs

While there is usually a history of animal bite, bat bites may not be recognized. The prodromal syndrome consists of pain at the site of the bite in association with fever, malaise, headache, nausea, and vomiting. The skin is sensitive to changes of temperature, especially air currents (aerophobia). Percussion myoedema can be present and persist throughout the disease. The CNS stage begins about 10 days after the prodrome and may be either encephalitic (“furious”) or paralytic (“dumb”). The encephalitic form (about 80% of the cases) produces the classic rabies manifestations of delirium alternating with periods of calm, extremely painful laryngeal spasms on attempting drinking (hydrophobia), autonomic stimulation (hypersalivation), and seizures. In the less common paralytic form, an acute ascending paralysis resembling Guillain-Barré syndrome predominates with relative sparing of higher cortical functions initially. Both forms progress relentlessly to coma, autonomic nervous system dysfunction, and death.

  1. Laboratory Findings

Biting animals that appear well should be quarantined and observed for 10 days. Sick or dead animals should be tested for rabies. A wild animal, if captured, should be sacrificed and the head shipped on ice to the nearest laboratory qualified to examine the brain for evidence of rabies virus. When the animal cannot be examined, raccoons, skunks, bats, and foxes should be presumed to be rabid.

Direct fluorescent antibody testing of skin biopsy material from the posterior neck (where hair follicles are highly innervated) has a sensitivity of 60–80%.

Quantitative reverse transcriptase-PCR, nucleic acid sequence-based amplification, direct rapid immunohistochemical test and viral isolation from the cerebrospinal fluid or saliva are advocated as definitive diagnostic assays. Antibodies can be detected in the serum and the cerebrospinal fluid. Pathologic specimens often demonstrate round or oval eosinophilic inclusion bodies (Negri bodies) in the cytoplasm of neuronal cells, but the finding is neither sensitive nor specific. MRI signs are diffuse and nonspecific.

 Treatment & Prognosis

Management requires intensive care with attention to the airway, maintenance of oxygenation, and control of seizures. Universal precautions are essential. The induction of coma by ketamine, midazolam, and supplemental barbiturates along with the use of amantadine and ribavirin (the Milwaukee protocol) was reportedly helpful in one case but failed to reproduce success in 26 subsequent cases. Corticosteroids are of no use.

If postexposure prophylaxis (discussed below) is given expediently, before clinical signs develop, it is nearly 100% successful in prevention of disease. Once the symptoms have appeared, death almost inevitably occurs after 7 days, usually from respiratory failure. Most deaths occur in persons with unrecognized disease who do not seek medical care or in individuals who do not receive postexposure prophylaxis. The very rare cases in which patients recover without intensive care are referred to as “abortive rabies.”

 Prevention

Immunization of household dogs and cats and active immunization of persons with significant animal exposure (eg, veterinarians) are important. The most important decisions, however, concern animal bites. Animals that are frequent sources of infection to travelers are dogs, cats, and non-human primates.

In the developing world, education, surveillance, and animal (particularly dog) vaccination programs (at recurrent intervals) are preferred over mass destruction of dogs, which is followed typically by invasion of susceptible feral animals into urban areas. In some Western European countries, campaigns of oral vaccination of wild animals led to the elimination of rabies in wildlife.

  1. Local Treatment of Animal Bites and Scratches

Thorough cleansing, debridement, and repeated flushing of wounds with soap and water are important. Rabies immune globulin or antiserum should be given as stated below. Wounds caused by animal bites should not be sutured.

  1. Postexposure Immunization

The decision to treat should be based on the circumstances of the bite, including the extent and location of the wound, the biting animal, the history of prior vaccination, and the local epidemiology of rabies.Any contact or suspect contact with a bat, skunk, or raccoon is usually deemed a sufficient indication to warrant prophylaxis. Consultation with state and local health departments is recommended. Postexposure treatment including both immune globulin and vaccination should be administered as promptly as possible when indicated.

The optimal form of passive immunization is human rabies immune globulin (HRIG; 20 international units/kg), administered once. As much as possible of the full dose should be infiltrated around the wound, with any remaining injected intramuscularly at a site distant from the wound. Finger spaces can be safely injected without development of a compartment syndrome. If HRIG is not available, equine rabies antiserum (40 international units/kg) can be used if available after appropriate tests for horse serum sensitivity. All of the rabies immunoglobulin should be injected at the wound site as much as possible and the remainder injected intramuscularly at a distant site from the vaccine administration.

Two vaccines are licensed and available for use in humans in the United States: a human diploid cell vaccine and a purified chick embryo cell vaccine. The current vaccines may be given as four injections of 1 mL intramuscularly in the deltoid or, in small children, into the anterolateral thigh muscles on days 0, 3, 7, and 14 after exposure. (The fifth dose at 28 days after exposure is no longer recommended except among immunosuppressed patients.) The vaccine should not be given in the gluteal area due to suboptimal response. An alternative vaccination strategy that only takes 1 week, with injections on days 0, 3, and 7 after exposure with a verocell vaccine is reportedly successful in achieving adequate neutralizing titers at days 14 and 28 in a study from Thailand.

Rabies vaccines and HRIG should never be given in the same syringe or at the same site. Allergic reactions to the vaccine are rare, although local reactions (pruritus, erythema, tenderness) occur in about 25% and mild systemic reactions (headaches, myalgias, nausea) in about 20% of recipients. Adverse reactions to HRIG seem to be more frequent in women and rare in young children. The vaccine is commercially available or can be obtained through health departments.

Globally diverse anti-rabies vaccines are used. In some countries, the full spectrum of vaccines, from human diploid rabies to chromatographically purified rabies vaccine are available, whereas in others, the gamut is smaller and intradermal application of smaller vaccine doses at multiple sites and at different times is commonly practiced in an attempt to lower costs, and is deemed safe and effective by the WHO.

In patients with history of past vaccination, the need for HRIG is eliminated (RIG is in short supply worldwide) but postexposure vaccination is still required. The vaccine should be given 1 mL in the deltoid twice (on days 0 and 3). Neither the passive nor the active form of postexposure prophylaxis is associated with fetal abnormalities and thus pregnancy is not considered a contraindication to vaccination.

  1. Preexposure Immunization

Preexposure prophylaxis with three injections of human diploid cell vaccine intramuscularly (1 mL on days 0, 7, and 21 or 28) is recommended for persons at high risk for exposure: veterinarians (who should have rabies antibody titers checked every 2 years and be boosted with 1 mL intramuscularly); animal handlers; laboratory workers; Peace Corps workers; and travelers with stays over 1 month to remote areas in endemic countries in Africa, Asia, and Latin America. An intradermal route is also available (0.1 mL on days 0, 7, and 21 over the deltoid) but not in the United States. Immunosuppressive illnesses and agents including corticosteroids as well as antimalarials—in particular chloroquine—may diminish the antibody response. A single dose booster at 10 years after initial immunization increases the level of antibody titers.

 When to Refer

Suspicion of rabies requires contact with public health personnel to initiate appropriate passive and active prophylaxis and observation of suspect cases.

 When to Admit

  • Respiratory, neuromuscular, or CNS dysfunction consistent with rabies.
  • Patients with suspect rabies require initiation of therapy until the disease is ruled out in suspect animals, and this requires coordination of care based on likelihood of patient compliance, availability of inpatient and outpatient facilities, and response of local public health teams.

Centers for Disease Control and Prevention (CDC). Recovery of a patient from clinical rabies—California, 2011. MMWR Morb Mortal Wkly Rep. 2012 Feb 3;61(4):61–5. [PMID: 22298301]

Dyer JL et al. Rabies surveillance in the United States during 2012. J Am Vet Med Assoc. 2013 Sep 15;243(6):805–15. [PMID: 24004227]

Roebling AD et al. Rabies prevention and management of cats in the context of trap-neuter-vaccinate-release programmes. Zoonoses Public Health. 2014 Jun;61(4):290–6. [PMID: 23859607]

World Health Organization. WHO Expert Consultation on rabies. Second report. World Health Organ Tech Rep Ser. 2013;(982):1–139, back cover. [PMID: 24069724]

  1. Arbovirus Encephalitides

 ESSENTIALS OF DIAGNOSIS

 Fever, malaise, stiff neck, sore throat, and vomiting, progressing to stupor, coma, and convulsions.

 Upper motor neuron lesion signs: exaggerated deep tendon reflexes, absent superficial reflexes, and spastic paralysis.

 Cerebrospinal fluid opening pressure and protein are often increased, with lymphocytic pleocytosis.

 General Considerations

The arboviruses are arthropod-borne pathogens that produce clinical manifestations in humans. The mosquito-borne pathogens that cause encephalitis include three togaviruses (causing Western, Eastern, and Venezuelan equine encephalitis), five flaviviruses (causing West Nile fever, St. Louis encephalitis, Japanese B encephalitis, dengue, and Murray Valley encephalitis), and bunyaviruses (the California serogroup of viruses, including the Lacrosse agent of California encephalitis). The tick-borne causes of encephalitis include the flavivirus of the Powassan encephalitis (northeastern United States and Canada), tick-borne encephalitis virus of Europe, and the Colorado tick fever reovirus. Tick-borne encephalitis virus, Colorado tick fever, and the arboviruses associated with viral hemorrhagic fever (including dengue) are discussed below, and only those viruses causing primarily encephalitis in the United States will be discussed here, although West Nile agent is being reported in many other areas, including Italy, Greece, Portugal, and Hungary as well as in Africa (Madagascar and South Africa), Canada, the Middle East, and West Asia.

West Nile virus is the leading cause of domestically acquired arboviral disease in the United States. Several other arboviruses can also cause sporadic cases, neuroinvasive disease, and seasonal outbreaks. La Crosse virus was reported in 78 patients in 2012 with a median age of 9 years—56% were male and neuroinvasive disease occurred in 91% with highest rates for neuroinvasion in West Virginia, North Carolina, Tennessee, and Ohio. La Crosse virus cases occur largely east of 90 degree longitude and between late spring and early fall. Only 7 patients developed Powassan virus infection in 2012, the median age was 58 and all cases were in May or June, in Minnesota, Wisconsin, and New York. Fifteen cases of neuroinvasive Eastern equine encephalitis virus were reported in 2012, with a median age of 76 and the highest case load from Massachusetts. Only 3 cases of St Louis encephalitis occurred in 2012, all nonfatal and all in Texas. Jamestown Canyon virus is rare with 15 cases reported between 2004 and 2011. There are no reported patients with Western equine encephalitis since 1999. There are recent reports of 3 cases of Japanese encephalitis imported from Southeast Asia among travelers from Germany and Spain and more distant reports from the United States.

Infection with West Nile virus was first identified in the United States in the New York City area in 1999. The virus spread rapidly, and current cases are reported throughout the continental United States. The homeless appear to be at particularly increased risk for infection. In 2012, a surge of cases occurred in North Texas, with Dallas alone showing 225 cases of West Nile fever, and 172 cases of West Nile neurologic disease. As of November 25, 2013, 2170 cases, including 88 deaths, of West Nile virus were reported to the CDC, from all of the continental United States (none from Alaska or Hawaii). One-half of the reports (1086 cases) were of neuroinvasive disease. In the United States, the highest incidence of neuroinvasive disease is among the Rocky Mountain states as well as the upper Midwest and upper Southwest, while the largest number of cases are from Texas, California, Illinois, and Louisiana.

Outbreaks with West Nile infection tend to occur in between mid-July and early September. Climatic factors, including elevated mean temperatures and rainfall, correlate with increased West Nile infection. In the Dallas outbreak above, changes in weather pattern with a decrease in absolute number of winter days with low temperatures below 28°F correlated strongly with incidence of West Nile neurologic disease.

Pathogen-specific reservoirs (typically small mammals or birds) are responsible for maintaining the encephalitis-producing viruses in nature. For the Eastern equine encephalitis virus, cotton rats and house sparrows serve as amplifying reservoirs. Birds are the main reservoir for West Nile virus and substantial avian mortality accompanies West Nile fever outbreaks (monitoring chickens is recommended and a possible mode of disease surveillance). The mosquito species associated with transmission is different in the Western vs Eastern United States (Culex tarsalis vs Culex pipiens) and consequently the terrain associated with high prevalence areas differs (open grasslands vs urban areas).

Only dengue and Venezuelan equine encephalitis viruses produce viremias high enough to allow continued transmission to other mosquitoes and ticks between humans and vectors (mosquitoes of distinct species). Human to human transmission of the other arboviruses is usually related to blood (including granulocyte) transfusion or organ transplantation (although most infected donors give a history of clinically significant disease). Perinatal, transplacental, breastfeeding (rarely), laboratory, solid organ transplant, and possibly aerosol transmission of West Nile virus can also occur. St. Louis encephalitis and Powassan encephalitis occur among adults; Western equine encephalitis, Venezuelan equine encephalitis, La Crosse and California encephalitis occur primarily among children. West Nile fever and Eastern equine encephalitis are diseases of both children and adults.

 Clinical Findings

  1. Symptoms and Signs

The human incubation period for arboviral encephalitides is 2–14 days. Symptoms include fever, malaise, sore throat, headache, gastrointestinal upset, lethargy, and stupor progressing to coma. Using blood donor surveys, it is estimated that only about 26% of infections are symptomatic (women and the highly viremic are more symptomatic). A nonpruritic maculopapular rash is variably present. Stiff neck and mental status changes are the most common neurologic signs. It is estimated that West Nile fever develops in 20–25% of those infected with West Nile virus, while neuroinvasive disease occurs in < 1%, but has a mortality rate of at least 10%. About 50% of hospitalized patients with West Nile virus infection in the United States have significant muscle weakness that may be initially confused with the Guillain-Barré syndrome. Acute flaccid (poliomyelitis-like) paralysis is seen in 10% of West Nile virus neuroinvasive disease and less commonly with the other arboviruses. Other signs include tremors, seizures, cranial nerve palsies, and pathologic reflexes. Myocarditis, pancreatitis, and hearing loss are also reported. The disease manifestations associated with West Nile virus infection are strongly age-dependent: the acute febrile syndrome and mild neurologic symptoms (but on occasion meningitis) are more common in the young, aseptic meningitis and poliomyelitis-like syndromes are seen in the middle aged, and frank encephalopathy is seen more often in the elderly. All forms of disease tend to be severe in immunocompromised persons in whom neuroinvasive manifestations and associated high mortality are more apt to develop.

Host genetic variation in the interferon response pathway is associated with both risk for symptomatic West Nile virus infection and West Nile virus disease progression.

  1. Laboratory Findings

The peripheral white blood cell count is variable. Cerebrospinal fluid protein is elevated; cerebrospinal fluid glucose is normal; there is usually a lymphocytic pleocytosis; and polymorphonuclear cells may predominate early. The diagnosis of arboviral encephalitides depends on serologic tests. Antibodies to arboviruses persist for life and the presence of IgG in the absence of a rising titer of IgM may indicate past exposure rather than acute infection. Individuals with chronic symptoms after West Nile virus infection may show persistent renal infection for up to 6 years with West Nile virus RNA present in urine. Documentation of a fourfold increase in acute/convalescence titers IgG or the presence of IgM antibodies is confirmatory. For West Nile virus, an IgM capture ELISA in serum or cerebrospinal fluid is almost always positive by the time the disease is clinically evident, and the presence of IgM in cerebrospinal fluid indicates neuroinvasive disease. These tests are available commercially but also through local or state health departments. Cross-reactivity exists among the different flaviviruses, so a plaque reduction assay may be needed to definitively distinguish between West Nile fever and St. Louis encephalitis. PCR assays (also available through the CDC) are less sensitive than serologic tests for the diagnosis of acute infections but are the preferred method for screening blood products and may be particularly useful in immunocompromised patients with abnormal antibody responses. CT scans of the brain usually show no acute disease, but MRI may reveal leptomeningeal, basal ganglia, thalamic, or periventricular enhancement.

 Differential Diagnosis

Mild forms of encephalitis must be differentiated from aseptic meningitis, lymphocytic choriomeningitis, and nonparalytic poliomyelitis.

Severe forms of arbovirus encephalitides are to be differentiated from other causes of viral encephalitis (HSV, mumps virus, poliovirus or other enteroviruses, HIV), encephalitis accompanying exanthematous diseases of childhood (measles, varicella, infectious mononucleosis, rubella), encephalitis following vaccination (a demyelinating type following rabies, measles, pertussis), toxic encephalitis (from drugs, poisons, or bacterial toxins such as Shigella dysenteriae type 1), Reye syndrome, and severe forms of stroke, brain tumors, brain abscess, autoimmune processes such as lupus cerebritis, and intoxications. In the California Encephalitis Project, anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a more common cause of encephalitis than viral diseases especially in the young, with 65% of encephalitis due to anti-NMDAR occurring among patients 18 or younger.

 Complications

Bronchial pneumonia, urinary retention and infection, prolonged weakness, and decubitus ulcers may occur. St. Louis encephalitis is reportedly associated with a postinfectious encephalomyelitis. A chronic syndrome consisting of myalgias, arthralgias, and difficulty with concentration and memory is reported in over half the symptomatic cases. Reactivation of West Nile virus–related chorioretinitis was recently reported a year after the initial diagnosis.

 Treatment

Although specific antiviral therapy is not available for most causative entities, vigorous supportive measures can be helpful. Such measures include reduction of intracranial pressure (mannitol) and monitoring of intraventricular pressure. The efficacy of corticosteroids in these infections is not established. Other therapeutic options including ribavirin, IVIG, interferon-alpha, and hyperimmune plasma and gamma globulin are also largely anecdotal and await more substantial confirmation of effectiveness.

 Prognosis

Although most infections are mild or asymptomatic, the prognosis is always guarded, especially at the extremes of age. Most fatalities occur with neuroinvasive disease (9% for 2012 data) and among those with encephalitis or myelitis rather than with meningitis. As of June 28, 2013, the case fatality rate for West Nile virus disease in the United States was 5% (286 of 5674). Age older than 50 years is the most important risk factor for severe disease and death. Other risk factors for mortality include black race, chronic kidney disease, hepatitis C virus infection, and immunosuppression. Recovery of persons with severe neurologic compromise may take months. Sequelae of West Nile virus infection include a poliomyelitis-like syndrome, cognitive complaints, movement disorders, epilepsy, and depression; and they may become apparent late in the course of what appears to be a successful recovery.

The long-term prognosis is generally better for Western equine than for Eastern equine or St. Louis encephalitis.

 Prevention

No human vaccine is currently available for the arboviruses prevalent in North America, although yellow fever virus-based chimeric vaccines and recombinant vaccines remain under development for West Nile virus. Mosquito control (repellents, protective clothing, and insecticide spraying) is effective in prevention. Since 2003, all blood donations in the United States are screened with nucleic acid amplification tests for West Nile virus. Laboratory precautions are indicated for handling all these pathogens, in particular the West Nile virus.

A vaccine against Japanese B encephalitis is recommended for travelers to rural areas of East Asia, though the risk of disease acquisition among the exposed is estimated at only 1:1,000,000. This vaccination appears to provide some protection against West Nile virus (both agents are related flaviviruses).

Beardsley R et al. Reactivation West Nile virus infection-related chorioretinitis. Semin Ophthalmol. 2012 May–Jul;27(3–4):43–5. [PMID: 22784261]

Bigham AW et al. Host genetic risk factors for West Nile virus infection and disease progression. PLoS One. 2011;6(9):e24745. [PMID: 21935451]

Centers for Disease Control and Prevention (CDC). West Nile virus and other arboviral diseases—United States, 2012. MMWR Morb Mortal Wkly Rep. 2013 Jun 28;62(25):513–7. [PMID: 23803959]

Gable MS et al. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clin Infect Dis. 2012 Apr;54(7):899–904. [PMID: 22281844]

Goodman DM et al. JAMA patient page. West Nile virus. JAMA. 2012 Sep 12;308(10):1052. [PMID: 22922642]

  1. Lymphocytic Choriomeningitis

 ESSENTIALS OF DIAGNOSIS

 “Influenza-like” prodrome of fever, chills, and cough, followed by a meningeal phase.

 Aseptic meningitis with stiff neck, headache, nausea, vomiting, and lethargy.

 Cerebrospinal fluid: slight increase of protein, lymphocytic pleocytosis (500–3000/mcL); low glucose in 25% of patients.

 Complement-fixing antibodies within 2 weeks.

 General Considerations

The lymphocytic choriomeningitis virus is an arenavirus (related to the pathogen causing Lassa fever, discussed below) that primarily infects the CNS. Its main reservoir is the house mouse (Mus musculus). Other rodents (such as rats, guinea pigs, and even pet hamsters), monkeys, dogs, and swine are also potential reservoirs. Lymphocytic choriomeningitis virus is shed by the infected animal via nasal secretions, urine, and feces; transmission to humans probably occurs through aerosolized particles, direct contact, or animal bites. The disease in humans is underdiagnosed and occurs most often in autumn. The lymphocytic choriomeningitis virus is typically not spread person to person, although vertical transmission is reported, and it is considered as an underrecognized teratogen. Rare cases related to solid organ transplantation and autopsies of infected individuals are also reported. All reported cases were donor derived. Outbreaks are uncommon, and usually occur in laboratory settings among those workers with significant rodent exposure.

The ubiquitous nature of its reservoir and the wide distribution of the reported cases suggest a widespread geographic risk for lymphocytic choriomeningitis virus infection. Serologic surveys in the southern and eastern United States suggest past infection in approximately 3–5% of those tested, although more recent data from upstate New York showed < 1% seroprevalence. The risk of infection can be reduced by limiting contact with pet rodents and rodent trappings.

 Clinical Findings

  1. Symptoms and Signs

The incubation period is 8–13 days to the appearance of systemic manifestations and 15–21 days to the appearance of meningeal symptoms. Symptoms are biphasic, with a prodromal illness characterized by fever, chills, headache, myalgia, cough, and vomiting, occasionally with lymphadenopathy and maculopapular rash. After 3–5 days the fever subsides only to return after 2–4 days alongside the meningeal phase, characterized by headache, nausea and vomiting, lethargy, and variably present meningeal signs. Arthralgias can develop late in the course. Transverse myelitis, deafness, Guillain-Barré syndrome and transient and permanent hydrocephalus are reported. Lymphocytic choriomeningitis virus is a well known, albeit underrecognized, cause of congenital infection frequently complicated with obstructive hydrocephalus and chorioretinitis. In fetuses and newborns with ventriculomegaly or other abnormal neuroimaging findings, screening for congenital lymphocytic choriomeningitis may be considered. Occasionally, a syndrome resembling the viral hemorrhagic fevers (see below) is described in transplant recipients of infected organs and in patients with lymphoma.

  1. Laboratory Findings

Leukocytosis or leukopenia and thrombocytopenia may be initially present. During the meningeal phase, cerebrospinal fluid analysis frequently shows lymphocytic pleocytosis (total count is often 500–3000/mcL) alongside a slight increase in protein, while a low to normal glucose is seen in at least 25%. The virus may be recovered from the blood and cerebrospinal fluid by mouse inoculation. Complement-fixing antibodies appear during or after the second week. Detection of specific IgM by ELISA is becoming widely used. Detection of lymphocytic choriomeningitis virus by PCR is available in research settings.

 Differential Diagnosis

The influenza-like prodrome and latent period may distinguish this from other aseptic meningitides, and bacterial and granulomatous meningitis. A history of exposure to mice or other potential vectors is an important diagnostic clue.

 Treatment

Treatment is supportive. In the survivor of a transplant-associated outbreak, ribavirin (which is effective against other arenaviruses) was used successfully along with decreasing immunosuppression.

 Prognosis

Complications and fatalities are rare in the general population. The illness usually lasts 1–2 weeks, though convalescence may be prolonged. Congenital infection is more severe with about 30% mortality rate among infected infants, and more than 90% of survivors suffering long-term neurologic abnormalities. Lymphocytic choriomeningitis in solid organ transplant recipients is associated with a poor prognosis; of reported cases, the mortality rate is more than 80%.

 Prevention

Pregnant women should be advised of the dangers to their unborn children inherent in exposure to rodents.

Anderson JL et al. Congenital lymphocytic choriomeningitis virus: when to consider the diagnosis. J Child Neurol. 2013 May 10. [Epub ahead of print] [PMID: 23666045]

Waggoner JJ et al. Rare and emerging viral infections in transplant recipients. Clin Infect Dis. 2013 Oct;57(8):1182–8. [PMID: 23839998]

  1. Prion Diseases

 ESSENTIALS OF DIAGNOSIS

 Rare in humans.

 Cognitive decline.

 Myoclonic fasciculations, ataxia, visual disturbances, pyramidal and extrapyramidal symptoms.

 Variant form presents in younger people with prominent psychiatric or sensory symptoms.

 Specific EEG patterns.

 General Considerations

The transmissible spongiform encephalopathies are a group of fatal neurodegenerative diseases affecting humans and animals. They are caused by infectious proteins called prions for proteinaceous infectious particles. These agents show slow replicative capacity and long latent intervals in the host. They induce the conformational change of a normal brain protein (prion protein; PrP[C]) into an abnormal isoform (PrP[Sc]) that accumulates and causes neuronal vacuolation (spongiosis), reactive proliferation of astrocytes and microglia and, in some cases, the deposition of beta-amyloid oligomeric plaques (PrP[C]).

Prion disease can be hereditary, sporadic, and transmissible in humans. Hereditary disorders are caused by germ line mutations in the PrP[C] gene causing familial Creutzfeldt–Jakob disease (fCJD), Gerstmann-Strāussler-Scheinker syndrome (GSS), and fatal familial insomnia.

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common of the human prion diseases, accounting for approximately 85% of cases; it has no known cause, although a spontaneous misfolding of PrP[C] as well as somatic mutations of PrP[C] or undetectable horizontal transmission are postulated as possible explanations. Transmissible prion disease is only described for kuru and Creutzfeldt-Jakob disease in its iatrogenic (iCJD) and variant (vCJD) form. Iatrogenic transmission of CJD is associated with prion contaminated human corneas, dura mater grafts, growth hormone, gonadotropins, stereotactic electroencephalography, electrodes, and neurosurgical instruments. An occupational risk for CJD among the health care community is not clearly evident from current European surveillance data.

Kuru, once prevalent in central New Guinea, is now rare, a decline in prevalence that started after the abandonment of cannibalism in the late 1950s (a protective allele of the PrP gene is now identified at codon 127).

More than 200 cases of vCJD (bovine spongiform encephalopathy [BSE] or “mad cow disease”) were reported in the United Kingdom since the first documented cases there in the mid-1990s. It is far less common in North America, with only 3 cases reported in the United States (the last 1 in 2006) and 19 in Canada. Of the US-reported cases, none acquired the disease locally (2 of them acquired the infection in the United Kingdom and 1 in Saudi Arabia). This disease is characterized by its bovine-to-human transmission through ingestion of meat from cattle infected with BSE. There is no animal-to-animal spread of BSE, and milk and its derived products are not considered to be infected. Reports of secondary transmission of vCJD due to blood transfusions from asymptomatic donors are reported in the United Kingdom. Although iCJD and vCJD are not associated with a known PrP gene mutation, a polymorphism in codon 129 is prevalent and seems to determine susceptibility and expression of clinical disease. The overall annual incidence of prion disease worldwide is approximately one in 1 million people per year. In the United States, among 3018 cases reported through November 11, 2013 to the US National Prion Disease Pathology Surveillance Center, 2539 (84.1%) were sporadic, 450 (14.9%) familial, 6 (0.2%) iatrogenic, and 3 (0.1%) vCJD.

 Clinical Findings

  1. Symptoms and Signs

Both sCJD and fCJD usually present in the sixth or seventh decade of life, whereas the iCJD form tends to occur in a much younger population. Clinical features of these three forms of disease usually involve mental deterioration (dementia, behavioral changes, loss of cortical function) progressive over several months, as well as myoclonus, extrapyramidal (hypokinesia) and cerebellar manifestations (ataxia, dysarthria). Finally, coma ensues, usually associated with an akinetic state and less commonly decerebrate/decorticate posturing. Like iCJD, vCJD usually affects younger patients (averaging ~28 years), but the duration of disease is longer (about 1 year). The degree of organ involvement is often extensive, and the clinical symptoms are unique, mainly characterized by prominent psychiatric and sensory symptoms.

  1. Laboratory Findings

CJD should be considered as a diagnosis in the proper clinical scenario, in the absence of alternative diagnoses after routine investigations. Abnormalities in cerebrospinal fluid are subtle and rarely helpful. The detection of 14-3-3 protein in the cerebrospinal fluid is helpful for the diagnosis of sCJD but not in vCJD and fCJD. Its sensitivity and specificity are widely variable among different studies. Cerebrospinal fluid detection of other proteins like tau, neuron-specific enolase, and S100B protein are reported in smaller studies. Recently, the combination of tau with S100B was reported to be more sensitive than 14-3-3 protein.

A new blood-based assay and a PCR in cerebrospinal fluid show some promising results in the diagnosis of vCJD with high specificity but 71% sensitivity. Further evaluation is under way.

In sCJD, EEG typically shows a pattern of paroxysms with high voltages and slow waves, while MRI is characteristic for bilateral areas of increased signal intensity, predominantly in the caudate and putamen. MRI has great potential for improving early diagnosis of sCJD because clinical findings are often missed. When an experienced neuroradiologist or a prion disease expert reviews the MRI, diagnostic sensitivity of MRI for sCJD increases to 91%. The cortical findings associated with sCJD tend to be the most common region not documented by referring centers. In contrast, vCJD shows a diffusely abnormal but nondiagnostic EEG. MRI characteristically reveals hyperintensity of the posterior thalamus (“pulvinar sign”). Positron emission tomography can help distinguish GSS disease. The differentiation and definitive diagnosis of these neurodegenerative diseases are established by neuropathologic confirmation.

 Treatment & Prevention

There is no specific treatment for CJD. Once symptoms appear, the infection invariably leads to death. Flupirtine (an analgesic drug) is sometimes useful in slowing the associated cognitive decline but does not affect survival.

Iatrogenic CJD can be prevented by limiting patient exposure to potentially infectious sources as mentioned above. Prevention of vCJD relies on monitoring livestock for possible infection. The American Red Cross does not accept blood donations from persons with a family history of CJD or with a history of dural grafts or pituitary-derived growth hormone injections.

An international referral and database for CJD is available at: http://www.cjdsurveillance.com/index.html.

Andréoletti O et al. Highly efficient prion transmission by blood transfusion. PLoS Pathog. 2012;8(6):e1002782. [PMID: 22737075]

Carswell C et al. MRI findings are often missed in the diagnosis of Creutzfeldt-Jakob disease. BMC Neurol. 2012 Dec 5;12:153. [PMID: 23216655]

Edgeworth JA et al. Detection of prion infection in variant Creutzfeldt-Jakob disease: a blood-based assay. Lancet. 2011 Feb 5;377(9764):487–93. [PMID: 21295339]

  1. Progressive Multifocal Leukoencephalopathy (PML)

PML is a rare demyelinating CNS disorder caused by the reactivation of the JC virus (John Cunningham virus or JCV). This polyomavirus usually causes its primary infection during childhood with > 60% of adults typically being seropositive. The virus remains latent in the kidneys, lymphoid tissues, epithelial cells, peripheral blood leukocytes, bone marrow, and possibly brain until the time reactivation occurs and symptoms become evident (see below). This reactivation is usually seen in adults with impaired cell-mediated immunity, especially AIDS patients (5–10% of whom develop PML), as well as those with idiopathic CD4 lymphopenia syndrome. It is also reported among those with lymphoproliferative and myeloproliferative disorders; granulomatous, inflammatory, and rheumatic diseases (systemic lupus erythematosus and rheumatoid arthritis in particular); as well as in those who have undergone solid and hematopoietic cell transplantation; and occasionally in those who have other medical states, including cirrhosis and kidney disease.

Medication-associated PML is described with the use of natalizumab, rituximab, infliximab (one case), and mycophenolate mofetil. Natalizumab, a monoclonal antibody used in the treatment of multiple sclerosis, is associated with the risk of PML developing in 1.35 cases per 1000 patients treated for more than a year and 1.78 per 1000 for patients treated > 2 years. The risk of PML appears to increase up to 36 months of therapy and levels off thereafter.

Although an immune reconstitution inflammatory state may follow cessation of monoclonal antibody therapy, the JCV presence and the residual neurologic deficits may not clear for years after therapy is stopped. The risk of developing PML associated with rituximab is at least 1 in 25,000 exposed patients with cases reported in various autoimmune conditions (systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis). The mean interval between the use of the drug to the diagnosis of PML is 5.5 months. Smoking is reportedly associated with an increased risk of PML.

 Clinical Findings

  1. Symptoms and Signs

JCV causes lytic infection of oligodendrocytes in the white matter and symptoms presenting subacutely reflect the diverse areas of CNS involvement. Symptoms include altered mental status, aphasia, ataxia, hemiparesis or hemiplegia and visual field disturbances. Seizures occur in about 18%. Involvement of cranial nerves and cervical spine is rare.

  1. Laboratory Findings

PCR for JCV in cerebrospinal fluid is used for diagnosis in patients with compatible clinical and radiologic findings. A quantitative PCR is more sensitive. Persistent JC viremia and increasing urinary JCV DNA may be predictive of PML. An anti-JCV immunoglobuin G (IgG) was higher 6 months before diagnosis but was not predictive of PML in a cohort of HIV-infected persons.

MRIs of the brain show multifocal areas of white matter demyelination without mass effect or contrast enhancement. These findings may not be distinguishable from immune reconstitution inflammatory syndrome. In HIV-infected patients, a syndrome of cerebellar degeneration is described.

 Treatment & Prevention

Limiting the immunosuppressed state represents the mainstay of therapy for PML. Treatment of HIV with HAART reduces the incidence of PML, improves the clinical symptoms, reverses some of the radiographic abnormalities, and improves the 1-year mortality rate, regardless of baseline CD4 count. Immune restoration can induce worsening of the clinical picture in a small number of cases. Immune reconstitution syndromes do not alter mortality but are associated with a form of PML called non-determined leukoencephalopathy associated with a distinct chemokine polymorphism. Significant neurologic sequelae to PML infections are the rule. Deficits associated with PML, including monoclonal associated forms, may persist for years.

Decreasing immunosuppression in non-AIDS patients with PML (eg, transplant patients) is also typically beneficial. Cidofovir may be beneficial in non-AIDS related cases while corticosteroids may be useful with immune reconstitution. Because the JCV infects cells through serotonin receptors, the use of risperidone and mirtazapine are recommended by some clinicians. Plasma exchange, which theoretically reduces the plasma level of agents associated with PML, may be useful in natalizumab-associated PML.

Casado JL et al. Continued declining incidence and improved survival of progressive multifocal leukoencephalopathy in HIV/AIDS patients in the current era. Clin Microbiol Infect Dis. 2014 Feb;33(2):179–87. [PMID: 23948752]

Lima MA. Progressive multifocal leukoencephalopathy: new concepts. Arq Neuropsiquiatr. 2013 Sep;71(9B):699–702. [PMID: 24141508]

Major EO et al. JC viremia in natalizumab-treated patients with multiple sclerosis. N Engl J Med. 2013 Jun 6;368(23):2240–1. [PMID: 23738566]

Martin-Blondel G et al. In situ evidence of JC virus control by CD8+ T cells in PML-IRIS during HIV infection. Neurology. 2013 Sep 10;81(11):964–70. [PMID: 23935178]

  1. Human T Cell Lymphotropic Virus (HTLV)

HTLV-1 and -2 are retroviruses that infect CD4 and CD8 T cells respectively, where they persist as a lifelong latent infection. HTLV-1 currently infects approximately 20 million individuals worldwide. It is endemic to many regions in the world including southern Japan, the Caribbean, multiple regions of sub-Saharan Africa, South America, Eastern Europe, and Oceania. The Caribbean basin and Southwestern Japan show the highest prevalence of infection (4–37%). Conversely, HTLV-2 is mainly found in native populations of South (1–58%), Central (8–10%), and North America (2–13%) as well as African pygmy tribes.

In the United States, studies done in blood donors show a seroprevalence of HTLV-1 of 0.005% and HTLV-2 of 0.014%, a decline since the early 1990s. Over 85% of the cases found in the United States are located in the West or Southwest. The virus is transmitted horizontally (sex), vertically (intrauterine, peripartum, and breast feeding), and parenterally (injection drug use and blood transfusion). Hence, a higher prevalence is seen among injection drug users.

 Clinical Findings

  1. Symptoms and Signs

HTLV-1 infection is associated with HTLV-1 adult T cell lymphoma/leukemia (ATL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). In contrast, HTLV-2 is significantly less pathogenic, with few reported cases of HAM/TSP as well as other neurologic manifestations. The causative association of HTLV-1 with ATL, attributed to the virally encoded oncoproteintax, is well established. The lifetime risk of developing ATL among seropositive persons is estimated to be 3% in women and 7% in men, with an incubation period of at least 15 years. The mean age of diagnosis of ATL is 40–50 years in Central and South America and 60 years in Japan.

ATL clinical syndromes may be classified as chronic, acute (leukemic), smoldering, or lymphomatous. A primary cutaneous tumor is also described and shows a worse prognosis compared with the smoldering type. Clinical features of ATL include diffuse lymphadenopathy, maculopapular skin lesions that may evolve into erythroderma, organomegaly, lytic bone lesions, and hypercalcemia. Opportunistic infections, such as Pneumocystis jirovecii pneumonia and cryptococcal meningitis, are common.

HAM/TSP, associated with both HTLV-1 and HTLV-2, develops in 0.3–4% of seropositive individuals and is more common in women. A chronic inflammation of the spinal cord leads to progressive motor weakness and symmetric spastic paraparesis, nociceptive low back pain, and paraplegia with hyperreflexia. Bladder and sexual disorders (eg, dyspareunia), sensory disturbances, erectile dysfunction, and constipation are also common. A progressive cognitive impairment is seen with HAM/TSP in children. Both viruses can also induce motor abnormalities, such as leg weakness, impaired tandem walk, and vibration sense, without overt HTLV-associated myelopathy. Seropositivity to both viruses is also associated with increases in depression and anxiety.

An HTLV-1 provirus load in peripheral blood mononuclear cells and cerebrospinal fluid cells, and an HTLV-1 mRNA load are proposed as markers of HAM risk and progression. HTLV positivity is associated with erythrocytosis, lymphocytosis (HTLV-2) and with thrombocytosis (HTLV-1).

HTLV-1 seropositivity is associated with an increased risk of tuberculosis, Strongyloides stercoralis hyperinfection, crusted scabies, and infective dermatitis. Inflammatory states associated with HTLV-1 infection include arthropathy, polymyositis, uveitis, Sjögren syndrome, vasculitis, cryoglobulinemia, infiltrative pneumonitis, and ichthyosis. Bronchioloalveolar carcinoma is increased in frequency in the presence of HTLV-1.

HTLV-2 appears to cause a myelopathy that is milder and slower to progress than HAM. All-cause and cancer mortality is higher among HTLV-2 seropositive patients.

HTLV-1/HIV coinfection is associated both with higher CD4 counts and a higher risk of HAM. Coinfections are underdiagnosed.

  1. Laboratory Findings

The peripheral smear can show atypical lymphoid cells with basophilic cytoplasm and convoluted nuclei (flower cells) but the diagnostic standard is evidence of clonal integration of the proviral DNA genome into tumor cell. The identification of HTLV-1 antibodies supports the diagnosis.

 Treatment, Prevention, & Prognosis

Management of ATL consists mainly of chemotherapy, with allogeneic stem cell transplantation and the use of monoclonal antibodies (anti-CCR4 and anti-CD25). A chemotherapy regimen in Japan using eight different agents shows a higher response rate than traditional biweekly CHOP (40% vs 25%). Therapy using interferon-alpha combined with zidovudine is effective in the smoldering type.

HAM is treated with a variety of immune-modulating agents (including corticosteroids) without consistent results. Combination therapy with antiretrovirals does not show benefit. Interferon-alpha may be of some efficacy. Small uncontrolled studies suggest plasmapheresis results in improvement in gait and sensory disturbance among some PML patients. Screening of the blood supply for HTLV-1 is required in the United States. There is significant cross-reactivity between HTLV-1 and HTLV-2 by serologic studies, but PCR can distinguish the two. Improved assays to screen organ donors for HTLV-1 and -2 infections are needed.

A 10-year follow-up study in the Gambia shows increased mortality associated with HTLV-1 or HTLV-2 seropositivity, particularly in the young.

Chang YB et al. Seroprevalence and demographic determinants of human T-lymphotropic virus type 1 and 2 infections among first-time blood donors—United States, 2000–2009. J Infect Dis. 2014 Feb;209(4):523–31. [PMID: 24068702]

Dhasmana D et al. Human T-lymphotropic virus/HIV co-infection: a clinical review. Curr Opin Infect Dis. 2014 Feb;27(1):16–28. [PMID: 24305042]

Okajima R et al. High prevalence of skin disorders among HTLV-1 infected individuals independent of clinical status. PLoS Negl Trop Dis. 2013 Nov 7;7(11):e2546. [PMID: 24244779]

OTHER SYSTEMIC VIRAL DISEASES

  1. Hemorrhagic Fevers

This diverse group of illnesses results from infection with one of several single-stranded RNA viruses (members of the families Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae). Flaviviruses, such as the pathogens causing dengue and yellow fever (both with occasional hemorrhagic complications), are discussed in separate sections.

Lassa fever (an Old World arenavirus) is rodent associated and transmission usually occurs through aerosolized particles (from rodents or infected individuals). Transmission through direct contact with infected biologic fluids or tissues is also documented and food-borne transmission, while considered, is not definitively proven. Similar modes of transmission are assumed for Junin virus and other members of the New World Arenaviridae (Machupo virus, Sabia virus, Guanarito virus, Whitewater Arroyo virus). Bats (fruit bats for Ebola) are the suspected reservoir for Ebola and Marburg viruses(Filoviridae) but their vectors are unknown. A subtype of Ebola (Bundibugyo) is reported in Uganda (earlier Ebola outbreaks occurred in Democratic Republic of Congo, Sudan, and one case in Cóte d’Ivoire) and was responsible for 93 cases and 37 deaths in 2007–2008. Another widespread Ebola outbreak began in Guinea in 2014. Cases of Marburg hemorrhagic fever are reported in travelers exploring caves and mines inhabited by bats in endemic areas of sub-Saharan Africa. The bunyaviruses include the Crimean-Congo hemorrhagic fever (transmitted by infected animal exposure or tick bite), the Rift Valley fever (transmitted by exposure to infected animal products or bite of an infected mosquito or flea), and the hantaviruses (associated with rodent exposure and discussed separately below). The geographic distribution of Crimean-Congo hemorrhagic fever, like that of its tick vector, is widespread with cases reported in Asia, the Middle East, and Eastern Europe. In 2002, Turkey experienced the largest reported outbreak with over 2500 cases. Hospital-associated transmission of Crimean-Congo hemorrhagic fever is well documented in Iran (where at least five variants have been detected). Rift Valley fever causes outbreaks in sub-Saharan and Northern Africa, including a 2007 outbreak with 155 deaths in Kenya following heavy rainfalls and associated with three different lineages of the virus. Rift Valley cases are also confirmed outside the African continent, in Saudi Arabia, and Yemen.

A new bunyavirus, a phlebovirus, associated with fever and thrombocytopenia, was identified in 2010 in Central and Northeastern China and is named for its symptoms: the severe fever with thrombocytopenia syndrome (SFTS) virus. Its differential diagnosis includes anaplasmosis, hemorrhagic fever with renal syndrome, or leptospirosis. The current candidate vector is a tick of the Ixodidae family. A mortality of 12% was noted among the first 171 patients. A new pathogenic virus (Heartland virus) similar to the SFTS virus was isolated in Missouri in 2009 from two farmers who had with fever, diarrhea, and fatigue. Transmission occurs via the Lone Star tick (Amblyomma americanum). There is no evidence for the transmission of viral hemorrhagic fever through air travel.

 Clinical Findings

  1. Symptoms and Signs

The incubation period can be as short as 2 days for the Rift Valley fever or as long as 21 days for Lassa fever. The clinical symptoms in the early phase of a viral hemorrhagic fever are very similar, irrespective of the causative virus, and resemble a flu-like illness or gastroenteritis. Hepatitis is common.

The late phase is more specific and is characterized by organ failure, persistent leukopenia, altered mental status, and hemorrhage. Exanthemas and mucosal lesions can occur. The range of pathology described with Crimean-Congo hemorrhagic fever continues to grow and include cardiac failure, bilateral alveolar hemorrhages, and retinal hemorrhages. Rift Valley fever is reportedly associated with encephalitis and also retinitis. Adrenal dysfunction is a common sequela of this class of infections and a cause for the development of the late-stage shock associated with these infections. The case-fatality rate ranges from 5% to 30% and may be as high as 90% in Ebola fever. The convalescence period can be long and complicated. There is no evidence of chronic infection among survivors. Risk factors for complications in patients with Crimean-Congo hemorrhagic fever include advanced age, thrombocytopenia, prolonged clotting factor parameters, and hepatitis; risk factors for mortality include altered sensorium and prolonged international normalized ratio.

  1. Laboratory Findings

Laboratory features usually include thrombocytopenia, leukopenia, (although with Lassa fever leukocytosis is noted), anemia, increased hematocrit, elevated liver function tests, and findings consistent with disseminated intravascular coagulation (although less prominently in Lassa fever). Urinalysis can reveal proteinuria and hematuria.

Special care should be taken for handling clinical specimens of suspected cases. Laboratory personnel should be warned about the diagnostic suspicion and the CDC must be contacted for guidance (Special Pathogens Branch, 404-639-1115). Diagnosis may be made by growing the virus from blood obtained early in the disease, antigen detection (by ELISA), nucleic acid amplification (PCR techniques), or by demonstration of a significant specific fourfold or greater rise in antibody titer. Detection of Ebola virus antigen in oral fluid samples by ELISA and RT-PCR may be possible; sample collection in this manner will be useful since certain ethnic customs prohibit blood collection. These tests are generally available only through the CDC. Crimean-Congo hemorrhagic fever is best diagnosed with an IgM serology, although IgG ELISA or immunofluorescence and quantitative reverse transcription PCR are nearly as effective.

 Differential Diagnosis

The differential diagnosis for hemorrhagic fever includes meningococcemia or other septicemias, Rocky Mountain spotted fever, dengue, typhoid fever, and malaria. The likelihood of acquiring hemorrhagic fevers among travelers is low.

 Treatment

Patients should be placed in private rooms with standard contact and droplet precautions. Barrier precautions to prevent contamination of skin or mucous membranes should also be adopted by the caring personnel. Airborne precautions should be considered in patients with significant pulmonary involvement or undergoing procedures that stimulate cough.

Certain arenaviruses (the Lassa pathogen, Junin virus in its viscerotropic phase, Machupo virus) and bunyaviruses (the Congo-Crimean hemorrhagic fever and Rift Valley fever pathogens) respond to oral ribavirin if it is started promptly: 30 mg/kg as loading dose, followed by 16 mg/kg every 6 hours for 4 days and then 8 mg/kg every 8 hours for 3 days. The efficacy for postexposure ribavirin in the management of Lassa fever, other arenaviruses, or hospital–associated Crimean-Congo hemorrhagic fever remains anecdotal. However, if ribavirin is used, it should be given in a high loading dose (35 mg/kg orally followed by 15 mg/kg three times daily for 10 days) and only for high-risk settings (eg, needle stick injury, mucous membrane contamination, emergency resuscitative contact, or prolonged intimate exposure during transport).

The filoviruses and the flaviviruses do not respond to ribavirin. Live attenuated vaccines are available for Junin hemorrhagic fever and the Rift Valley fever, and they are under study for the Crimean-Congo hemorrhagic fever, Ebola, and Marburg viruses. In addition, recombinant and virus-like particle vaccines are under development for most of these pathogens (including the Lassa fever virus but not the Junin hemorrhagic fever virus). Therapeutic interventions that target the hematologic system are at most only marginally effective.

 When to Admit

  • Persons with symptoms compatible with those of any hemorrhagic fever and who have traveled from a possible endemic area should be isolated for diagnosis and symptomatic treatment.
  • Isolation is particularly important because diseases due to some of these agents, such as Ebola virus, are highly transmissible and carry a mortality rate of 50–90%.

Feldmann H et al. Ebola haemorrhagic fever. Lancet. 2011 Mar 5; 377(9768):849–62. [PMID: 21084112]

Gilsdorf A et al. Guidance for contact tracing of cases of Lassa fever, Ebola or Marburg haemorrhagic fever on an airplane: results of a European expert consultation. BMC Public Health. 2012 Nov 21;12:1014. [PMID: 23170851]

LaBeaud AD et al. Advances in Rift Valley fever research: insights for disease prevention. Curr Opin Infect Dis. 2010 Oct;23(5):403–8. [PMID: 20613512]

McMullan LK et al. A new phlebovirus associated with severe febrile illness in Missouri. N Engl J Med. 2012 Aug 30; 367(9):834–41. [PMID: 22931317]

Mertens M et al. The impact of Crimean-Congo hemorrhagic fever virus on public health. Antiviral Res. 2013 May;98(2):248–60. [PMID: 23458713]

Nderitu L et al. Sequential Rift Valley fever outbreaks in eastern Africa caused by multiple lineages of the virus. J Infect Dis. 2011 Mar 1;203(5):655–65. [PMID: 21282193]

Russier M et al. Immune responses and Lassa virus infection. Viruses. 2012 Nov 5;4(11):2766–85. [PMID: 23202504]

  1. Dengue

 ESSENTIALS OF DIAGNOSIS

 Exposure 7–10 days before onset.

 Sudden onset of high fever, chills, severe myalgias and arthralgias, headache, sore throat, and depression.

 Biphasic fever curve: initial phase, 3–7 days; remission, few hours to 2 days; second phase, 1–2 days.

 Biphasic rash: evanescent, then maculopapular, scarlatiniform, morbilliform, or petechial changes from extremities to torso.

 Leukopenia and thrombocytopenia in the hemorrhagic form.

 General Considerations

Dengue is due to a flavivirus transmitted by the bite of the Aedes mosquito. It may be caused by one of four serotypes (possibly five, with a potentially new serotype from Malaysia under study) widely distributed globally between the tropics of Capricorn and Cancer. An estimated 70–500 million cases of dengue fever and several hundred thousand cases of dengue hemorrhagic fever occur each year with numbers growing in both dengue fever and dengue hemorrhagic fever as a consequence of climatic factors, travel, and urbanization. It is thus along with malaria one of the two most common and important vector-borne diseases of humans, with 2.5 billion people living in dengue-infected regions and regions of major intermittent outbreaks. The incubation period is 3–15 days (usually 7–10 days). When the virus is introduced into susceptible populations, usually by viremic travelers, epidemic attack rates range from 50% to 70%. Dengue is endemic in the lower Rio Grande Valley and adjacent border towns, with 40% of Brownsville, Texas residents showing serologic evidence of past infection and the virus being detected in mosquito larvae among 30% of households. The seroprevalence of Haitians by age 3 is over 53%.

Severe epidemics of dengue hemorrhagic fever (serotype 3) occurred over the past 20 years in East Africa, Sri Lanka, and Latin America. Dengue is the second most common cause of fever (after malaria) in travelers returning from developing countries. In one US series based on CDC reports, the highest proportion of laboratory-confirmed and probable cases were among travelers returning from the Dominican Republic (121 cases, 20% of total), Mexico (55 cases, 9% of total) and India (43 cases, 7% of total). The first European sustained outbreak of dengue since the 1920s occurred on the Portuguese archipelago of Madeira in 2012 with over 2000 people infected. In general, the more advanced forms of disease (hemorrhagic fever and shock) occur less often in the Americas than in Asia. Since the 1980s, locally acquired cases of dengue are reported from Guam, Puerto Rico, Samoa, the US Virgin Islands, and in the continental United States at the Texas-Mexico border, and Key West, Florida. Health care–associated transmission (needlestick, mucocutaneous exposure or transplant related) and vertical transmission occur rarely.

 Clinical Findings

  1. Symptoms and Signs

A history of travel to a dengue-endemic area within 14 days of symptom onset is helpful in establishing a diagnosis of dengue. Dengue infection may range from asymptomatic to severe hemorrhagic fever to fatal shock (dengue shock syndrome). Dengue fever is usually a nonspecific, self-limited biphasic febrile illness. More than half of infected children are asymptomatic. The illness is more severe and begins more suddenly in adults. After an incubation period of 4–5 days, there is a sudden onset of high fever, chills, and “break bone” aching of the head, back, and extremities accompanied by sore throat, prostration, and malaise. There may be conjunctival redness. Initially, the skin appears flushed or blotched, but 3–4 days after the lysis of the fever, a maculopapular rash, which spares palms and soles, appears in over 50% of cases. As the rash fades, localized clusters of petechiae on the extensor surface of the limbs become apparent. Up to 25% may manifest signs of cardiac involvement. Hepatitis frequently complicates dengue fever with acute fulminant hepatitis in up to 5%.

Dengue hemorrhagic fever usually affects children living in endemic areas and is most likely to occur in secondary infections and in infections with serotype 2. A few days into the illness, signs of hemorrhage such as ecchymoses, gastrointestinal bleeding, and epistaxis appear. Symptoms found more often among the dengue hemorrhagic fever subset of patients include restlessness, epistaxis, and abdominal pain. Gastroenterologic complications, including hemorrhage, tenderness, and ascites, are more common with dengue hemorrhagic fever and often require intensive care observation.

A subset of patients (more often girls than boys) often with secondary infection, may progress to severe dengue, which is defined by the presence of serum leakage, hemorrhage, or organ involvement (typically liver, heart, CNS). Acute fever, hemorrhagic manifestations, and marked capillary leak may be prominent, with the latter manifesting as pleural effusions and ascites, and there is a tendency for shock to develop. In infants, even primary infection can lead to dengue shock syndrome. While the infection is difficult to distinguish from malaria, yellow fever, or influenza, the rash makes dengue far more likely. Continuous abdominal pain with vomiting, bleeding, a decrease in the level of consciousness, rash, conjunctival congestion, and hypothermia should raise concern about dengue shock syndrome. Acute kidney injury in dengue largely occurs with dengue shock syndrome and shows a high mortality. While acute severe hepatitis can occur with dengue, concomitant other hepatotropic agents are usually responsible.

Distinguishing between dengue and other causes of febrile illness in endemic areas is difficult. Fevers due to dengue are more often associated with neutropenia and thrombocytopenia and with myalgias, arthralgias/arthritis, and lethargy among adults.

  1. Laboratory Findings

Leukopenia is characteristic, and elevated transaminases are found frequently in dengue fever. Thrombocytopenia, increased fibrinolysis, and hemoconcentration occur more often in the hemorrhagic form of the disease. Liver biochemical test abnormalities are nearly universal. Thrombocytopenia, plasma leakage, and acute hepatitis are identified as predictors of severe manifestations of dengue and higher mortality. The nonspecific nature of the illness mandates laboratory verification for diagnosis, usually with IgM and IgG ELISAs after the febrile phase. Virus may be recovered from the blood during the acute phase. PCR or detection of the specific viral protein NS1 by ELISA may be diagnostic during the first few days of infection and may be appropriate for febrile travelers. Immunohistochemistry for antigen detection in tissue samples and dried blood spots can also be used. Because the erythrocyte sedimentation rate is normal in most cases, elevation may suggest an alternative diagnosis. Chest radiographs in dengue hemorrhagic fever show infiltrates and effusions, which follow the course of laboratory abnormalities.

 Complications

Usual complications include pneumonia, bone marrow failure, hepatitis, iritis, retinal hemorrhages and maculopathy, orchitis, and oophoritis. Depression and chronic fatigue, occurring more often in older women, are also reported. Neurologic complications (such as encephalitis, Guillain-Barré syndrome, phrenic neuropathy, subdural hematoma, and transverse myelitis) are less common, although encephalitic complications are increasingly recognized. Aplastic anemia and hemophagocytosis syndrome are very rare complications. Dengue is rarely associated with stroke in patients with focal neurologic deficit and encephalopathy. Maternal infection poses a risk for premature birth and hemorrhage in both the mother and the infant if infection occurs near term.

Bacterial superinfection occurs more commonly with advanced age, higher fever, gastrointestinal bleeding, kidney disease, and altered consciousness.

 Treatment

Treatment entails the appropriate use of volume support, blood products, and pressor agents, and acetaminophen rather than nonsteroidal anti-inflammatory drugs for analgesia. Activities are gradually restored during prolonged convalescences. Endoscopic therapy is useful in evaluating and managing gastrointestinal hemorrhage, although injection therapy with sclerosing agents is not beneficial in most dengue hemorrhagic states. Platelet counts do not usefully predict clinically significant bleeding. Platelet transfusions, however, should be considered for severe thrombocytopenia (< 10,000/mcL) or when there is evidence of bleeding. Monitoring vital signs and blood volume may help in anticipating the complications of dengue hemorrhagic fever or shock syndrome.

The efficacy of corticosteroids in the management of dengue is not proven and corticosteroids do not appear to lessen the risk of progression to a shock state. There is anecdotal evidence for the efficacy of statins (which are under study) in the management of acute dengue and for the efficacy of intravenous anti-D globulin in the management of dengue hemorrhagic fever.

 Prognosis

Fatalities are rare but do occur (and more often among girls and the very young), especially during epidemic outbreaks, with occasional patients dying of fulminant hepatitis. Acute kidney injury in dengue shock syndrome portends an especially poor prognosis. Convalescence for most patients is slow. Factors associated with development of severe disease in Sri Lanka included elevated aspartate aminotransferase (AST), lymphopenia, and thrombocytopenia, while factors associated with mortality in Brazil included age 50 years or older, limited education, need for hospitalization, rural residency, male gender, and elevated hematocrit (but not moderate thrombocytopenia).

The 2009 classification of dengue into acute and severe has met with resistance.

 Prevention

Available prophylactic measures include control of mosquitoes by screening and insect repellents, particularly during early morning and late afternoon exposures. Testing of blood supplies is increasingly necessary especially in endemic areas as dengue spreads. Stochastic models using rainfall and temperature are useful in predicting geographic areas at increased risk for dengue.

A 2012 randomized, controlled trial in healthy Thai school children using a live attenuated, yellow fever backbone vaccine showed immunogenicity for all the serotypes and an overall efficacy of 30% (higher for serotypes 1, 3, and 4 and very low for serotype 2). A second live attenuated vaccine studied at the National Institutes of Health shows efficacy of at least 60%.

Anders KL et al. An evaluation of dried blood spots and oral swabs as alternative specimens for the diagnosis of dengue and screening for past dengue virus exposure. Am J Trop Med Hyg. 2012 Jul;87(1):165–70. [PMID: 22764309]

Chao DL et al. Controlling dengue with vaccines in Thailand. PLoS Negl Trop Dis. 2012;6(10):e1876. [PMID: 23145197]

Halstead SB. Dengue: the syndromic basis to pathogenesis research. Inutility of the 2009 WHO case definition. Am J Trop Med Hyg. 2013 Feb;88(2):212–5. [PMID: 23390220]

Sabchareon A et al. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet. 2012 Nov 3;380(9853):1559–67. [PMID: 22975340]

World Health Organization. Dengue: guidelines for diagnosis, treatment, prevention and control. New edition, 2009. http://whqlibdoc.who.int/publications/2009/9789241547871_eng.pdf

  1. Hantaviruses

 ESSENTIALS OF DIAGNOSIS

 Transmitted by rodents and cause two clinical syndromes.

 Hemorrhagic fever with renal syndrome (HFRS): mild to severe illness.

 Hantavirus pulmonary syndrome (HPS): 40% mortality rate.

 Ribavirin is used with some success in HFRS.

 General Considerations

Hantaviruses are enveloped RNA bunyaviruses naturally hosted in rodents, moles, and shrews. Currently, over 21 hantavirus strains are known to cause human disease. These differ in rodent hosts, geographic distribution, and degree of pathogenicity. Two major clinical syndromes are described: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Each year, over 150,000 cases of these two syndromes occur globally, with HPS being far less common. While they share many clinical features, a specific strain is not associated with a specific syndrome and overlap is seen between the syndromes. Usually seen in the southwestern United States, Sin Nombre virus (Muerto Canyon, Four Corners) is the most common hantavirus infection in the United States and is the main North American virus responsible for HPS. The presence of antibodies in Mexican rodents suggests HPS is probably unrecognized in Mexico. While retrospective diagnostics show that the disease occurred decades earlier in the United States, it was not until 1993 when the first outbreak was recognized. Through July 9, 2013, 624 cases were reported in 34 states, including all continental states west of the Mississippi River except Missouri and Arkansas, with over one-half the cases from the Four Corners area and another focus recognized in Yosemite National Park, California. Other strains native to North America known to cause HPS include Bayou, Black Creek Canal, New York, and Monongahela viruses. Outbreaks of HPS associated with other hantavirus types are also reported in Central and South America.

Hantaviruses are ubiquitous, with infections described in North and South America (New World hantaviruses) as well as Europe, Africa, and Asia (Old World hantaviruses). The Hantaan viruses cause severe hemorrhagic fever with renal syndrome and are found primarily in Korea, China, and eastern Russia. The Seoul viruses produce a less severe form of disease and are found primarily in Korea and China. Cases of domestically acquired Seoul hantavirus were recently described in the United States. The Puumala and Dobrava-Belgrade viruses are found in Scandinavia and Europe and are associated with a mild form of the syndrome termed “nephropathia epidemica,” which presents with fever, headache, gastrointestinal symptoms, and impaired kidney function. Between 16% and 48% of Dobrova-Belgrade virus cases, however, may require dialysis.

Aerosols of virus-contaminated rodent urine and feces are thought to be the main vehicle for transmission to humans. Person-to-person transmission is rare and confined to one hantavirus, the Andes virus. Occupation is the main risk factor for transmission of all hantavirus, with animal trappers, forestry workers, laboratory personnel, farmers, and military personnel considered to be at highest risk. Climate change appears to be impacting the incidence of hantavirus infection mainly through effects on reservoir ecology.

 Clinical Findings

  1. Symptoms and Signs

Vascular leakage is the hallmark of the disease for both syndromes, with lungs being the main target on HPS and the kidneys on HFRS.

HPS is a more severe disease than HFRS, with a mortality rate of about 40%. The clinical course of HPS is divided into a febrile prodrome, a cardiopulmonary stage, oliguric and diuretic phase followed by convalescence. A 14- to 17-day incubation period is followed by a prodromal phase, typically lasting 3–6 days, that is associated with myalgia, malaise, gastrointestinal disturbance, headache, chills, and fever of abrupt onset. An ensuing cardiopulmonary phase is characterized by the acute onset of pulmonary edema. In this stage, cough is generally present, gastrointestinal manifestations may dominate the clinical presentations, and in severe cases, significant myocardial depression occurs. Acute kidney injury and myositis may occur. Sequelae include neuropsychological impairments in some HPS survivors.

HFRS manifests as mild, moderate, or severe illness depending on the causative strain, with a mortality rate of up to 12%. A 2- to 3-week incubation period is followed by a protracted clinical course, typically consisting of five distinct phases: febrile period, hypotension, oliguria, diuresis, and convalescence phase. Various degrees of renal involvement are usually seen, occasionally with frank hemorrhage. Pulmonary edema is not typically seen but when present usually occurs in the final stages of disease (oliguric and diuretic phase). Encephalitis and pituitary involvement are rare findings with hantavirus infection, although a few cases are reported with Puumala virus.

  1. Laboratory Findings

Laboratory features include hemoconcentration and elevation in lactate dehydrogenase, serum lactate, and hepatocellular enzymes. Early thrombocytopenia and leukocytosis (as high as 90,000 cells/mcL in HPS) are seen in both HFRS and HPS. In HPS, immunoblasts (activated lymphocytes with plasmacytoid features) can be seen in blood, lungs, kidneys, bone marrow, liver, and spleen. The severity of “nephropathia epidemica” correlates with plasma interleukin-6 levels.

The viremia of human hantavirus infections is short-term, and therefore, viral RNA cannot be readily detected in the blood or urine of patients. An indirect fluorescent assay and enzyme immunoassay are available for detection of specific IgM or low-avidity IgG virus-specific antibodies. Seroconversion in the absence of pulmonary symptoms probably occurs often, is documented to be common in Panama.

A plaque reduction neutralization test is considered the gold standard serologic assay and distinguishes between the different hantavirus species, although cross reaction between Old World and New World viruses exist. This test needs to be performed in a laboratory with appropriate biosafety (level 3).

 Differential Diagnosis

The differential diagnosis of the acute febrile syndrome seen with HFRS or early HPS includes scrub typhus, leptospirosis, and dengue. HPS requires differentiation from other respiratory infections caused by such pathogens as Legionella, Chlamydia, and Mycoplasma. Coxsackievirus infections should also be considered in the differential diagnosis.

 Treatment

Treatment is mainly supportive. Cardiorespiratory support with vasopressors and sometimes extracorporeal membrane oxygenation are frequently needed in severe cases. Intravenous ribavirin is used in HFRS (Hantaan virus) with some success in decreasing the severity of the kidney injury. Its effectiveness in HPS, however, is not established. A randomized, controlled trial in Chile showed high-dose corticosteroids have no clinical benefit in the treatment of HPS and suggests there may be no benefit with HFRS as well.

 Prognosis

The outcome is highly variable depending on severity of disease. In Sin Nombre virus infections, the persistence of elevated IgG titers correlates with a favorable outcome.

 Prevention

Because infection is thought to occur by inhalation of rodent wastes, prevention is aimed at eradication of rodents in houses and avoidance of exposure to rodent excreta in rural settings, including forest service facilities. Potential vaccines are being studied in animals.

Hartline J et al. Hantavirus infection in North America: a clinical review. Am J Emerg Med. 2013 Jun;31(6):978–82. [PMID: 23680331]

Hooper JW et al. A novel Sin Nombre virus DNA vaccine and its inclusion in a candidate pan-hantavirus vaccine against hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS). Vaccine. 2013 Sep 13;31(40):431421. [PMID: 23892100]

Knust B et al. Twenty-year summary of surveillance for human hantavirus infections, United States. Emerg Infect Dis. 2013 Dec;19(12):1934–7. [PMID: 24274585]

Vaheri A et al. Hantavirus infections in Europe and their impact on public health. Rev Med Virol. 2013 Jan;23(1):35–49. [PMID: 22761056]

Vial PA et al; Hantavirus Study Group in Chile. High-dose intravenous methylprednisolone for hantavirus cardiopulmonary syndrome in Chile: a double-blind, randomized controlled clinical trial. Clin Infect Dis. 2013 Oct;57(7):943–51. [PMID: 23784924]

  1. Yellow Fever

 ESSENTIALS OF DIAGNOSIS

 Endemic area exposure (tropical South and Central America, Africa, but not Asia).

 Sudden onset of severe headache, aching in legs, and tachycardia.

 Brief (1 day) remission, followed by bradycardia, hypotension, jaundice, hemorrhagic tendency.

 Proteinuria, leukopenia, bilirubinemia, bilirubinuria.

 Rare and potentially fatal reactions to vaccination.

 General Considerations

Yellow fever is a zoonotic flavivirus infection transmitted by Aedes and jungle mosquitoes. It occurs in an urban and jungle cycle in Africa and in a jungle cycle in South America (where genetic studies suggest it arose through the slave trade 300–400 years ago). Epidemics have extended far into the temperate zone during warm seasons.

Infection is transmitted by an infected mosquito bite. The incubation period in humans is 3–6 days. Adults and children are equally susceptible, though attack rates are highest among adult males because of their work habits. Between 5% and 50% of infections are asymptomatic.

 Clinical Findings

  1. Symptoms and Signs
  2. Mild form—Symptoms are malaise, headache, fever, retroorbital pain, nausea, vomiting, and photophobia. Relative bradycardia, conjunctival injection, and facial flushing may be present.
  3. Severe form—Severe illness develops in about 15%. Initial symptoms are similar to the mild form, but a brief fever remission lasting hours to a few days is followed by a “period of intoxication” manifested by fever and relative bradycardia (Faget sign), hypotension, jaundice, hemorrhage (gastrointestinal, nasal, oral), and delirium that may progress to coma.
  4. Laboratory Findings

Leukopenia occurs, although it may not be present at the onset. Kidney disease with proteinuria is present, sometimes as high as 5–6 g/L, and usually disappears completely with recovery. Levels of liver enzymes and bilirubin can be remarkably abnormal with the levels of AST usually doubling those of alanine aminotransferase (ALT). Prothrombin time may be elevated as well. Serologic diagnosis is made by using capture ELISA to measure IgM during the acute and convalescent phases. Viral culture is used in epidemic settings. Rapid test involving PCR and monoclonal antibodies assays against circulating viral antigens are available through reference laboratories. The plaque reduction neutralization assay is the most frequently used. IgM antibodies are shown to persist in up to 73% of recipients 3–4 years after vaccination.

 Differential Diagnosis

It may be difficult to distinguish yellow fever from hepatitis, malaria, leptospirosis, louse-borne relapsing fever, dengue, and other hemorrhagic fevers on clinical evidence alone. Albuminuria is a constant feature in yellow fever patients and its presence helps differentiate yellow fever from other viral hepatitides. Serologic confirmation is often needed.

 Treatment

No specific antiviral therapy is available. Treatment is directed toward symptomatic relief and management of complications. If not in an endemic area, the patient should be isolated from mosquitoes to prevent transmission, since blood in the acute phase is potentially infectious.

 Prognosis

The mortality rate of the severe form is 20–50%, with death occurring most commonly between the sixth and the tenth days. In survivors, the temperature returns to normal by the seventh or eighth day. The prognosis in any individual case is guarded at the onset, since sudden changes for the worse are common. Intractable hiccups, copious black vomitus, melena, anuria, jaundice, and elevated AST are unfavorable signs. Convalescence is prolonged, including 1–2 weeks of asthenia. Infection confers lifelong immunity to those who recover.

 Prevention

Transmission is prevented through mosquito control. Live virus vaccine is highly effective and should be provided for immunocompetent persons over 9 months of age living in or traveling to endemic areas. In one study of US international travelers visiting a yellow fever endemic country, only 70% were adequately vaccinated. The highest rate of seroconversion occurs 21 days after administration. Boosting at 10-year intervals, as advocated in the past, is not necessary because a single dose of vaccine provides life-long immunity. Vaccine-induced reactions—including neurotropic (encephalitis-like syndrome) and viscerotropic (resembling yellow fever; with one space-time cluster of viscerotropic disease among five patients with four deaths reported from Ica, Peru in 2007) diseases—are reported particularly among patients aged 60 years or older, patients with immune dysfunction or with multiple sclerosis (whose rate of exacerbation in increased 1–5 weeks after vaccination). The very young (< 6 months) and the aged should probably not be vaccinated and those with immune dysfunction or multiple sclerosis should not be vaccinated, although HIV-infected persons with high CD4 counts safely receive the vaccine with an adverse event rate of about 3%. The safety of the vaccine in pregnant patients is probable but not verified; it is possible that minor dysmorphisms, including pigmented nevi, are increased in frequency but this may be a bias of evaluation. Pregnant women should consider deferring travel to endemic areas (see Chapter 30). Eradication is difficult because of the sylvatic cycle (mainly maintained by non-human primates). Transmission from mother to infant during breastfeeding is documented.

The vaccine is prepared in hen eggs and those with egg allergies can be successfully desensitized.

Carrington CV et al. Evolutionary and ecological factors underlying the tempo and distribution of yellow fever virus activity. Infect Genet Evol. 2013 Jan;13:198–210. [PMID: 22981999]

Heinz FX et al. Flaviviruses and flavivirus vaccines. Vaccine. 2012 Jun 19;30(29):4301–6. [PMID: 22682286]

Hodges-Vazquez M et al. The yellow fever 17D vaccine and risk of malignant melanoma in the United States military. Vaccine. 2012 Jun 22;30(30):4476–9. [PMID: 22561488]

Jentes ES et al; Global TravEpiNet Consortium. Travel characteristics and yellow fever vaccine usage among US Global TravEpiNet travelers visiting countries with risk of yellow fever virus transmission, 2009–2011. Am J Trop Med Hyg. 2013 May;88(5):954–61. [PMID: 23458961]

LaRocque RC et al. Global TravEpiNet: a national consortium of clinics providing care to international travelers—analysis of demographic characteristics, travel destinations, and pretravel healthcare of high-risk US international travelers, 2009–2011. Clin Infect Dis. 2012 Feb 15;54(4):455–62. [PMID: 22144534]

Patel D et al. Yellow fever vaccination: is one dose always enough? Travel Med Infect Dis. 2013 Sep–Oct;11(5):266–73. [PMID: 24074827]

Rutkowski K et al. Administration of yellow fever vaccine in patients with egg allergy. Int Arch Allergy Immunol. 2013;161(3):274–8. [PMID: 23548550]

Thomas RE et al. The safety of yellow fever vaccine 17D or 17DD in children, pregnant women, HIV+ individuals, and older persons: systematic review. Am J Trop Med Hyg. 2012 Feb;86(2):359–72. [PMID: 22302874]

World Health Organization. Vaccines and vaccination against yellow fever. WHO position paper—June 2013. Wkly Epidemiol Rec. 2013 Jul 5;88(27):269–83. [PMID: 23909008]

  1. Tick-Borne Encephalitis

 ESSENTIALS OF DIAGNOSIS

 Flaviviral encephalitis found in Eastern, Central, and occasionally Northern Europe and Asia.

 Transmitted via ticks or ingestion of unpasteurized milk.

 Long-term neurologic sequelae occur in 2–25% of cases.

 Therapy is largely supportive.

 Prevention is based on avoiding tick exposure, pasteurization of milk, and vaccination.

 General Considerations

Tick-borne encephalitis (TBE), a flaviviral infection caused by TBE virus, is the most common arbovirus infection transmitted by ticks in Europe. An estimated 10,000 to 12,000 cases occur each year in parts of Eurasia (from eastern France to northern Japan, from northern Siberia to Albania), with annual increases thought to be a function of increased recognition, climatic changes, and personal or social habits. TBE is endemic in Japan and parts of China as well. TBE occurs predominantly in the late spring through fall. It is usually a consequence of exposure to infected ticks, although unpasteurized milk from viremic livestock is also a recognized form of transmission. Surges in cases over the last 20 years are thought to be a consequence of agricultural policies that alter land cover, host prevalence, climatic factors, and human behavior (including pesticide usage and travel to endemic areas). In recent years, the maximum altitude for occurrence of cases has increased to 5000 feet (about 1500 meters). The incubation period is 7–14 days for tick-borne exposures but only 3–4 days for milk ingestion. The principal reservoirs for TBE virus are small rodents; humans are an accidental host. The vectors for most cases are Ixodes ricinus (most of Europe, including Turkey, Iran, and the Caucasus) and Ixodes persulcatus (in the belt from Eastern Europe to China and Japan).

Related viruses found in Eastern and mid-Western North America are the Powassan agent and the deer tick virus. Increasing prevalence of deer ticks in North America is thought to be responsible for the increased (but still small) number of North American cases of these two serologically indistinguishable viruses.

 Clinical Findings

  1. Symptoms and Signs

Most cases are subclinical and many resemble a flu-like syndrome. There are two variants of clinical presentation: the Western subtype occurs mainly in the fall (but as early as April) and is most severe among the elderly, and the Eastern subtype is more severe among children.

Western subtype disease is biphasic in which after 2–10 days of fever (usually with malaise, headache, and myalgias), a 1–21 day symptom-free interval leads to a second phase with resumed fevers followed by neurologic symptoms. Eastern subtype disease is progressive without an asymptomatic interval. The neurologic manifestations range from febrile headache (accounting for up to 50% of Eastern subtype cases) to aseptic meningitis and encephalitis with or without myelitis (preferentially of the cervical anterior horn) and spinal paralysis (usually flaccid). A myeloradiculitic form can also develop but is less common. Peripheral facial palsies, sometimes bilaterally, tend to occur infrequently, late in the course of infection, usually after encephalitis, and usually are associated with a favorable outcome within 30–90 days. Double infection with Borrelia burgdorferi (the agent of Lyme disease; transmitted by the same tick vector) may result in a more severe disease. Mortality in TBE is usually a consequence of brain edema or bulbar involvement.

  1. Diagnosis

Leukocytosis and neutrophilia are common. Abnormal cerebrospinal fluid findings include a pleocytosis that may persist for up to 4 months. Neuroimaging shows hyperintense lesions in the thalamus, brainstem, and basal ganglia. TBE virus IgM and IgG are detected by ELISA techniques when neurologic symptoms occur. Cross-reactivity with other flaviviruses or a vaccinated state (see below) may require confirmation by detection of TBE virus–specific antibodies in cerebrospinal fluid. RT-PCR of blood (at earlier stages of the disease) or cerebrospinal fluid can sometimes, if available, assist with the diagnosis. TBE virus can be differentiated from serologically indistinguishable viruses (Powassan agent and deer tick virus) by plaque-reduction neutralization tests.

 Complications

The main sequela of disease is paresis, which occurs in up to 10% of Western and up to 25% of Eastern subtype disease. Other causes of long-term morbidity include protracted cognitive dysfunction and persistent spinal nerve paralysis. The postencephalitic syndrome, characterized by headache, difficulties concentrating, balance disorders, dysphasia, hearing defects, and chronic fatigue, occurs with both subtypes. A progressive motor neuron disease and partial continuous epilepsy are complications seen with the Eastern subtype. Cognitive impairments may develop in children after infection.

 Differential Diagnosis

The differential diagnosis includes other causes of aseptic meningitis such as enteroviral infections, herpes simplex encephalitis, and a variety of tick-borne pathogens including tularemia, the rickettsial diseases, babesiosis, Lyme disease, poliomyelitis (no longer reported from Eastern Europe), and other flaviviral infections.

 Treatment

Therapy is largely supportive. Some clinicians believe corticosteroids may be useful, although no controlled clinical trials exist.

 Prevention

There are two inactivated TBE virus vaccines for adults and two vaccines for children licensed in Europe. Their effectiveness is about 99% when properly administered but cannot be given concomitantly because of immune interference. The initial vaccination schedule requires 1 year with boosters every 3–5 years. There are decreased antibody titers (quantity not quality) and booster response in recipients of TBE vaccines who are over 50 years of age, indicating the need for a modified immunization strategy in older patients.

Vaccine efficacy has been most prominent in Austria where case loads are less than 16% of pre-vaccination numbers. Neuritis and neuropathies of peripheral nerves (plexus neuropathy—paresis of lower limb muscles, polyradiculopathy) are recognized complications of TBE vaccination. Rare cases of olfactory dysfunction and myelitis are also reported. A single-dose live attenuated vaccine with a West Nile virus backbone is under development.

Other prevention recommendations include avoidance of tick exposure and pasteurization of cow and goat milk.

Centers for Disease Control and Prevention (CDC). Tick-borne encephalitis among U.S. travelers to Europe and Asia—2000–2009. MMWR Morb Mortal Wkly Rep. 2010 Mar 26;59(11):335–8. [PMID: 20339345]

Fowler Å et al. Tick-borne encephalitis carries a high risk of incomplete recovery in children. J Pediatr. 2013 Aug;163(2):555–60. [PMID: 23452585]

Hudopisk N et al. Tick-borne encephalitis associated with consumption of raw goat milk, Slovenia, 2012. Emerg Infect Dis. 2013 May;19(5):806–8. [PMID: 23697658]

Lotric-Furlan S et al. Peripheral facial palsy in patients with tick-borne encephalitis. Clin Microbiol Infect. 2012 Oct;18(10):1027–32. [PMID: 22192120]

Rumyantsev AA et al. Single-dose vaccine against tick-borne encephalitis. Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):13103–8. [PMID: 23858441]

World Health Organization. Vaccines against tick-borne encephalitis: WHO position paper—recommendations. Vaccine. 2011 Nov 8;29(48):8769–70. [PMID: 21777636]

  1. Colorado Tick Fever

 ESSENTIALS OF DIAGNOSIS

 Onset 1–19 days (average, 4 days) following tick bite.

 Fever, chills, myalgia, headache, prostration.

 Leukopenia, thrombocytopenia.

 Second attack of fever after remission lasting 2–3 days.

 General Considerations

Colorado tick fever is a reportable biphasic, febrile illness caused by a reovirus infection transmitted by Dermacentor andersoni tick bite. The disease is limited to the western United States and Canada and is most prevalent during the tick season (March to November). There is a discrete history of tick bite or exposure in 90% of cases. The virus infects the marrow erythrocyte precursors, leading to viremia lasting the life span of the infected red cells. Blood transfusions can be a vehicle of transmission.

 Clinical Findings

  1. Symptoms and Signs

The incubation period is 3–6 days, rarely as long as 19 days. The onset is usually abrupt with fever (to 38.9–40.6°C), sometimes with chills. Severe myalgia, headache, photophobia, anorexia, nausea and vomiting, and generalized weakness are prominent. Physical findings are limited to an occasional faint rash. The acute symptoms resolve within a week. Remission is followed in 50% of cases by recurrent fever and a full recrudescence lasting 2–4 days. In an occasional case, there may be three bouts of fever.

The differential diagnosis includes influenza, Rocky Mountain spotted fever, numerous other viral infections and, in the right setting, relapsing fevers.

  1. Laboratory Findings

Leukopenia (2000–3000/mcL) with a shift to the left and atypical lymphocytes occurs, reaching a nadir 5–6 days after the onset of illness. Thrombocytopenia may occur. Viremia may be demonstrated by inoculation of blood into mice or by fluorescent antibody staining of the patient’s red cells (with adsorbed virus). An RT-PCR assay may be used to detect early viremia. Detection of IgM by capture ELISA or plaque reduction neutralization is possible after 2 weeks from symptom onset and is the most frequently used diagnostic tool.

 Complications

Aseptic meningitis (particularly in children), encephalitis, and hemorrhagic fever occur rarely. Malaise may last weeks to months. Fatalities are very uncommon. Rarely, spontaneous abortion or multiple congenital anomalies may complicate Colorado tick fever infection acquired during pregnancy.

 Treatment

No specific treatment is available. Ribavirin has shown efficacy in an animal model. Antipyretics are used, although salicylates should be avoided due to potential bleeding with the thrombocytopenia seen in patients with Colorado tick fever. Tick avoidance is the best prevention.

 Prognosis

The disease is usually self-limited and benign.

 Prevention

The essence of prevention is vector (tick) control, particularly from March to November.

  1. Chikungunya Fever

Chikungunya (“that which bends up” in Bantu) fever is a flaviviral infection transmitted to humans by Aedes aegypti and Aedes albopictus (the “Asian tiger mosquito”) and is considered a classic “arthrogenic” virus. The virus is indigenous to tropical Africa and Asia with recent outbreaks reported from areas that adjoin the Indian Ocean, Southeast Asia and its neighboring islands (2005–2007), South India (2005) a major outbreak in Reunión Island (where women and recent immigrants from France were preferentially infected), but also from Europe (2007) including cases in Italy and France. In 2013, the first cases of locally-acquired Chikungunya Fever were found on islands in the Caribbean with a small number of travelers to that area diagnosed in Florida in 2014. The attack rates are often as high as 50%. Corneal transplants were a source of the outbreak on Reunión. Vertical transmission is documented, but teratogenicity is not established. The endemicity of A aegypti in the Americas and the introduction of A albopictus into Europe and the New World raise the concerns of a global extension of the epidemic. The Rh-negative population appears to be immune. There are reports of cases of Chikungunya coinfection with yellow fever, malaria, and dengue fever.

 Clinical Findings

  1. Symptoms and Signs

After an incubation period of 1–12 days (average 2–4), there is an abrupt onset of fever; headache; intestinal complaints; myalgias; and arthralgias/arthritis affecting small, large, and axial joints. The simultaneous involvement of more than 10 joints and the presence of tenosynovitis (especially in the wrist) are characteristic. The stooped posture of patients gives the disease its name. Joint symptoms persist for 4 months in 33% and linger for years in about 10%. A centrally distributed pigmented or pruritic maculopapular rash is reported in 50% of the patients, but it can be bullous with sloughing in children. Mucosal disease occurs in about 15%. Facial edema and localized petechiae are reported. Neurologic complications, including encephalitis, myelopathy, peripheral neuropathy, myeloneuropathy, and myopathy, are usually associated with a good outcome. In infants, primary manifestations of disease include fever, lethargy, acrocyanosis, and erythema evolving into vesiculobullous lesions. Hemorrhagic fever–like presentations are exceptional. Coinfection with other respiratory viruses, in particular dengue, is common. Death is rare and usually related to underlying comorbidities.

  1. Laboratory Findings

Diagnosis is made epidemiologically and clinically. Mild leukopenia occurs as does thrombocytopenia, which is seldom severe. Elevated inflammatory markers do not correlate well with the severity of arthritis. Radiographs of affected joints are normal.

Serologic confirmation requires elevated IgM titers or fourfold increase in convalescent IgG levels using an ELISA. RT-PCR and culture techniques (viral isolation in insect or mammalian cell lines or by inoculation of mosquitoes or mice) are seldom available. Suspected cases in the United States should be promptly reported to public health authorities including the CDC Arboviral Diseases Branch, 970-221-6400. The differential includes other tropical febrile diseases, such as malaria, leishmaniasis, or dengue.

 Complications

A major complication of Chikungunya fever is long-term weakness, asthenia, and arthritis, noted to occur in up to 66.5% of cases at 1-year in a series from Italy but in between 4% and 25% in series from India.

 Treatment & Prevention

Treatment is largely supportive with nonsteroidal anti-inflammatory drugs. Chloroquine may be useful for managing refractory arthritis. No vaccine is available, and prevention relies on avoidance of the mosquito vectors. Transplantation of tissue from immigrants or from travelers to known endemic areas such as Reunión should be discouraged. Prophylaxis with specific Chikungunya immunoglobulins may be useful for exposed neonates or immunosuppressed persons. Establishing the immunopathologic profile of acute versus chronic cases, new trials with immunoglobulins and vaccine development are ongoing areas of investigation.

Kucharz EJ et al. Chikungunya fever. Eur J Intern Med. 2012 Jun;23(4):325–9. [PMID: 22560378]

Moro ML et al. Long-term chikungunya infection clinical manifestations after an outbreak in Italy: a prognostic cohort study. J Infect. 2012 Aug;65(2):165–72. [PMID: 22522292]

Schilte C et al. Chikungunya virus-associated long-term arthralgia: a 36-month prospective longitudinal study. PLoS Negl Trop Dis. 2013;7(3):e2137. [PMID: 23556021]

Weaver SC et al. Chikungunya virus and prospects for a vaccine. Expert Rev Vaccines. 2012 Sep;11(9):1087–101. [PMID: 23151166]

COMMON VIRAL RESPIRATORY INFECTIONS

  1. Respiratory Syncytial Virus (RSV) & Other Paramyxoviruses

 ESSENTIALS OF DIAGNOSIS

 RSV is a major cause of morbidity and mortality at the extremes of age.

 Care for patients with RSV infections is largely supportive.

 A monoclonal antibody against RSV, palivizumab, is good but expensive prophylaxis among patients with certain at-risk cardiopulmonary conditions.

 No active vaccination for RSV is available to date.

 General Considerations

Respiratory syncytial virus (RSV) is a paramyxovirus that causes annual outbreaks during the wintertime with usual onset of pulmonary symptoms between mid October and early January in the continental United States (excluding Florida). Outside the United States, RSV usually peaks during wet months in areas with high annual precipitation and during cooler months in hot and dry areas. There are two major subtypes, A and B, and it appears that the A genotype is associated with disease severity. RSV is the leading cause of hospitalization in US children, with annual hospitalization rates of 17 per 1000 children under 6 months and 3 per 1000 children under 5 years of age. Risk factors for infection in children include prematurity, low birth weight, younger age (especially younger than 6 months), bronchopulmonary dysplasia, congenital heart disease, later birth order, and day care exposure. HIV-infected children are at higher risk for hospitalization and poorer outcomes than uninfected children. RSV infection in children is associated with persistence of airway reactivity later in life.

RSV also causes upper and lower respiratory tract infection in adults with increased severity in the elderly, persons with severe combined immunodeficiency, and following lung or bone marrow transplantation (because CD8 T cells are not available for viral clearance). Recurrent infections occur throughout life. The virus enters through contact with mucosal surfaces. The average incubation period is 5 days.

In immunocompromised patients, such as bone marrow transplant recipients, serious pneumonia can occur and outbreaks with a high mortality rate (> 70%) are reported.

Other paramyxoviruses important in human disease include human metapneumovirus, parainfluenza virus, and Nipah virus.

Human metapneumovirus is less common and less pathogenic than RSV in children and is mainly a seasonal virus circulating during late winter to early spring. It is divided into subgroups A and B. Clinical presentations include mild upper respiratory tract infections to severe lower respiratory tract infections (eg, bronchiolitis, croup, and pneumonia) among slightly older children and lower respiratory tract (sometimes severe) infections among immunocompromised and elderly adults. In lung transplant recipients, human metapneumovirus is a common cause of respiratory illness and is thought to increase the risk of acute and chronic graft rejection.

Human parainfluenza viruses (HPIVs) are commonly seen in children and are the most common cause of laryngotracheitis (croup). Four different serotypes are described, and they differ in their clinical presentations as well as epidemiology. HPIV-1 and HPIV-2 are responsible for croup. HPIV-3 is associated with bronchiolitis and pneumonia. HPIV-4 is a less frequently reported pathogen. Reinfections are common throughout life. HPIVs can also cause severe disease in the elderly, immunocompromised persons, and those with chronic illnesses.

Nipah virus, is a highly virulent paramyxovirus first described in 1999. Cases are concentrated mainly in Southeast Asia (Malaysia, Singapore, Bangladesh and India). Fruit bats are identified as the natural host of the virus. Direct pig-human, cow-human, human-human, and nosocomial transmission are reported. Nipah virus causes acute encephalitis with a high fatality rate (67–92%), although respiratory symptoms are also described. Cranial nerves palsies, encephalopathy, and dystonia are among neurologic sequelae (15–32%) seen on infected individuals. Relapses occurring weeks and months after initial infection are described (3.4–7.5%).

Bocavirus infections are discussed under Erythrovirus (parvovirus) infections below.

 Clinical Findings

  1. Symptoms and Signs

In RSV bronchiolitis, proliferation and necrosis of bronchiolar epithelium develop, producing obstruction from sloughed epithelium and increased mucus secretion. An interleukin-1 receptor polymorphism is shown to be associated with more severe bronchiolitis. Signs of infection include low-grade fever, tachypnea, and wheezes. Apnea is a common presenting symptom. Hyperinflated lungs, decreased gas exchange, and increased work of breathing are present. In children, RSV is globally the most common cause of acute lower respiratory infection and also a common cause of acute and recurrent otitis media. In patients with Down syndrome, RSV develops at a later age and is associated with more protracted hospitalizations.

  1. Laboratory Findings

A rapid diagnosis of RSV infection is made by viral antigen identification of nasal washings using an ELISA or immunofluorescent assay. PCR is increasingly used in many pediatric centers. Coinfection with bacteria is relatively uncommon in industrialized countries although Clostridium difficile–associated diarrhea is documented to occur after RSV infections in a Canadian study. Coinfection withBordetella pertussis and other viruses occurs in a subset of patients hospitalized for RSV infection. Tests for rapid detection of viral antigens with immunofluorescence or ELISA, and PCR techniques are also widely available although detection of parainfluenza by culture is also possible. RSV viral load assay values at day 3 of infection may correlate with requirement of intensive care and respiratory failure in children.

Human metapneumovirus is best diagnosed by PCR. ELISA (serum and cerebrospinal fluid) and PCR (urine, respiratory secretions but not blood) are both used for Nipah virus infection diagnosis.

 Treatment & Prevention

Treatment of RSV consists of supportive care, including hydration, humidification of inspired air, and ventilatory support as needed. Neither bronchodilating agents nor corticosteroids have demonstrated efficacy in bronchiolitis although individual patients with significant bronchospasm or history of asthma might respond to them.

The use of aerosolized ribavirin can be considered in high-risk patients, such as those with a history of bone marrow transplantation, and appears to lessen mortality. Pregnant women, including hospital staff, should avoid ribavirin exposure. Therapy with surfactant lacks evidence to make recommendations on its use. In the United States, RSV immunoglobulin G is no longer available and has been replaced with palivizumab, a monoclonal RSV antibody. Prophylactic administration of palivizumab (15 mg/kg intramuscularly monthly during the season of high transmission) is recommended for infants with high-risk factors, such as chronic lung disease of prematurity, bronchopulmonary dysplasia, and congenital heart disease. There are data to support the use of palivizumab in upper airway anomalies, other pulmonary diseases, and cystic fibrosis as well as in children with Down syndrome. Future studies may entail the use of small inhibitory RNA molecules and variants of palivizumab that target prefusion proteins.

No RSV vaccine is licensed to date. An encouraging phase 1 study using RSV fusion protein (F) shows that it is well tolerated and induces high levels of several antibodies associated with decreased rates of hospitalization. The use of RNA interference therapy in lung transplant patients may have some beneficial effects.

Prevention in hospitals entails rapid diagnosis, hand-washing, contact isolation, and perhaps passive immunization. The use of conjugated pneumococcal vaccination appears to decrease the incidence of concomitant pneumonia associated with viral infections in children in some countries.

Therapeutic modalities for human metapneumovirus and parainfluenza virus infections under investigation include intravenous ribavirin administration. During the initial Nipah virus outbreak, ribavirin was used empirically, although its efficacy remains questionable. Humanized monoclonal antibodies used in animal models show promising results.

Chu HY et al. Respiratory syncytial virus disease: prevention and treatment. Curr Top Microbiol Immunol. 2013;372:235–58. [PMID: 24362693]

El Saleeby CM et al. Respiratory syncytial virus load, viral dynamics, and disease severity in previously healthy naturally infected children. J Infect Dis. J Infect Dis. 2011 Oct 1;204(7):996–1002. [PMID: 21881113]

Glenn GM et al. Safety and immunogenicity of a Sf9 insect cell-derived respiratory syncytial virus fusion protein nanoparticle vaccine. Vaccine. 2013 Jan 7;31(3):524–32. [PMID: 23153449]

Haynes AK et al. Respiratory syncytial virus circulation in seven countries with Global Disease Detection Regional Centers. J Infect Dis. 2013 Dec 15;208(Suppl 3):S246–54. [PMID: 24265484]

Moyes J et al; South African Severe Acute Respiratory Illness Surveillance Group. Epidemiology of respiratory syncytial virus-associated acute lower respiratory tract infection hospitalizations among HIV-infected and HIV-uninfected South African children, 2010–2011. J Infect Dis. 2013 Dec 15;208 (Suppl 3):S217–26. [PMID: 24265481]

Sánchez-Solis M et al. Is palivizumab effective as a prophylaxis of respiratory syncytial virus infections in cystic fibrosis patients? A meta-analysis. Allergol Immunopathol (Madr). 2013 Nov 11. [Epub ahead of print] [PMID: 24231153]

Waghmare A et al. Respiratory syncytial virus lower respiratory disease in hematopoietic cell transplant recipients: viral RNA detection in blood, antiviral treatment, and clinical outcomes. Clin Infect Dis. 2013 Dec;57(12):1731–41. [PMID: 24065324]

  1. Seasonal Influenza

 ESSENTIALS OF DIAGNOSIS

 Cases usually in epidemic pattern.

 Onset with fever, chills, malaise, cough, coryza, and myalgias.

 Aching, fever, and prostration out of proportion to catarrhal symptoms.

 Leukopenia.

 General Considerations

Influenza (an orthomyxovirus) is a highly contagious disease transmitted by the respiratory route in humans. Transmission occurs primarily by droplet nuclei rather than fomites or direct contact. There are three types of influenza viruses. While type A can infect a variety of mammals (humans, swine, horses, etc) and birds, types B and C almost exclusively infect humans. Type A viruses are further divided into subtypes based on the hemagglutinin (H) and the neuraminidase (N) expressed in their surface. There are 18 subtypes of hemagglutinin and 10 subtypes of neuraminidase. Annual epidemics usually appear in the fall or winter in temperate climatic areas (although sporadic cases occur as summer outbreaks in northern areas such as Alaska or the southern hemisphere). Epidemics affect 10–20% of the global population on average each year and are typically the result of frequent minor antigenic variations of the virus, or antigenic drift, which are more common in influenza A virus. On the other hand, pandemics—associated with higher mortality—appear at longer and varying intervals (decades) as a consequence of a major genetic reassortment of the virus (antigenic shift) or the mutation of an avian virus that adapts to the human (as with the pandemic virus of 1918 with H1N1 properties).

The main circulating seasonal influenza viruses that are the target of current vaccines are a human-origin A (H3N2) subtype (H3N2 from 2011, A/Victoria/361/2011), the 2009 H1N1 strain (which replaced the seasonal H1N1 variants that circulated before 2009, A/California/7/2009) and two lineages of type B (B/Brisbane/60/2008 and B/Massachusetts/2/2012). The highly pathogenic avian (H5N1) and the H7N9 subtypes are discussed in the next section. The novel swine-origin influenza A (pandemic H1N1) virus, which emerged in Mexico in March 2009, and quickly spread through North America, is of particular concern, as with other pathogenic influenza viruses for pregnant women and immunosuppressed persons.

The outbreak of swine-origin (H1N1) influenza virus (formerly Swine-Origin Influenza Virus [S-OIV] or H1N1/A/California/04/2009, currently “A [H1N1] pdm09”) emerged in Mexico City in March 2009. After initially spreading in the United States and Canada, the virus spread globally with cases reported from over 40 nations by mid-2009. The WHO declared a pandemic on June 11, 2009, which lasted until August 10, 2010. This was the first pandemic since 1968 with circulation outside the usual influenza season in the Northern Hemisphere. The 2009 pandemic H1N1 influenza virus replaced seasonal A (H1N1), previously the most common disease causing subtype was influenza A. It is estimated that this strain will continue to spread for years to come, akin to past spreading of seasonal influenza viruses. This virus originates from triple-reassortment North American swine, human and avian virus lineages and Eurasian swine virus lineages.

 Clinical Findings

  1. Symptoms and Signs

Seasonal influenza viruses of types A and B produce clinically indistinguishable infections, whereas type C usually causes a minor illness. The incubation period is 1–4 days. In unvaccinated persons, uncomplicated influenza often begins abruptly. Symptoms include fever, chills, malaise, myalgias, substernal soreness, headache, nasal stuffiness, and occasionally nausea. Fever lasts 1–7 days (usually 3–5). Coryza, nonproductive cough, and sore throat are present. Elderly patients may present with only lassitude and confusion, often without fever or respiratory symptoms. Signs include mild pharyngeal injection, flushed face, and conjunctival redness. Moderate enlargement of the cervical lymph nodes may be observed. The presence of fever (> to 38.2°C) and cough during influenza season is highly predictive of influenza infection in those older than 4 years of age.

The pandemic 2009 strain of H1N1 showed a similarly broad range of clinical symptoms ranging from typical symptoms (fever, malaise, myalgias, cough, sore throat, rhinorrhea, shortness of breath) commonly accompanied by gastrointestinal (especially diarrhea) and respiratory (pneumonia) manifestations. The principal clinical syndrome leading to hospitalization and ICU admission is diffuse viral pneumonitis with severe hypoxemia and sometimes shock and renal failure. Neurologic complications, including seizures and encephalopathy, and cardiac dysfunction, including myocarditis and pulmonary thromboemboli, have occurred. While most patients with asthma have uncomplicated courses, asthmatic patients with pneumonia are at higher risk for ICU admission and death. Cases with pandemic H1N1 associated hemophagocytic syndrome are reported. Most patients with mild disease make full recovery, but 9–31% of hospitalized cases require ICU admission, where the mortality ranges between 14% and 46%. Adult hospitalized patients with H1N1 infection, when compared with patients with seasonal influenza, show statistically more significant complications and a higher mortality despite younger age. The disease has an incubation period of 1.5 to 7 days.

Attack rates with this pandemic strain are highest in children and young adults, particularly Hispanics, blacks, and Native Americans, with relative sparing of adults older than 60 years of age presumably due to previous exposure with related strains (conferring some degree of cross-protection). High-risk groups include patients with severe obesity, asthma, immunosuppression, or neurologic disorders, and especially pregnant and postpartum women. Infection during pregnancy increases the risk for hospitalization and may be associated with severe illness, sepsis, pneumothorax and respiratory failure, spontaneous abortion, preterm labor, and fetal distress. Overall case fatality rate is < 0.5% with 90% of deaths in those under 65 years of age and higher mortality recognized among men and patients with liver disease or a cancer diagnosis within the last year.

  1. Laboratory Findings

Leukopenia is common, but leukocytosis can occur. Proteinuria may be present. The virus may be isolated from throat swabs or nasal washings by inoculation of embryonated eggs or cell cultures. Rapid immunofluorescence assays and enzyme immunoassays for detection of influenza antigens from nasal or throat swabs are becoming widely available. The sensitivity of such assays is suboptimal (at most 60–80%), especially among adults, and with very significant intertest variability, only a few can distinguish between influenza A and B. More sensitive nucleic acid (PCR) techniques are increasingly accessible. Complement-fixing and hemagglutination-inhibiting antibodies (for which fourfold or greater rises in levels are needed to establish diagnosis) appear during the second week. With the pandemic strain, elevated alkaline phosphatase, creatine kinase, creatinine, thrombocytopenia and metabolic acidosis suggest a poor prognosis. A nasopharyngeal swab, nasal aspirate, combined nasopharyngeal swab with oropharyngeal swab, or material from a bronchoalveolar lavage can be tested for any influenza strain.

Local laboratories can perform rapid influenza antigen enzyme or direct immunofluorescent assays to distinguish influenza viruses types A and B, but the results of these assays should be interpreted with caution due to a limited sensitivity (11–70%) and difficulties distinguishing seasonal influenza and the 2009 pandemic H1N1 influenza viruses. Test material can be kept at 4°C up to 4 days (not frozen) and shipped with an ice pack. The CDC or many state public health laboratories can then perform a real-time PCR or viral culture. Chest radiographic findings rarely show lobal infiltrates and pathologic findings show similar particular propensities toward diffuse alveolar damage.

 Differential Diagnosis

The differential diagnoses for influenza-like infections includes parainfluenza infections and RSV infections.

 Complications

Influenza causes necrosis of the respiratory epithelium, which predisposes to secondary bacterial infections. In turn, bacterial enzymes (eg, proteases, trypsin-like compounds, and streptokinase) activate influenza viruses. Frequent complications are acute sinusitis, otitis media, purulent bronchitis, and pneumonia. Children under 5 years of age, pregnant women, residents of nursing homes and long-term–care facilities, the elderly (aged 65 years or older), children and teens under 19 years of age who are receiving long-term aspirin therapy, and persons with underlying medical conditions (pulmonary, renal, cardiovascular, hepatic, hematologic, neurologic and neurodevelopmental conditions and immune-deficient conditions such as HIV) are at high risk for complications. Persons who are morbidly obese (body mass index > 40), American Indians, and Alaskan natives are also at high risk for complications.

Primary influenza pneumonia may occur, particularly in young children with cardiovascular disease and pregnant women, and is associated with a high mortality. Secondary bacterial pneumonia due to pneumococci, staphylococci, or Haemophilus spp is not uncommon. Pericarditis and myocarditis occur rarely. There is an association of acute myocardial infarction with preceding respiratory infection, including influenza; a UK study showed that influenza vaccination is associated with a lower rate of acute myocardial infarction. Rhabdomyolysis and leukocytoclastic vasculitis are rare complications of influenza.

Reye syndrome (fatty liver with encephalopathy) is a rare and severe complication of influenza (usually B type) and other viral diseases (eg, varicella), particularly in young children. It consists of rapidly progressive hepatic failure and encephalopathy, and there is a 30% mortality rate. The pathogenesis is unknown, but the syndrome is associated with aspirin use in the management of viral infections. Hypoglycemia, elevation of serum aminotransferases and blood ammonia, prolonged prothrombin time, and change in mental status all occur within 2–3 weeks after onset of the viral infection. Histologically, the periphery of liver lobules shows striking fatty infiltration and glycogen depletion. Treatment is supportive and directed toward the management of cerebral edema.

Other encephalopathic complications of influenza are uncommon and include an acute necrotizing encephalopathy associated with disseminated intravascular coagulation and cytokine storm, with worsening when treated with certain nonsteroidal anti-inflammatory drugs (diclofenac and mefenamic acid), and an acute encephalopathy associated with febrile seizures and the use of theophylline. Influenza infections are an infrequent trigger of the Guillain-Barré syndrome. A recent analysis of Medicare utilization data shows no increase in the Guillain-Barré syndrome following either seasonal or H1N1 influenza vaccination.

 Treatment

Many patients with influenza prefer to rest in bed. Analgesics and a cough mixture may be used. Treatment should be considered for all persons with acute illness, in particular those with a suggestive clinical presentation or with laboratory confirmed influenza and at high risk for developing complications (nursing home residents; patients with chronic pulmonary, cardiovascular, kidney, or liver disease; those with diabetes mellitus, active malignancy, immunosuppression, or impairment for managing respiratory secretions), or living with persons at significant risk for them. Maximum benefit is expected with the earliest initiation of therapy. Although the benefit of antiviral therapy after 48 hours of illness is reduced, it should be considered if the patient is hospitalized. There is no benefit to double-dose oseltamivir in severe influenza infections although some influenza experts continue to recommend double-dose therapy among immunocompromised patients.

The neuraminidase inhibitors, either inhaled zanamivir, 10 mg (2 inhalations) twice daily for 5 days, or oral oseltamivir, 75 mg twice daily for 5 days, are equally effective in the treatment of susceptible strains of influenza. Clinical trials show a reduction in the duration of symptoms as well as secondary complications, such as otitis, sinusitis, or pneumonia, but not in the rate of hospitalizations or mortality when using these agents. When administered early (within the first 2 days of illness), antiviral medications (neuraminidase inhibitors) are most effective. Patients with asthma who are hospitalized with pneumonia should be treated early with antivirals.

Since high levels of resistance to the adamantanes (amantadine and rimantadine) persist among 2009 influenza A (H1N1) and A (H3N2) viruses and these agents are not effective against influenza B viruses, adamantanes are generally not recommended for treatment. Resistance to neuraminidase inhibitors (oseltamivir and zanamivir) can occur with prolonged use in immunocompromised patients or in avian (H5N1)-infected patients.

Zanamivir is relatively contraindicated among persons with asthma because of the risk of bronchospasm and is not formulated for use in mechanically ventilated patients. Transient neuropsychiatric events, occasionally resulting in self-injury and death, have been reported post marketing for both neuraminidase inhibitors. Patients receiving these drugs should be closely monitored for any unusual behavior, and healthcare professionals should be notified immediately if such signs occur. Laninamivir is a long-acting inhaled neuraminidase inhibitor used for the treatment of seasonal influenza, including infection caused by oseltamivir-resistant virus. It is licensed in Japan but is awaiting FDA approval in the United States. Antibacterial antibiotics should be reserved for treatment of bacterial complications. Acetaminophen or ibuprofen rather than aspirin should be used for fever in children.

Oseltamivir-resistant virus is recognized and such virus usually remains sensitive to zanamivir, available through compassionate use programs available through GlaxoSmithKline at 877-626-8019 or 866-341-9160 or gskclinicalsupportHD@gsk.com (http://www.clinicalsupporthd.gsk.com/) (http://www.flu.nc.gov/providers/documents/IVzanamivirRequestInformation.pdf).

Person-to-person transmission with oseltamivir-resistant pandemic H1N1 is documented.

For oseltamivir-resistant 2009 H1N1 viral infection, intravenous zanamivir is preferred. While a case of multidrug-resistant pandemic H1N1 virus with resistance to oseltamivir, zanamivir, and peramivir is reported, this particular isolate is less pathogenic in animal studies than standard H1N1 strains. The use of high frequency oscillatory ventilation and extracorporeal membrane oxygenation can improve oxygenation but the impact on mortality in unknown. Corticosteroids for an associated ARDS are not useful and may increase the mortality except that the use of corticosteroids are associated with a lower rate of mechanical ventilation if used in high doses (1 mg/kg prednisone equivalence orally at the time of diagnosis) in patients with a history of hematologic stem cell transplantation.

Updated advice is available at http://www.cdc.gov/h1n1flu/recommendations.htm.

 Prognosis

The duration of the uncomplicated illness is 1–7 days, and the prognosis is excellent in healthy, nonelderly adults. Hospitalization typically occurs in those with underlying medical disease, at the extremes of age and in pregnant woman. Young adults and obese individuals were also at increased risk for hospitalization during the 2009 H1N1 pandemic. Purulent bronchitis and bronchiectasis may result in chronic pulmonary disease and fibrosis that persist throughout life. Most fatalities are due to bacterial pneumonia although exacerbations of other diseases processes, in particular cardiac diseases, occur which contributed to the overall increase in fatalities. Pneumonia resulting from influenza (in particular the H1N1 strain) has a high mortality rate among pregnant women and persons with a history of rheumatic heart disease. Mortality among adults hospitalized with influenza ranges from 4% to 8%, although higher mortality (>10–15%) may be seen during pandemics and among immunocompromised individuals.

If the fever recurs or persists for more than 4 days with productive cough and white cell count over 10,000/mcL, secondary bacterial infection should be suspected. Pneumococcal pneumonia is the most common secondary infection, and staphylococcal pneumonia is the most serious.

 Prevention

Annual administration of influenza vaccine is the most effective measure for preventing influenza and its complications. Vaccines available for use in the United States are the FDA-approved trivalent inactivated influenza vaccine (TIV) and the quadrivalent live attenuated influenza vaccine (LAIV). They both contain antigens from 1 strain each of pandemic influenza A (H1N1), influenza A (H3N2), and influenza B. The 2013–2014 seasonal influenza vaccines contain A/California/7/2009 (H1N1), A/Victoria/361/2011 (H3N2)-like, and B/Massachusetts/2/2012-like virus antigens. The quadrivalent alternative contains an additional influenza B antigen (B/Brisbane/60/2008-like virus) and the CDC recommend that either trivalent or quadrivalent vaccine may be used. New cell-culture technologies for the manufacture of influenza vaccines that will supplement egg-based growth media are available and may contribute to improved strain selection and more robust vaccine supplies.

Chemotherapeutic regimens containing rituximab show persistent perturbations of B cell and Ig synthesis and these modifications decrease humoral responses to the influenza vaccine.

The Advisory Committee on Immunization Practices (ACIP) and the American College of Obstetricians and Gynecologists’ Committee recommend annual influenza vaccination for all persons over 6 months of age. In particular, vaccination is emphasized for women who will be pregnant through the influenza season (October through May in the United States) and vaccination early in the season regardless of gestational age. No study to date has shown any major adverse consequence of inactivated influenza vaccine in pregnant women or their offspring. Fluzone High-Dose is an FDA-approved TIV containing four times more hemagglutinin than standard TIV and is recommended for persons age 65 or older. Fluzone intradermal trivalent vaccine (15 mcg hemagglutinin per strain, with current data suggesting 60 mg is the more appropriate dose) is an intradermal vaccine that is equally immunogenic and safe but more expensive than the traditional intramuscular vaccine.

The LAIV is available for use in healthy individuals between 2 and 49 years of age; it should not be given to asthmatic patients or pregnant women. For children, the LAIV shows superior efficacy compared with the TIV in most but not all studies.

Among the HIV-infected and the elderly, preliminary data suggest that a quadruple-dose influenza vaccine is associated with higher seroconversion rates.

The seasonal influenza vaccines can reduce influenza hospitalizations by an estimated 61%. All of these vaccines are contraindicated in persons with well-substantiated hypersensitivity to chicken eggs or other components of the vaccine (skin testing can be performed by an allergist), in persons with a history of vaccine-associated Guillain-Barré syndrome, or in persons with an acute febrile illness until symptomatic improvement. Concomitant warfarin or corticosteroid therapy is not a contraindication to influenza vaccination. Side effects are infrequent and include tenderness, redness, or induration at the intramuscular site of the TIV and mild upper respiratory symptoms for the LAIV.

Chemoprophylaxis is considered for individuals who are unvaccinated, for those in whom vaccination is contraindicated, and in those exposed to an infected patient within 2 weeks after vaccination with TIV. Chemoprophylaxis is not necessary and is contraindicated for those vaccinated with the LAIV, since this vaccine confers more rapid protection. Other circumstances that warrant consideration of chemoprophylaxis include outbreaks in long-term–care facilities, persons living with or in close contact with high-risk individuals, persons with immune deficiencies who might not respond to vaccination, unvaccinated staff during response to an outbreak in a closed institutional setting with residents at high risk, and first responders to epidemic situations.

Winter school breaks during periods of high influenza transmission appear to decrease rates of visits to primary care practitioners for influenza illness among children and adults.

Chemoprophylaxis against influenza A and B is accomplished with a single daily dose of the neuraminidase inhibitors oseltamivir (75 mg/d, oral) or zanamivir (10 mg/d, inhaled). These agents reduce the attack rate among unvaccinated individuals if begun within 48 hours after exposure. The CDC recommends chemoprophylaxis for up to 10 days after exposure. For outbreak control in long-term–care facilities and hospitals, a minimum of 2 weeks is recommended, including in vaccinated person, and until 1 week after identification of the last known case. Zanamivir should not be given as chemoprophylaxis to asthmatic persons, nursing home residents, or children under 5 years of age. Hand hygiene and surgical facemasks appear to prevent household transmission of influenza virus isolates when implemented within 36 hours of recognition of symptoms in an index patient. Such nonpharmaceutical interventions assist in mitigating the spread of pandemic and interpandemic influenza to nonvaccinated persons. Patients with 2009 H1N1 influenza infection should be considered potentially infectious from 1 day before to about 7 days following illness onset. Children and immunosuppressed persons exhibit prolonged viral shedding and may be infectious longer. Any hospital patient in whom the infection is suspected should be isolated in individual rooms with standard and contact precautions plus eye protection.

For pandemic H1N1 infection, the WHO guidelines recommend surgical masks for all patient care with the exception of N95 masks for aerosol generating procedures (eg, bronchoscopy, elective intubation, suctioning, administering nebulized medications). For such procedures, an airborne infection isolation room can be used, with air exhausted directly outside or recirculated after filtration by a high efficiency particulate air (HEPA) filter. Strict adherence to hand hygiene with soap and water or an alcohol-based hand sanitizer and immediate removal of gloves and other equipment after contact with respiratory secretions is essential. Precautions should be maintained until 7 days from symptom onset or until the resolution of symptoms, whichever is longer. Postexposure prophylaxis should be considered for close contacts of patients (confirmed, probable, or suspected) who are at high risk for complications of influenza (see section on seasonal influenza) as well as for healthcare personnel, public health workers, or first responders who experienced a recognized, unprotected close contact exposure to a person with novel (H1N1) influenza virus infection (confirmed, probable, or suspected) during that person’s infectious period. The CDC continues to recommend considering postexposure prophylaxis with neuraminidase inhibitors to contacts of the infected person.

The MMWR and WHO website (http://www.who.int/csr/disease/swineflu/en/) provide updates about this pandemic.

 When to Admit

  • Limited availability of supporting services.
  • Pneumonia or decreased oxygen saturation.
  • Changes in mental status.
  • Consider with pregnancy.

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  1. Avian Influenza (H5N1 & Analogues)

 ESSENTIALS OF DIAGNOSIS

 Cases to date in humans, mostly from Southeast Asia and Egypt.

 Clinically indistinguishable from seasonal influenza.

 Epidemiologic factors assist in diagnosis.

 Rapid antigen assays confirm diagnosis but do not distinguish avian from seasonal influenza.

 General Considerations

The normal hosts for avian influenza viruses are aquatic waterfowl. Although avian influenza was first recognized in Italy in 1878, the current outbreak of highly pathogenic influenza A subtype (H5N1) in poultry was recognized in 1997 in Hong Kong and was followed by the first documented human cases. A massive slaughter of poultry contained the disease. Outbreaks of H5N1 influenza in poultry reemerged in 2003 and now involve more than 65 countries of East and Southeast Asia, Eurasia, Western and Eastern Europe, Northern Africa, and Haiti. The 641 confirmed human cases as of October 2013 include 380 deaths (59% of cases and 75% of deaths are reported from Egypt, Indonesia, and Vietnam) (the details are maintained and updated by the Global Outbreak Alert and Response Network, WHO:

http://www.who.int/influenza/human_animal_interface/EN_GIP_20131008CumulativeNumberH5N1cases.pdf).

Although highly contagious among birds, the transmission of this H5N1 strain from human-to-human is inefficient and not sustained although recent studies documented transmissibility of laboratory mutated virus via aerosols between ferrets. Evidence from cluster outbreaks suggests that host genetic susceptibility limits human-to-human transmission. The result is only rare cases of person-to-person infection. Occasional transmission to other mammals, including domestic cats and dogs, is also documented. Cases of influenza H7N7, transmitted from poultry to persons, especially poultry handlers and their contacts in the Netherlands occurred in 2003. More recently, two cases of conjunctivitis without fever or respiratory symptoms of H7N3 occurred this year in Mexico and one case with H7N2 occurred in New York. Cases of H7N9 are reported from China, initially in poultry, but an outbreak of 11 cases was reported in 2013 with 76.6% requiring ICU care and 27% dying. Unique characteristics were bilateral ground-glass opacities, lymphocytopenia, and thrombocytopenia. ARDS developed in patients who had underlying coexisting medical conditions. Person-to-person transmission was also documented.

Rare cases of influenza H9N2, another poultry pathogen, are reported from Bangladesh and human-to-human transmission of this pathogen is not documented.

Most human cases of H5N1 and analogous viruses occur after exposure to infected poultry or surfaces contaminated with poultry droppings. Because infection in humans is associated with a mortality rate > 50% and the avian H5N1 subtype continues to spread among birds (with many parts of Southeast Asia now considered endemic for the virus), there is worldwide concern that the virus may undergo genetic reassortment or mutation (as with the 1918 strain) and develop greater human-to-human transmissibility with the potential to produce a global pandemic.

 Clinical Findings

  1. Symptoms and Signs

Distinguishing avian influenza from regular influenza is difficult. History of exposure to dead or ill poultry in the prior 10 days, recent travel to Southeast Asia or Egypt, or contact with known cases should be investigated. The symptoms and signs include fever and predominantly respiratory symptoms (cough and dyspnea), but a variety of other systems may be involved, producing headaches and gastrointestinal complaints in particular. Subclinical disease is relatively rare. With cytokines responsible for much of the pathology, prolonged febrile states and generalized malaise are common. Children are preferentially impacted. Respiratory failure is the usual cause of death.

  1. Laboratory Findings

Current commercial rapid antigen tests are not optimally sensitive or specific for detection of H5N1 influenza but are still first-line diagnostic tests because of their widespread availability. Diagnostic yield can be improved by early collection of samples. More sensitive RT-PCR assays are available through many hospitals and state health departments. An initial negative result in the right clinical setting warrants retesting. Throat or lower respiratory swabs may provide higher yield of detection than nasal swabs. When highly pathogenic strains (eg, H5N1) are suspected, extreme care in the handling of these samples must be observed during preliminary testing. Positive samples must then be forwarded to the appropriate public health authorities for further investigations (eg, culture) in laboratories with the adequate level of biosafety (level 3).

 Treatment

Resistance of avian H5N1 influenza strains to amantadine and rimantadine is present in most geographic areas. The current first-line recommendation is to use the neuraminidase inhibitor oseltamivir, 75 mg orally twice daily for 5 days administered within 48 hours from onset of illness. Overall oseltamivir, by modeling, is associated with a 49% reduction in mortality from H5N1 infections. A higher dose (150 mg twice daily), longer duration (7–10 days), and possible combination therapy with amantadine or rimantadine (in countries where A [H5N1] viruses are likely to be susceptible to adamantanes) may be considered in patients with pneumonia or progressive disease. Twice daily oseltamivir is also recommended for H7N9 influenza infections. Evidence of resistance to oseltamivir is reported. Although inhaled zanamivir is proven effective in treating seasonal influenza, no data of its efficacy against H5N1 strains are available. Zanamivir is recommended, intravenously, for patients not improving with oseltamivir after 2 days of treatment.

 Prevention

Postexposure prophylaxis with 75 mg of oseltamivir orally once daily for 7–10 days should be given to close contacts and considered for moderate contacts of documented cases of H5N1and H7N9 influenza infections although human-to-human transmission appears to be limited. Personnel exposed to patients should be monitored for symptoms. Careful surveillance for human cases and prudent stockpiling of medications with establishment of an infrastructure for dissemination are essential modalities of control. Nonpharmacologic means of control include masks, social distancing, quarantine, travel limitations, and infrastructure development, particularly for emergency departments.

Human vaccines against H5N1 influenza are licensed by Sanofi Pasteur (but not marketed) in the United States with the government stockpiling supplies in the event of need. Other vaccines are licensed by GlaxoSmithKline in Europe and CS Limited in Australia. It appears to be only moderately immunogenic. A vaccine candidate made with an oil-in-water emulsion-based adjuvant is highly immunogenic and well tolerated. Several other vaccine candidates are undergoing clinical trials. A major concern with H5N1 vaccinology is the evolution of the virus in vaccinated poultry, especially in the endemic nations of Egypt and Indonesia, and the need to maintain current surveillance and update vaccine development should avian influenza become more pathogenic in humans. Seasonal and H5N1 vaccines in phase 2 studies can be given either combined or in sequence safely and without affecting immunogenicity. Contrary to popular belief, persons born before 1968 are not necessarily (as had been seen in earlier studies) more likely to respond to an avian influenza A/H9N2 vaccine than those born after 1968. Prevention of exposure to avian influenza strains also includes hygienic practices during handling of poultry products, including hand washing and prevention of cross-contamination, as well as thorough cooking of poultry products (to 70°C). There is no risk of acquiring avian influenza through the consumption of cooked poultry products, although there is a risk associated with handling feathers or birds from endemic areas, and the US government bans the importation of poultry from infected areas. While no commercial H7N9 vaccines are available, two large trials are underway with vaccine and treatment evaluation units. Culling of infected H7N9 poultry is difficult because most animals are asymptomatic.

Atmar RL et al. Evaluation of age-related differences in the immunogenicity of a G9 H9N2 influenza vaccine. Vaccine. 2011 Oct 19;29(45):8066–72. [PMID: 21864622]

Centers for Disease Control and Prevention (CDC). Notes from the field: highly pathogenic avian influenza A (H7N3) virus infection in two poultry workers—Jalisco, Mexico, July 2012. MMWR Morb Mortal Wkly Rep. 2012 Sep 14;61(36):726–7. [PMID: 22971746]

Gao HN et al. Clinical findings in 111 cases of influenza A (H7N9) virus infection. N Engl J Med. 2013 Jun 13;368(24):2277–894. [PMID: 23697469]

Herfst S et al. The future of research and publication on altered H5N1 viruses. J Infect Dis. 2012 Jun;205(11):1628–31. [PMID: 22454474]

Khurana S et al. H5N1-SeroDetect EIA and rapid test: a novel differential diagnostic assay for serodiagnosis of H5N1 infections and surveillance. J Virol. 2011 Dec;85(23):12455–63. [PMID: 21957281]

Lopez P et al. Combined, concurrent, and sequential administration of seasonal influenza and MF59-adjuvanted A/H5N1 vaccines: a phase II randomized, controlled trial of immunogenicity and safety in healthy adults. J Infect Dis. 2011 Jun 15; 203(12):1719–28. [PMID: 21606530]

Qi X et al. Probable person to person transmission of novel avian influenza A (H7N9) virus in Eastern China, 2013: epidemiological investigation. BMJ. 2013 Aug 6;347:f4752. [PMID: 23920350]

  1. Severe Acute Respiratory Syndrome (SARS)

 ESSENTIALS OF DIAGNOSIS

 Mild, moderate, or severe respiratory illness.

 Travel to endemic area within 10 days before symptom onset, including mainland China, Hong Kong, Singapore, Taiwan, Vietnam, and Toronto.

 Persistent fever; dry cough, dyspnea in most.

 Diagnosis confirmed by antibody testing or isolation of virus.

 No specific treatment; mortality as high as 14% in clinically diagnosed cases.

 General Considerations

SARS is a respiratory syndrome caused by a unique coronavirus, transmitted through direct or indirect contact of mucous membranes with infectious respiratory droplets. The virus is shed in stools but the role of fecal–oral transmission is unknown. The natural reservoir appears to be the horseshoe bat.

The earliest cases were traced to a health care worker in Guangdong Province in China in late 2002, with rapid spread thereafter throughout Asia and Canada, considered a consequence of spread through travel. The most recent cases were reported in 2004.

 Clinical Findings

  1. Symptoms and Signs

SARS is an atypical pneumonia that affects persons in all age groups. Severity ranges from asymptomatic disease to severe respiratory illness. Many subclinical cases probably go undiagnosed. Seasonality, as with influenza, is not established. The incubation period is 2–7 days, and it can be spread to contacts of affected patients for 10 days. The mean time from onset of clinical symptoms to hospital admission is 3–5 days. In all clinical cases, persistent fever is present; chills or rigor (or both), cough, shortness of breath, rales, and rhonchi are the rule. Headache, myalgias, and sore throat are common with watery diarrhea occurring in a subset of patients. Elderly patients may report malaise and delirium, without the typical febrile response.

  1. Laboratory Findings and Imaging

Leukopenia (particularly lymphopenia) and low-grade disseminated intravascular coagulation are common. Modest elevations of ALT and creatine kinase are frequently seen. Arterial oxygen saturation < 95% with associated nonspecific pulmonary infiltrates is evident in 80% of affected individuals. A high-resolution CT scan is abnormal in 67% of patients with initially normal chest radiographs.

Serum serologies, including enzyme immunoassays and fluorescent antibody assays, are available through public health departments at the state level, although seroconversion may not occur until 3 weeks after the onset of symptoms. The detection rates for the virus using conventional RT-PCR are generally low in the first week of illness. Urine, nasopharyngeal aspirate, and stool specimens are positive in 42%, 68%, and 97%, respectively, on day 14 of illness. Although viral isolation is possible, it is a technically laborious and time-consuming procedure.

 Complications

ARDS, with extensive bilateral consolidation, occurs in about 16% patients, and about 20–30% of patients require intubation and mechanical ventilation.

 Treatment

Severe cases require intensive supportive management. Different agents including, lopinavir/ritonavir, ribavirin, interferon, IVIG, and systemic corticosteroids were used during the 2003 epidemic, but the treatment efficacy of these agents remains inconclusive. In vitro studies with ribavirin show no activity against the virus, and a retrospective analysis of the epidemic in Toronto suggests worse outcomes in patients who received the drug. A meta-analysis studying the use of Chinese herbs failed to show any efficacy in treating SARS. Studies using monoclonal antibodies are underway based on the response of some patients to immune convalescent sera of convalescent patients.

 Prognosis

The overall mortality rate of identified cases is about 14%. Poor prognostic factors include advanced age (mortality rate > 50% in those over 65 years of age compared to < 1% for those under 2 years of age), chronic hepatitis B infection treated with lamivudine, high initial or high peak lactate dehydrogenase concentration, high neutrophil count on presentation, diabetes mellitus, acute kidney disease, and low counts of CD4 and CD8 on presentation.

 Prevention

Health care workers engaged in procedures that involve contact with respiratory droplets are at risk. Isolation of high-risk patients is essential, and simple hygienic measures may help reduce transmission.

Control measures include quarantining in the home for high-risk exposed persons and the use of facemasks for preventing hospital-acquired infections. The validity of using such masks in the community remains unsubstantiated. Continual reporting of suspected cases is crucial, as is awareness of restrictions on international travel. The most cautious modalities include monitoring for 10 days after the last potential exposure and confinement of recovering patients for a similar interval.

Balboni A et al. The SARS-like coronaviruses: the role of bats and evolutionary relationships with SARS coronavirus. New Microbiol. 2012 Jan;35(1):1–16. [PMID: 22378548]

Elshabrawy HA et al. Human monoclonal antibodies against highly conserved HR1 and HR2 domains of the SARS-CoV spike protein are more broadly neutralizing. PLoS One. 2012;7(11):e50366. [PMID: 23185609]

Liu X et al. Chinese herbs combined with Western medicine for severe acute respiratory syndrome (SARS). Cochrane Database Syst Rev. 2012 Oct 17;10:CD004882. [PMID: 23076910]

Yang L et al. Novel SARS-like beta coronaviruses in bats, China, 2011. Emerg Infect Dis. 2013 Jun;19(6):989–91. [PMID: 23739658]

  1. Middle East Respiratory Syndrome–Coronavirus (MERS-CoV)

 ESSENTIALS OF DIAGNOSIS

  • Mild, moderate, or severe respiratory illness.
  • Travel to endemic area, including Saudi Arabia, Qatar, and Jordan, within 10 days before symptom onset.
  • Fever, cough, and dyspnea are most common symptoms.
  • Serologic assays are not developed for diagnosis; CDC can assist with real time-PCR using serum, respiratory samples, or stool.
  • No specific treatment available; mortality as high as 45%.

 General Considerations

Middle East respiratory syndrome (MERS) is a newly described syndrome that appears to be due to a coronavirus similar to that which causes SARS. All patients with MERS have had a history of residence or travel in the Middle East, in particular Saudi Arabia, or contact with such patients. The virus is probably transmitted through direct or indirect contact of mucous membranes with infectious respiratory droplets. The virus is shed in stools but the role of fecal–oral transmission is unknown. The natural reservoir is unknown.

The earliest cases were identified in 2012 in Saudi Arabia. As of November 15, 2013, 153 cases have been recognized worldwide and 64 of these have been fatal (42%). Cases in the Middle East have also occurred in Jordan, Oman, Qatar, and the United Arab Emirates, while 9 cases are currently reported from other countries, including North Africa (Tunisia, 3) and Europe (France, 2; Italy, 1; and United Kingdom, 3).

Person-to-person transmission occurs, both within families and at the hospital, although in series to date it is not common (5 cases among 217 household contacts and 2 among 200 hospital contacts). The median incubation period in hospital cases was 5.2 days but the reported range is 2–13 days.

 Clinical Findings

  1. Symptoms and Signs

MERS is an acute respiratory syndrome, with the most common symptoms being fever (98%), cough (83%), and dyspnea (72%). Chills and rigors are common (87%) and gastrointestinal symptoms may occur with diarrhea the most common (26%), followed by nausea and abdominal pain. Patients often have several comorbid conditions, including diabetes mellitus (68%), hypertension (34%), or chronic heart or kidney disease. Middle-aged persons are most affected (median age of 50 years), although all ages are affected (age range of 2–94 year), and men outnumber women.

  1. Laboratory Findings and Imaging

Hematologic findings in the largest series to date include thrombocytopenia (36%), lymphopenia (34%), and lymphocytosis (11%). Moderate elevations in lactate dehydrogenase (49%), AST (15%), and ALT (11%) are recognized. Chest radiograph abnormalities are nearly universal and include increased bronchovascular markings, patchy infiltrates or consolidations, interstitial changes, opacities (reticular and nodular) as well as pleural effusions and total lung opacification. The findings mimic those of many other causes of pneumonia.

A case definition is available from the CDC. Serum serologies remain a research and surveillance tool. RT-PCR is available through CDC (contact information below, on MMWR reference site) and can be performed on airway washings, serum, or stool.

 Complications

Respiratory failure is such a common complication that in a series from Saudi Arabia, 89% of patients required intensive care and mechanical ventilation and patients with MERS-CoV appear to advance faster to respiratory failure than do those with the SARS agent.

 Treatment

Respiratory support is essential. No antivirals are effective.

 Prognosis

The overall mortality rate of identified cases is about 45%. Advance age is associated with a poor prognosis.

 Prevention

Isolation and quarantine of cases is authorized by CDC. Strict infection control measures are essential as well as care and management of household contacts and hospital workers engaged in the care of patients. Travelers to Saudi Arabia (including the many pilgrims to the holy sites) should practice frequent hand washing and avoid contact with those who have respiratory ailments. Evaluation of patients with suspect symptoms within 14 days of return from Saudi Arabia is essential. Because health care workers engaged in procedures that involve contact with respiratory droplets are at risk, isolation of high-risk patients is essential, as are simple hygienic measures. Control measures, including quarantining in the home for high-risk exposed persons and the use of facemasks for preventing hospital-acquired infections, are prudent but not fully proven recommendations. Assisting public health authorities with case reporting and surveillance is essential. Mathematical models to date do not suggest a potential for a global pandemic.

MMWR periodically updates the infection control recommendations and the extent of the outbreak.

Assiri A et al. Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study. Lancet Infect Dis. 2013 Sep;13(9):752–61. [PMID: 23891402]

Assiri A et al; KSA MERS-CoV Investigation Team. Hospital outbreak of Middle East respiratory syndrome coronavirus. N Engl J Med. 2013 Aug 1;369(5):407–16. Erratum in: N Engl J Med. 2013 Aug 29;369(9):886. [PMID: 23782161]

Breban R et al. Interhuman transmissibility of Middle East respiratory syndrome coronavirus: estimation of pandemic risk. Lancet. 2013 Aug 24;382(9893):694–9. [PMID: 23831141]

Centers for Disease Control and Prevention (CDC). Updated information on the epidemiology of Middle East respiratory syndrome coronavirus (MERS-CoV) infection and guidance for the public, clinicians, and public health authorities, 2012–2013. MMWR Morb Mortal Wkly Rep. 2013 Sep 27;62(38):793–6. [PMID: 24067584]

Memish ZA et al. Family cluster of Middle East respiratory syndrome coronavirus infections. N Engl J Med. 2013 Jun 27;368(26):2487–94. Erratum in: N Engl J Med. 2013 Aug 8;369(6):587. [PMID: 23718156]

ADENOVIRUS INFECTIONS

 General Considerations

About a half of the existing adenoviruses (there are over 52 serotypes described to date and divided into 7 subgroups A–G) produce a variety of clinical syndromes. Adenoviruses show a worldwide distribution and occur throughout the year. These infections are usually self-limited or clinically inapparent and most common among infants, young children, and military recruits. However, these infections may cause significant morbidity and mortality in immunocompromised persons, such as HIV-infected persons and COPD patients, as well as in patients who have undergone solid organ and hematopoietic stem cell transplantation or cardiac surgery or in those who have received cancer chemotherapy. A few cases of donor-transmitted adenoviral infection are reported in the past years. Adenoviruses, although a common cause of human disease, also receive particular recognition through their role as vectors in gene therapy.

 Clinical Findings

  1. Symptoms and Signs

The incubation period is 4–9 days. Clinical syndromes of adenovirus infection, often overlapping, include the following. The common cold (see Chapter 8) is characterized by rhinitis, pharyngitis, and mild malaise without fever. Nonstreptococcal exudative pharyngitis is characterized by fever lasting 2–12 days and accompanied by malaise and myalgia. Conjunctivitis is often present. Lower respiratory tract infection may occur, including bronchiolitis, suggested by cough and rales, or pneumonia (types 1 to 3, 4, and 7 commonly cause acute respiratory disease and atypical pneumonia) and infections are especially severe in Native American children. Adenovirus type 14 is increasingly reported as a cause of severe and sometimes fatal pneumonia in those with chronic lung disease, but it is also seen in healthy young adults and military recruit outbreaks. Viral or bacterial coinfections occur with adenovirus in 15–20% of cases. Pharyngocon-junctival fever is manifested by fever and malaise, conjunctivitis (often unilateral), mild pharyngitis, and cervical adenitis. Epidemic keratoconjunctivitis (transmissible person-to-person, most often types 8 (and showing considerable variation by season), 19, and 37) occurs in adults and is manifested by bilateral conjunctival redness, pain, tearing, and an enlarged preauricular lymph node (multiple types may be involved in a single outbreak). Keratitis may lead to subepithelial opacities (especially with the above types). Acute hemorrhagic cystitis is a disorder of children often associated with adenovirus type 11 and 21. Sexually transmitted genitourinary ulcers and urethritis may be caused by types 2, 8, and 37 in particular. Adenoviruses also cause acute gastroenteritis (types 40 and 41), mesenteric adenitisacute appendicitis, and intussusception. Rarely, they are associated with encephalitis, acute flaccid paralysis, and pericarditis. Adenovirus is commonly identified in endomyocardial tissue of patients with myocarditis and dilated cardiomyopathy. Risk factors associated with severity of infection include youth, chronic underlying infections, recent transplantation, and serotypes 5 or 21.

Hepatitis (type 5 adenovirus), pneumonia, and hemorrhagic cystitis (types 11 and 34) tend to develop in infected liver, lung, or kidney transplant recipients, respectively. Syndromes that may develop in hematopoietic stem cell transplant patients include hepatitis, pneumonia, hemorrhagic cystitis, tubulointerstitial nephritis, colitis, and encephalitis.

  1. Laboratory Findings and Imaging

Antigen detection assays including direct fluorescence assay or enzyme immunoassay are rapid and show sensitivity of 40–60% compared with viral culture (considered the standard). Samples with negative rapid assays require PCR assays or viral cultures for diagnosis. Quantitative real-time rapid-cycle PCR is useful in distinguishing disease from colonization, especially in hematologic cell transplant patients. Adenovirus differs from other viral and bacterial respiratory infections seen on chest CT imaging, appearing as a multifocal consolidation or ground-glass opacity without airway inflammatory findings.

 Treatment & Prognosis

Treatment is symptomatic. Ribavirin and cidofovir are used in immunocompromised individuals with occasional success, although cidofovir is attendant with significant renal toxicity and reduced immunosuppression is often required. Adoptive immunotherapy with transfusion of adenovirus-specific T cells is currently being investigated. IVIG is used in immunocompromised patients, but data are still limited. Typing of isolates is useful epidemiologically and in distinguishing transmission from endogenous reactivation. Complications of adenovirus pneumonia in children include bronchiolitis obliterans. Deaths are reported on occasion (eight in one season among the American military).

Vaccines are not available for general use.

Kim JK et al. Epidemiology of respiratory viral infection using multiplex rt-PCR in Cheonan, Korea (2006–2010). J Microbiol Biotechnol. 2013 Feb;23(2):267–73. [PMID: 23412071]

Lu MP et al. Clinical characteristics of adenovirus associated lower respiratory tract infection in children. World J Pediatr. 2013 Nov;9(4):346–9. [PMID: 24235068]

Miller WT Jr et al. CT of viral lower respiratory tract infections in adults: comparison among viral organisms and between viral and bacterial infections. AJR Am J Roentgenol. 2011 Nov;197(5):1088–95. [PMID: 22021500]

Potter RN et al. Adenovirus-associated deaths in US military during postvaccination period, 1999–2010. Emerg Infect Dis. 2012 Mar;18(3):507–9. [PMID: 22377242]

OTHER EXANTHEMATOUS VIRAL INFECTIONS

  1. Erythrovirus (Parvovirus) Infections

Erythrovirus, formerly parvovirus B19, infects human erythroid precursor cells. It is quite widespread (by age 15 years about 50% of children have detectable IgG) and its transmission occurs through respiratory secretions and saliva, through the placenta (vertical transmission with 30–50% of pregnant women nonimmune), and through administration of blood products. The incubation period is 4–14 days. Chronic forms of the infection can occur. Bocavirus, another erythrovirus (parvovirus), is a cause of winter acute respiratory disease in children and adults.

 Clinical Findings

  1. Symptoms and Signs

Erythrovirus (parvovirus B19) causes several syndromes and manifests differently in various populations.

  1. Children—In children, an exanthematous illness (“fifth disease,” erythema infectiosum) is characterized by a fiery red “slapped cheek” appearance, circumoral pallor, and a subsequent lacy, maculopapular, evanescent rash on the trunk and limbs. Malaise, headache, and pruritus (especially on the palms and soles) occur. Systemic symptoms and fever are mostly abated by the time of rash appearance. Eosinophilic cellulitis (Well syndrome) is also reported with parvovirus. Parvovirus is also one of the most common causes of myocarditis in childhood.
  2. Immunocompromised patients—In immunosuppressed patients, including those with HIV infection or transplanted organs, or with hematologic conditions such as sickle cell disease, transient aplastic crisis and pure red blood cell aplasia may occur. Bone marrow aspirates reveal absence of mature erythroid precursors and characteristic giant pronormoblasts. The parvovirus B19 gene is detected in 16–19% of acute leukemic and chronic myeloid leukemia patients.
  3. Adults—A limited nonerosive symmetric polyarthritis that mimics lupus erythematosus and rheumatoid arthritis, which may in some cases be a type II mixed cryoglobulinemia, can develop in middle-aged persons (especially women) but can also occur in children. Rashes, especially facial, are less common in adults.

Chloroquine and its derivatives exacerbate erythrovirus (parvovirus)-associated anemia and are linked with significantly lower hematocrit in hospital admissions in malaria endemic areas. Rare reported presentations include myocarditis with infarction, constrictive pericarditis, chronic dilated cardiomyopathy, hepatitis, pneumonitis, neutropenia, thrombocytopenia, a lupus-like syndrome, glomerulopathy, CNS vasculitis, papular-purpuric “gloves and socks” syndrome, and a chronic fatigue syndrome. A subclinical infection is documented among patients with sickle cell disease. Other CNS manifestations of erythrovirus (parvovirus) include encephalitis, meningitis, stroke (usually in sickle cell anemia patients with aplastic crises), and peripheral neuropathy (brachial plexitis and carpal tunnel syndrome) with occasional chronic residua.

The symptoms of erythrovirus (parvovirus) infection can mimic those of autoimmune states such as lupus, systemic sclerosis, antiphospholipid syndrome, or vasculitis. The molecular mimicry of erythrovirus (parvovirus) to human cytokeratin and transcription factors engaged in hematopoiesis is the basis for theories that implicate erythrovirus (parvovirus) in the pathogenesis of these autoimmune states.

In pregnancy, premature labor, hydrops fetalis, and fetal loss are reported sequelae. Pregnant women with a recent exposure or with suggestive symptoms should be tested for the disease and carefully monitored if results are positive.

  1. Laboratory Findings

The diagnosis is clinical (Table 32–2) but may be confirmed by an elevated titer of IgM anti-erythrovirus (parvovirus) antibodies in serum or with PCR in serum or bone marrow. Autoimmune antibodies (antiphospholipid and antineutrophil cytoplasmic antibodies) can be present and are thought to be a consequence of molecular mimicry.

 Complications

Uncommon complications include the CNS diseases listed above, chronic hemolytic anemia, thrombotic thrombocytopenic purpuric syndrome, acute postinfectious glomerulonephritis, and hepatitis.

 Treatment

Treatment in healthy persons is symptomatic (nonsteroidal anti-inflammatory drugs are used to treat arthralgias, and transfusions are used to treat transient aplastic crises). In immunosuppressed patients including those infected with HIV, IVIG is very effective in the short-term reduction of anemia. Relapses tend to occur about 4 months after administration of IVIG. There is no reduction in encephalitic complications with IVIG. Intrauterine blood transfusion can be considered in severe fetal anemia, although such transfusions have been linked to impaired neurologic development.

 Prevention & Prognosis

Several nosocomial outbreaks are documented. In these cases, standard containment guidelines, including hand-washing after patient exposure and avoiding contact with pregnant women are paramount.

The prognosis is generally excellent in immunocompetent individuals. In immunosuppressed patients, persistent anemia may require prolonged transfusion dependence. Remission of erythrovirus (parvovirus) infection in AIDS patients may occur with HAART, though the immune restoration syndrome is also reported.

Crabol Y et al; Groupe d’experts de l’Assistance Publique-Hópitaux de Paris. Intravenous immunoglobulin therapy for pure red cell aplasia related to human parvovirus b19 infection: a retrospective study of 10 patients and review of the literature. Clin Infect Dis. 2013 Apr;56(7):968–77. [PMID: 23243178]

da Costa AC et al. Investigation of human parvovirus B19 occurrence and genetic variability in different leukaemia entities. Clin Microbiol Infect. 2013 Jan;19(1):E31–43. [PMID: 23167493]

De Jong EP et al. Intrauterine transfusion for parvovirus B19 infection: long-term neurodevelopmental outcome. Am J Obstet Gynecol. 2012 Mar;206(3):204.e1–5. [PMID: 22381602]

Lamont RF et al. Parvovirus B19 infection in human pregnancy. BJOG. 2011 Jan;118(2):175–86. [PMID: 21040396]

Molina KM et al. Parvovirus B19 myocarditis causes significant morbidity and mortality in children. Pediatr Cardiol. 2013 Feb;34(2):390–7. [PMID: 22872019]

  1. Poxvirus Infections

Among the nine poxviruses causing disease in humans, the following are the most clinically important: variola/vaccinia, molluscum contagiosum, orf and paravaccinia, and monkeypox.

  1. Variola/vaccinia—Smallpox (variola) was a highly contagious disease associated with high mortality and disabling sequelae. Its manifestations include severe headache, acute onset of fever, prostration and a rash characterized by the uniform progression from macules to papules to firm, deep-seated vesicles or pustules. The synchronous progression in smallpox readily differentiates lesions from those of varicella (see alsoChapter 6).

Complications of smallpox include bacterial superinfections (cellulitis and pneumonia), encephalitis, and keratitis with corneal ulcerations (risk factor for blindness). Effective vaccination led to its global elimination by 1979 and routine vaccination stopped in 1985. Despite the recommendation of destroying remaining samples of this virus, significant concern exists for the potential misuse of these repositories in military or terrorist activities.

Smallpox should be considered, in concordance with the CDC’s Smallpox Response Plan (www.bt.cdc.gov/agent/smallpox/response-plan/index.asp), in any patient with fever and a characteristic rash (see above) for which other etiologies—such as herpes infections, erythema multiforme, drug reactions (eczema herpeticum may be differentiated from suspect smallpox by appropriate serologic stains), or other infections—are unlikely. One hundred and fifteen cases of vaccine-related disease from contact with a smallpox vaccinee in the United States between 2003 and 2011 (including sexually transmission) were reported. Two cases of vaccinia infection after contact with oral rabies animal baits (which uses the vaccinia vector) are reported. Patients with suspected infection should be placed in airborne and contact isolation and the official agency contacted (CDC Emergency Preparedness and Response Branch; 770-488-7100). Original smallpox vaccine was crudely manufactured with a significant side-effect profile, including eczema vaccinatum and acute vaccinia syndrome (fatigue, headaches, myalgias, and fever). Subsequent smallpox vaccines had similar side-effect profiles, but myocarditis and pericarditis also developed in some patients. The most recent vaccine, ACAM2000 (Acambis, Inc) shows similar safety profiles and is currently used by the US military and stockpiled in the event of biologic warfare.

Contraindications to vaccination include immunosuppression, eczema or other dermatitis in the vaccinee or household contacts, allergy to any component of the vaccine, infants younger than 1 year and pregnant or breastfeeding women. According to current recommendation, it is unnecessary for anyone not handling the smallpox vaccine to be vaccinated. Israeli studies suggest about 4% of their population show contraindications to vaccination. Inoculation of the vaccine in inappropriate sites (eg, eyes) is unfortunately common. Asymptomatic vaccinia viremia can be detected up to 21 days post vaccination and no blood donation should occur during this interval. Cidofovir may be considered for treatment of poxviral conditions and intravenous human vaccinia immunoglobulin may be useful for vaccinia.

  1. Molluscum contagiosum—Molluscum contagiosum may be transmitted sexually or by other close contact. It may occur also in an extensive form in children with genetic defects in dendritic and T cell migration (the DOCK8 [dedicator of cytokinesis] deficiency). The disease is manifested by pearly, raised, umbilicated skin nodules sparing the palms and soles. Keratoconjunctivitis can occur. There may be an association with atopic dermatitis or eczema. Marked and persistent lesions in AIDS patients respond readily to combination antiretroviral therapy. Treatment options include destructive therapies (curettage, cryotherapy, cantharidin, and keratolytics, among others), immunomodulators (imiquimod, cimetidine, andCandidaantigen), and antiviral agents (topical cidofovir is effective anecdotally in refractory cases and there is some efficacy suggested for a new lipid acyclic nucleoside phosphonate called CMX001, an agent used for other viral infections, including in particular CMV). No treatment is uniformly effective and multiple courses of therapy are often needed. Cryptococcal skin lesions can mimic molluscum contagiosum.
  2. Orf and paravaccinia—Orf (contagious pustular dermatitis, or ecthyma contagiosa) and paravaccinia (milker’s nodules) are occupational diseases acquired by contact with sheep and cattle, respectively. Recently, household meat processing and animal slaughter have been implicated as non-traditional risk factors. A nosocomial outbreak occurred in 2012 in Turkey in a burn unit. Five cases in France were due to sheep exposures during the Muslim Feast of the Sacrifice (Eid al-Adha). Orf also occurs among children with ruminant exposures. Orf anecdotally responds to imiquimod.
  3. Monkeypox—First identified in 1970, monkeypox is enzootic in the rain forests of equatorial Africa and presents in humans as a syndrome similar to smallpox. The incubation period is about 12 days, and limited person-to-person spread occurs. African mortality rates vary from 3% to 11% depending on the immune status of the patient. Secondary attack rates appear to be about 10%. The first community-acquired outbreak in the United States of monkeypox occurred in 2003 in Wisconsin and other states of the upper Midwest. Recent African outbreaks have been reported from the Sudan and the Democratic Republic of Congo. The source appeared to be imported Gambian giant rats via consequent exposure of prairie dogs. Other susceptible animals include nonhuman primates, rabbits, and rodents. Confusion with smallpox and varicella occurs; however, both lymphadenopathy (seen in up to 90% of unvaccinated persons) and a febrile prodrome are prominent features in monkeypox infection. Distinguishing characteristics of the monkeypox rash are its deep seated and well-circumscribed nature, it appears at the same stage of development (unlike varicella but like smallpox), and is centrifugal (including the palms and soles). Suspected cases should be placed on standard, contact and droplet precautions; and local and state public health officials, and the CDC should be notified for assistance with confirmation of the diagnosis (electron microscopy, viral culture, ELISA, PCR). Cidofovir is effective against monkeypox, and IVIG can be used in selected cases.

Other general precautions that should be taken are avoidance of contact with prairie dogs and Gambian giant rats (whose illness is manifested by alopecia, rash, and ocular or nasal discharge), appropriate care and isolation of those exposed within 3 prior weeks to such animals, and veterinary examination and investigation of suspect animals through health departments. Vaccinia immunization is effective against monkeypox and is recommended, if no contraindication exists (outlined above), for those involved in the investigation of the outbreak and for healthcare workers caring for those infected with monkeypox. Post exposure vaccination is also advised for documented contacts of infected persons or animals. US federal agencies currently prohibit the importation of African rodents.

Centers for Disease Control and Prevention (CDC). Human Orf virus infection from household exposures—United States, 2009–2011. MMWR Morb Mortal Wkly Rep. 2012 Apr 13;61(14):245–8. [PMID: 22495228]

Centers for Disease Control and Prevention (CDC). Secondary and tertiary transmission of vaccinia virus after sexual contact with a smallpox vaccine—San Diego, California, 2012. MMWR Morb Mortal Wkly Rep. 2013 Mar 1;62(8):145–7. [PMID: 23446513]

Centers for Disease Control and Prevention (CDC). Updated interim CDC guidance for use of smallpox vaccine, cidofovir, and vaccinia immune globulin (VIG) for prevention and treatment in the setting of an outbreak of monkeypox infections. http://www.cdc.gov/ncidod/monkeypox/treatment-guidelines.htm

Chen X et al. Molluscum contagiosum virus infection. Lancet Infect Dis. 2013 Oct;13(10):877–88. [PMID: 23972567]

Levy Y et al. Estimated size of the population at risk of severe adverse events after smallpox vaccination in Israel. Vaccine. 2012 Oct 19;30(47):6632–5. [PMID: 22963804]

Midilli K et al. Nosocomial outbreak of disseminated orf infection in a burn unit, Gaziantep, Turkey, October to December 2012. Euro Surveill. 2013 Mar 14;18(11):20425. Erratum in: Euro Surveill. 2013;18(14):20442. [PMID: 23517869]

Nougairede A et al. Sheep-to-human transmission of Orf virus during Eid al-Adha religious practices, France. Emerg Infect Dis. 2013 Jan;19(1):102–5. [PMID: 23260031]

Wertheimer ER et al. Contact transmission of vaccinia virus from smallpox vaccinees in the United States, 2003–2011. Vaccine. 2012 Feb 1;30(6):985–8. [PMID: 22192851]

VIRUSES & GASTROENTERITIS

Viruses are responsible for at least 30–40% of cases of infectious diarrhea in the United States. These agents include rotaviruses; caliciviruses, including noroviruses such as Norwalk virus; astroviruses; enteric adenoviruses; and, less often, toroviruses, coronaviruses, picornaviruses (including the Aichi virus), and pestiviruses. Rotaviruses and noroviruses are responsible for most of nonbacterial cases of gastroenteritis.

Rotavirus infections follow an endemic pattern, especially in the tropics and low-income countries, although they peak during the winter in temperate regions. The virus is transmitted by fecal-oral route and can be shed in feces for up to 3 weeks in severe infections. In outbreak settings (eg, daycare centers), the virus is ubiquitously found in the environment, and secondary attack rates are between 16% and 30% (including household contacts). Nosocomial outbreaks are reported. The disease is usually mild and self-limiting. A 2- to 3-day prodrome of fever and vomiting is followed by nonbloody diarrhea (up to 10–20 bowel movements per day) lasting for 1–4 days. The method of choice for diagnosis is PCR of the stool. It is thought that rarely systemic disease occurs and rare reported presentations include cerebellitis and pancreatitis. Treatment is largely symptomatic, with fluid and electrolyte replacement. A trial with nitazoxanide was attendant with moderate success among a small cohort of patients with gastroenteritis from Egypt with efficacy in both the rotavirus and norovirus subgroups. The enkephalinase inhibitor racecadotril (also known as acetorphan, given 1.5 mg/kg every 8 hours orally) is available in many countries (but not the United States), and in a meta-analysis appears to be clinically effective in reducing diarrheal symptoms. Local intestinal immunity gives protection against successive infection.

Two oral rotavirus vaccines are available in the United States: a live, oral, pentavalent human-bovine reassortment rotavirus vaccine (PRV, RotaTeq; to be given at 2, 4, and 6 months of age) and a live, oral attenuated monovalent human rotavirus vaccine (HRV, Rotarix; to be given at 2 and 4 months of age). The two vaccines show equal efficacy and the RotaTeq shows efficacy even with incomplete two-dose regimens. The pentavalent vaccine showed 40% efficacy in reducing the rate of new acute water diarrhea in a study among children under age 5 in Nicaragua. Contraindications include allergy to any of the vaccine ingredients, previous allergic reaction to the vaccine, and immunodeficiency. The risk of intussusception, which is far lower with this than earlier rotavirus preparations, is small (1:51,000 to 1:68,000 vaccinated infants) and is considered significantly lower than the risk associated with untreated rotavirus gastroenteritis.

The finding of small segments of a porcine circovirus in both Rotarix and RotaTeq is thought to be a contaminant derivative of the manufacturing process. These porcine circoviruses are abbreviated PCV and are not to be confused with pneumococcal conjugate vaccine. The manufacturers assure the public that both products are safe. Vaccine coverage is inadequate in the United States for rotavirus (68% in the 2012 National Immunization Study), particularly among the poor.

A new live, oral vaccine given as two doses at 2-month intervals, Rotavin-M1, was released in Vietnam in April 2012, and appears to be safe, effective, and easy to administer. A new oral vaccine in India is awaiting approval. This vaccine, RotaVac, is to be given at 6, 10, and 14 months, is safely coadministered with oral polio vaccines, and costs only a tenth of standard rotavirus vaccines. Neonatal viral strains are being used for vaccine development in Australia, the United States, and India, and alternative parenteral modes of immunization remain under study.

Noroviruses, such as Norwalk virus (one of a variety of small round viruses divided into 5 genogroups and at least 34 genotypes), are major causes of severe diarrhea in adults and are recognized as the major cause of epidemic gastroenteritis (with food handlers largely responsible and associated foods most often leafy vegetables, fruits/nuts, and molluscs). They are responsible for a significant percentage of childhood hospitalizations for gastroenteritis in the developing world (15% in surveys from India, 31% from Peru) and about 13% of gastroenteritis-associated ambulatory visits in the United States. The efficacy of the rotavirus vaccination is increasing the percentage of gastroenteritis caused by norovirus. The noroviruses appear to evolve by antigenic drift (similar to influenza). While 90% of young adults show serologic evidence of past infection, no long-lasting protective immunity develops and reinfections are common. In the United States, noroviruses are responsible for over 90% of reported nonbacterial gastroenteritis outbreaks during cold weather intervals (hence the colloquial name “gastric flu”). Outbreak environments include long-term–care facilities (nursing homes in particular), restaurants, hospitals, schools, daycare centers, vacation destinations (including cruise ships), and military bases. Persons at particular risk are the young, the elderly, the institutionalized, and the immunosuppressed. A new strain that began in Australia (GII.4 Sydney) is responsible for increasing proportions of US cases and is transmitted most often in long-term–care facilities. Although transmission is usually fecal, oral, airborne, person-to-person, and waterborne transmission are also documented. A short incubation period (24–48 hours), a short symptomatic illness (12–60 hours, but up to 5 days in hospital-associated cases and in children under 11 years of age), a high frequency (> 50%) of vomiting, and absence of bacterial pathogens in stool samples are highly predictive of norovirus gastroenteritis. RT-PCR of stool samples is used for epidemiologic purposes. Treatment is largely symptomatic. Deaths are rare, and the more common associated diseases are aspiration pneumonia, septicemia, and necrotizing enterocolitis.

Outbreak control for both rotavirus and norovirus infections include strict adherence to general hygienic measures. Despite the promise of alcohol-based sanitizers for the control of pathogen transmission, such cleansers may be relatively ineffective against the noroviruses compared with antibacterial soap and water, reinforcing the need for new hygienic agents against this prevalent group of viruses. Cohorting of sick patients, contact precautions for symptomatic hospitalized patients, exclusion from work of symptomatic staff until symptom resolution (or 48–72 h after this for norovirus disease), and proper decontamination procedures are crucial.

The reports of efficacy with nitazoxanide or racecadotril in acute gastroenteritis suggest that new avenues of therapy may become more widely available in the future. Vaccine developments are attendant with the complications associated with the rapid evolution (“antigenic drift”) of noroviruses, duration of immunity, and the probable need for annual strain selection to match circulating variants. Studies for an intranasally derived vaccine remain underway.

Atmar RL et al. Norovirus vaccine development: next steps. Expert Rev Vaccines. 2012 Sep;11(9):1023–5. [PMID: 23151158]

Becker-Dreps S et al. Community diarrhea incidence before and after rotavirus vaccine introduction in Nicaragua. Am J Trop Med Hyg. 2013 Aug;89(2):246–50. [PMID: 23817336]

Bresee JS et al; US Acute Gastroenteritis Etiology Study Team. The etiology of severe acute gastroenteritis among adults visiting emergency departments in the United States. J Infect Dis. 2012 May 1;205(9):1374–81. [PMID: 22454468]

Centers for Disease Control and Prevention (CDC). Building laboratory capacity to support the global rotavirus surveillance network. MMWR Morb Mortal Wkly Rep. 2013 May 24;62(20):409–12. [PMID: 23698607]

Cortese MM et al. Effectiveness of monovalent and pentavalent rotavirus vaccine. Pediatrics. 2013 Jul;132(1):e25–33. [PMID: 23776114]

Gastañaduy PA et al. Burden of norovirus gastroenteritis in the ambulatory setting—United States, 2001–2009. J Infect Dis. 2013 Apr;207(7):1058–65. [PMID: 23300161]

Hall AJ et al. Epidemiology of foodborne norovirus outbreaks, United States, 2001–2008. Emerg Infect Dis. 2012 Oct;18(10):1566–73. [PMID: 23017158]

Payne DC et al. Norovirus and medically attended gastroenteritis in U.S. children. N Engl J Med. 2013 Mar 21;368(12):1121–30. [PMID: 23514289]

Soares-Weiser K et al. Vaccines for preventing rotavirus diarrhoea: vaccines in use. Cochrane Database Syst Rev. 2012 Nov 14;11:CD008521. [PMID: 23152260]

Trivedi TK et al. Hospitalizations and mortality associated with norovirus outbreaks in nursing homes, 2009–2010. JAMA. 2012 Oct 24;308(16):1668–75. [PMID: 23079758]

Vesikari T. Rotavirus vaccination: a concise review. Clin Microbiol Infect. 2012 Oct;18(Suppl 5):57–63. [PMID: 22882248]

ENTEROVIRUSES THAT PRODUCE SEVERAL SYNDROMES

The most famous enterovirus, the poliomyelitis virus, is discussed above under Vaccine Preventable Diseases. Other clinically relevant enteroviral infections are discussed in this section.

  1. Coxsackievirus Infections

Coxsackievirus infections cause several clinical syndromes. As with other enteroviruses, infections are most common during the summer. Two groups, A and B, are defined either serologically or by mouse bioassay. There are more than 50 serotypes.

 Clinical Findings

  1. Symptoms and Signs

The clinical syndromes associated with coxsackievirus infection are summer grippe; herpangina; epidemic pleurodynia; aseptic meningitis and other neurologic syndromes; acute nonspecific pericarditis; myocarditis; hand, foot, and mouth disease; epidemic conjunctivitis; and other syndromes.

  1. Summer grippe (A and B)—A febrile illness, principally of children, summer grippe usually lasts 1–4 days. Minor symptoms of upper respiratory tract infection are often present.
  2. Herpangina (A2–6, 10: B3)—There is sudden onset of fever, which may be as high as 40.6°C, sometimes with febrile convulsions. Other symptoms are headache, myalgia, and vomiting. The sore throat is characterized early by petechiae or papules on the soft palate that ulcerate in about 3 days and then heal. An outbreak in Taiwan with A2 was associated with herpangina and coincided with an enterovirus 71 (below) outbreak, characterized by hand, foot, and mouth disease. Dual A6/A10 outbreaks are reported from Europe. Treatment is symptomatic.
  3. Epidemic pleurodynia (Bornholm disease) (B1–5)—Pleuritic pain is prominent. Tenderness, hyperesthesia, and muscle swelling are present over the area of diaphragmatic attachment. Other findings include headache, sore throat, malaise, nausea, and fever. Orchitis and aseptic meningitis occur in < 10% of patients. Most patients are ill for 4–6 days.
  4. Aseptic meningitis (A and B) and other neurologic syndromes—Fever, headache, nausea, vomiting, stiff neck, drowsiness, and cerebrospinal fluid lymphocytosis without chemical abnormalities may occur, and pediatric clusters of group B (especially B5) meningitis are reported. Focal encephalitis and transverse myelitis are reported with coxsackievirus group A. Disseminated encephalitis occurs after group B infection, and acute flaccid paralysis is reported with both coxsackievirus group A and B. An outbreak of aseptic meningitis occurred in central China (Gansu Province) in 2008, with 85 cases reported of coxsackie A9 disease. Severe neonatal illnesses are reported with B1 infections, including encephalomyocarditis and neonatal deaths due to multiorgan failure.
  5. Acute nonspecific pericarditis (B types)—Sudden onset of anterior chest pain, often worse with inspiration and in the supine position, is typical. Fever, myalgia, headache, and pericardial friction rub appear early and these symptoms are often transient. Evidence for pericardial effusion on imaging studies is often present, and the occasional patient has a paradoxical pulse. Electrocardiographic evidence of pericarditis is often present. Relapses may occur.
  6. Myocarditis (B1–5)—Heart failure in the neonatal period secondary to in utero myocarditis and over 20% of adult cases of myocarditis and dilated cardiomyopathy are associated with group B (especially B3) infections.
  7. Hand, foot, & mouth disease (A5, 6, 10, 12, and 16, B5)—This disease is sometimes epidemic and is characterized by stomatitis, a vesicular rash on hands and feet, nail dystrophies and onychomadesis (nail shedding). Enterovirus 71 is also a causative agent (see below).
  8. Epidemic conjunctivitis—As with enterovirus 70 (see below), the A24 variant of coxsackievirus is associated with acute epidemic hemorrhagic conjunctivitis in tropical areas with outbreaks reported in the last few years in southern China, Pakistan, southern Sudan, the Comoros, Uganda, and Cuba.
  9. Other syndromes associated with coxsackievirus infections—These include rhabdomyolysis, fulminant neonatal hepatitis (occurs rarely), infant sepsis (A10), glomerulopathy (group B infections), onychomadesis (B1), types 1 and 2 diabetes mellitus (mainly group B infections),and thyroid disease (group B4), although definitive causality is not established. A pathogenic role in primary Sjögren syndrome and acute myocardial infarction has also been proposed for group B coxsackievirus infections. A recent report of confirmed infective endocarditis due to coxsackievirus B2 in a patient with a prosthetic cardiac device suggests that viral etiologies of culture-negative infective endocarditis should be considered.
  10. Laboratory Findings

Routine laboratory studies show no characteristic abnormalities. Neutralizing antibodies appear during convalescence. The virus may be isolated from throat washings or stools inoculated into suckling mice. Viral culture is expensive, labor demanding, and requires several days for results. A PCR test for enterovirus RNA is available and, although it cannot identify the serotype, it appears to be useful, particularly in cases of meningitis.

 Treatment & Prognosis

Treatment is symptomatic. With the exception of meningitis, myocarditis, pericarditis, diabetes, and rare illnesses such as pancreatitis or poliomyelitis-like states, the syndromes caused by coxsackieviruses are benign and self-limited. Two controlled trials showed a potential clinical benefit with pleconaril for patients with enteroviral meningitis although the compassionate use of this drug has stopped. There are anecdotal reports of success with IVIG in severe disease. Coxsackie A16 and enterovirus 71 (see below) in outbreaks of hand, foot, and mouth disease can be controlled with 5 minutes of exposure to 3120 ppm sodium hypochlorite.

Abzug MJ. The enteroviruses: problems in need of treatments. J Infect. 2014 Jan;68(Suppl 1):S108–14. [PMID: 24119825]

Centers for Disease Control and Prevention (CDC). Notes from the field: severe hand, foot, and mouth disease associated with coxsackievirus A6—Alabama, Connecticut, California, and Nevada, November 2011–February 2012. MMWR Morb Mortal Wkly Rep. 2012 Mar 30;61(12):213–4. [PMID: 22456122]

Gkrania-Klotsas E et al. The association between prior infection with five serotypes of Coxsackievirus B and incident type 2 diabetes mellitus in the EPIC-Norfolk study. Diabetologia. 2012 Apr;55(4):967–70. [PMID: 22231126]

Xu M et al. Enterovirus genotypes causing hand foot and mouth disease in Shanghai, China: a molecular epidemiological analysis. BMC Infect Dis. 2013 Oct 22;13:489. [PMID: 24148902]

  1. Echovirus Infections

Echoviruses are enteroviruses that produce several clinical syndromes, particularly in children. Infection is most common during summer. Among reported specimens, death ensues in about 3%. Males younger than 20 years are more commonly infected than other persons.

Over 30 serotypes of echoviruses are recognized and the most common serotypes for disease are types 6, 9, 11, and 30. Most can cause aseptic meningitis, which may be associated with a rubelliform rash. Transmission is primarily fecal–oral. Handwashing is an effective control measure in outbreaks of aseptic meningitis. Outbreaks related to fecal contamination of water sources, including drinking water and swimming and bathing pools, were reported in the past.

Besides meningitis, other conditions associated with echoviruses range from common respiratory diseases (bronchiolitis occurs often in children) and epidemic diarrhea to myocarditis, a hemorrhagic obstetric syndrome, keratoconjunctivitis, hepatitis with coagulopathy, leukocytoclastic vasculitis, and neonatal as well as adult cases of encephalitis and sepsis, interstitial pneumonitis, hemophagocytic syndromes (in children with cancer), sudden deafness, encephalitis, optic neuritis, uveitis, and septic shock. Echoviruses and enteroviruses are also a common cause of nonspecific exanthems.

As with other enterovirus infections, diagnosis is best established by correlation of clinical, epidemiologic, and laboratory evidence. Cytopathic effects are produced in tissue culture after recovery of virus from throat washings, blood, or cerebrospinal fluid. An enterovirus PCR of the cerebrospinal fluid can assist in the diagnosis and is associated with a shorter duration of hospitalization in febrile neonates. Fourfold or greater rises in antibody titer signify systemic infection.

Treatment is usually symptomatic, and the prognosis is excellent, though there are reports of mild paralysis after CNS infection. In vitro data suggest some role for amantadine or ribavirin but clinical studies supporting these findings are not available. Pleconaril is no longer available for compassionate use.

From a public health standpoint, clustered illnesses such as swimming in sewage-infested sea water in travelers suggest point-source exposure. Prevention of fecal–oral contamination and maintenance of pool hygiene through chlorination and pH control are important public health control measures.

Centers for Disease Control and Prevention (CDC). Nonpolio enterovirus and human parechovirus surveillance—United States, 2006–2008. MMWR Morb Mortal Wkly Rep. 2010 Dec 10;59(48):1577–80. [PMID: 21150865]

Maan HS et al. Genetic variants of echovirus 13, northern India, 2010. Emerg Infect Dis. 2013 Feb;19(2):293–6. [PMID: 23343581]

Wildenbeest JG et al. Pleconaril revisited: clinical course of chronic enteroviral meningoencephalitis after treatment correlates with in vitro susceptibility. Antivir Ther. 2012;17(3):459–66. [PMID: 22293148]

  1. Enteroviruses 70, 71, & Related Agents

Several distinct clinical syndromes are being described in association with enteroviruses. Enterovirus 70 (HEV-70), a ubiquitous agent first identified in 1969 and responsible for abrupt bilateral eye discharge and subconjunctival hemorrhage with occasional systemic symptoms, is most commonly associated with acute hemorrhagic conjunctivitis. Enterovirus infection of the pancreas can trigger cell-mediated autoimmune destruction of beta-cells resulting in diabetes. Enterovirus myocarditis can be a serious infection in neonates, complicated by cardiac dysfunction and arrhythmias. Enterovirus 71 (HEV-71) almost always occurs in the Asia-Pacific region and is associated with hand, foot, and mouth disease (HFMD), herpangina as well as a form of epidemic encephalitis associated on occasion with pulmonary edema, and acute flaccid paralysis often mimicking poliomyelitis. An outbreak of HFMD in Fuyang China in 2008 was caused by a recombinant virus between HEV-71 and coxsackievirus A16. In Taiwan, 29% of HEV-71 in children is asymptomatic. There is an association reported between gastrointestinal enterovirus infection and type 1 diabetes.

Human enteroviruses are neurotropic and a potential role for these viruses in amyotropic lateral sclerosis is the subject of some investigation.

Mortality is especially high in enterovirus 71-associated brainstem encephalitis, which is often complicated by pulmonary edema, particularly when it occurs in children younger than 5 years. A complication is autonomic nervous system dysregulation, which may develop prior to the pulmonary edema. Because of lower herd immunity, HFMD tends to infect the very young (under age 5) in nonendemic areas. Disease is usually more severe and sequelae more common than with other enteroviruses. Some children with enterovirus-associated cardiopulmonary failure require the usage of extracorporeal life support, which can improve the outcome. Recognized sequelae include central hypoventilation, dysphagia, and limb weakness.

Diagnosis of both entities is facilitated by the clinical and epidemiologic findings with the isolation of the suspect agent from conjunctival scraping for enterovirus 70 or vesicle swabs, body secretions, or cerebrospinal fluid for enterovirus 71. Enzyme immunoassays and complement fixation tests show good specificity but poor sensitivity (< 80%). RT-PCR may increase the detection rate in enterovirus infections and is useful in the analysis of cerebrospinal fluid samples among patients with meningitis and of blood samples among infants with a sepsis-like illness.

Treatment of both entities remains largely symptomatic. The role of immunoglobulins is under investigation. The major complication associated with enterovirus 70 is the rare development of an acute neurologic illness with motor paralysis akin to poliomyelitis. Attention-deficit with hyperactivity occurs in about 20% with confirmed infection.

Household contacts, especially children under 6 months of age, are at particular risk for enterovirus 71 acquisition. A commercial disinfectant, Virkon S, at 1–2% application, appears to reduce infectivity titers. A stage-based supportive treatment for enterovirus 71 infections, recognizing the potential for late onset CNS disease and cardiopulmonary failure is important. An E71 vaccine is in phase III clinical trials.

Enterovirus 72 (HEV-2) is another term for hepatitis A virus (see Chapter 16). Enterovirus EV-104A is related to rhinoviruses and associated with respiratory illness in reports from Italy and Switzerland.

Enterovirus 68 (HEV-68) is a unique enterovirus that shares epidemiologic characteristics with human rhinovirus and is typically associated with respiratory illness. Several clusters are reported from the Netherlands, Japan, the Philippines, the United States, and Thailand. The agent is implicated in a recent, fatal case of meningomyeloencephalitis.

Centers for Disease Control and Prevention (CDC). Clusters of acute respiratory illness associated with human enterovirus 68—Asia, Europe, and United States, 2008–2010. MMWR Morb Mortal Wkly Rep. 2011 Sep 30;60(38):1301–4. [PMID: 21956405]

Li YP et al. Immunogenicity, safety, and immune persistence of a novel inactivated human enterovirus 71 vaccine: a phase II, Randomized, double-blind, placebo-controlled Trial. J Infect Dis. 2014 Jan 1;209(1):46–55. [PMID: 23922377]

Oikarinen M et al. Type 1 diabetes is associated with enterovirus infection in gut mucosa. Diabetes. 2012 Mar;61(3):687–91. [PMID: 22315304]

  1. Human Parechovirus Infection (HPeV)

HPeV is a member of the Picornaviridae family. The pathogen mainly affects small children although disease can also occur in older adults. Cases are spread worldwide. There were 16 genotypes recognized worldwide by 2013. Clinical presentation is mainly driven by gastrointestinal and respiratory illness, although otitis, neonatal sepsis, flaccid paralysis, myalgias, diffuse maculopapular and palmar-plantar rashes, aseptic meningitis, and encephalitis are described in the literature.

The added screening with a human parechovirus-specific PCR provides a significant increase in determining the viral cause of neonatal sepsis or CNS symptoms in children younger than 5 years. Human parechoviruses are one of the leading causes of viral sepsis and meningitis in young children. HPeV1 is the most prevalent genotype found among stool and nasopharyngeal samples in children (under 2 years old), whereas HPeV6 affects older individuals (> 20 years old). HPeV3 is responsible for encephalitis, neonatal sepsis, and was recently reported in association with necrotizing enterocolitis and hepatitis. It is the most prevalent picornavirus type found in cerebrospinal fluid samples of CNS-related infections in very young children. Respiratory and gastrointestinal illnesses are seen with types HPeV4–HPeV6, HPeV10, HPeV13-HPeV15. Neonatal deaths are reported with HPeV3 and HPeV6. Treatment is largely supportive and rapid identification of the viral antigen by PCR in stools, respiratory samples, and cerebrospinal fluid may decrease use of unnecessary antibiotics and shorten hospital stay, although current PCR assays are not always sufficiently sensitive to exclude parechoviruses. Reported complications of neonatal cerebral infections include learning disabilities, epilepsy, and cerebral palsy.

Alam MM et al. Human parechovirus genotypes -10, -13 and -15 in Pakistani children with acute dehydrating gastroenteritis. PLoS One. 2013 Nov 12;8(11):e78377. [PMID: 24265685]

Chen H et al. Molecular detection of human parechovirus in children with acute gastroenteritis in Guangzhou, China. Arch Virol. 2013 Nov 13. [Epub ahead of print] [PMID: 24221251]

Eis-Hübinger AM et al. Two cases of sepsis-like illness in infants caused by human parechovirus traced back to elder siblings with mild gastroenteritis and respiratory symptoms. J Clin Microbiol. 2013 Feb;51(2):715–8. [PMID: 23241372]

RICKETTSIAL DISEASES

TYPHUS GROUP

  1. Epidemic Louse-Borne Typhus

 ESSENTIALS OF DIAGNOSIS

 Prodrome of headache, then chills and fever.

 Severe, intractable headaches, prostration, persisting high fever.

 Macular rash appearing on the fourth to seventh days on the trunk and in the axillae, spreading to the rest of the body but sparing the face, palms, and soles.

 Diagnosis confirmed by specific antibodies using complement fixation, microagglutination, or immunofluorescence.

 General Considerations

Epidemic louse-borne typhus is caused by Rickettsia prowazekii, an obligate parasite of the body louse Pediculus humanus corporis (Table 32–3). Transmission is favored by crowded, unsanitary living conditions, famine, war, or any circumstances that predispose to heavy infestation with lice. After biting a person infected with R prowazekii, the louse becomes infected by the organism, which persists in the louse gut and is excreted in its feces. When the same louse bites an uninfected individual, the feces gain entry into the bloodstream when the person scratches the itching wound. Dry, infectious louse feces may also enter via the respiratory tract. Cases can be acquired by travel to pockets of infection (eg, central and northeastern Africa, Central and South America). Outbreaks have been reported from Peru, Burundi, and Russia. Because of aerosol transmissibility, R prowazekii is considered a possible bioterrorism agent. In the United States, cases occur among the homeless, refugees, and the unhygienic, most often in the winter.

Table 32–3. Rickettsial diseases.

R prowazekii can survive in lymphoid and adipose (in endothelial reservoirs) tissues after primary infection, and years later, produce recrudescence of disease (Brill-Zins ser disease) without exposure to infected lice. This phenomenon can serve as a point source for future outbreaks.

An extrahuman reservoir of R prowazekii in the United States is flying squirrels, Glaucomys volans. Transmission to humans can occur through their ectoparasites, usually causing atypical mild disease. A case of recrudescent (Brill-Zinsser) disease 11 years after disease acquired by contact with flying squirrels is reported. Foci of sylvatic typhus are found in the eastern United States and are reported to occur in Brazil, Ethiopia, and Mexico.

 Clinical Findings

  1. Symptoms and Signs

(Table 32–2). Prodromal malaise, cough, headache, backache, arthralgia, and chest pain begin after an incubation period of 10–14 days, followed by an abrupt onset of chills, high fever, and prostration, with flu-like symptoms progressing to delirium and stupor. The headache is severe and the fever is prolonged.

Other findings consist of conjunctivitis, mild vitritis, retinal lesions, optic neuritis, and hearing loss from neuropathy of the eighth cranial nerve, flushed facies, rales at the lung bases, abdominal pain, myalgias, and often splenomegaly. A macular rash (that may become confluent) appears first in the axillae and then over the trunk, spreading to the extremities but rarely involving the face, palms, or soles. In severely ill patients, the rash becomes hemorrhagic, and hypotension becomes marked. There may be acute kidney injury, stupor, seizures, and delirium. Improvement begins 13–16 days after onset with a rapid drop of fever and typically a spontaneous recovery.

  1. Laboratory Findings

The white blood cell count is variable. Thrombocytopenia, elevated liver enzymes, proteinuria and hematuria commonly occur. Serum obtained 5–12 days after onset of symptoms usually shows specific antibodies for R prowazekii antigens as demonstrated by complement fixation, microagglutination, or immunofluorescence. In primary rickettsial infection, early antibodies are IgM; in recrudescence (Brill-Zinsser disease), early antibodies are predominantly IgG. A PCR test exists, but its availability is limited. R prowazekii is differentiated into 7 genotypes.

  1. Imaging

Radiographs of the chest may show patchy consolidation.

 Differential Diagnosis

The prodromal symptoms and the early febrile stage lack enough specificity to permit diagnosis in nonepidemic situations. The rash is sufficiently distinctive for diagnosis, but it may be absent in up to 50% of cases or may be difficult to observe in dark-skinned persons. A variety of other acute febrile diseases should be considered, including typhoid fever, meningococcemia, and measles.

 Complications

Pneumonia, thromboses, vasculitis with major vessel obstruction and gangrene, circulatory collapse, myocarditis, and uremia may occur.

 Treatment

Treatment consists of either doxycycline (100 mg orally twice daily) or chloramphenicol (50–100 mg/kg/d in four divided doses, orally or intravenously) for 4–10 days. Chloramphenicol is considered less effective than doxycycline, but it is still the drug of choice in pregnancy. In epidemic conditions, a single dose of doxycycline can be effective and is less costly.

 Prognosis

The prognosis depends greatly on the patient’s age and immune status. In children under age 10 years, the disease is usually mild. The mortality rate is 10% in the second and third decades but in the past reached 60% in the sixth decade. Brill-Zinsser disease (recrudescent epidemic typhus) has a more gradual onset than primary R prowazekii infection, fever and rash are of shorter duration, and the disease is milder and rarely fatal.

 Prevention

Prevention consists of louse control with insecticides, particularly by applying chemicals to clothing or treating it with heat, and frequent bathing. The control of typhus in Finland during World War II is attributed to sauna use.

A deloused and bathed typhus patient is not infectious. The disease is not transmitted from person to person. Patients are infectious for the lice during the febrile period and perhaps 2–3 days after the fever returns to normal. Infected lice pass rickettsiae in their feces within 2–6 days after the blood meal and can be infectious earlier if crushed. Rickettsiae remain viable in a dead louse for weeks.

No vaccine is currently available for the prevention of R prowazekii infection.

Badiaga S et al. Human louse-transmitted infectious diseases. Clin Microbiol Infect. 2012 Apr;18(4):332–7. [PMID: 22360386]

Faucher JF et al. Brill-Zinsser disease in Moroccan man, France, 2011. Emerg Infect Dis. 2012 Jan;18(1):171–2. [PMID: 22261378]

  1. Endemic Flea-Borne Typhus (Murine Typhus)

Rickettsia typhi, a ubiquitous pathogen recognized on all continents, is transmitted from rat to rat through the rat flea (Table 32–3). Serosurveys of animals show high prevalence of antibodies to R typhi in opossums, followed by dogs and cats. Humans usually acquire the infection in an urban or suburban setting when bitten by an infected flea, which releases infected feces while sucking blood. Rare human cases in the developed world follow travel, usually to Southeast Asia, Africa (Burundi and Ethiopia have foci of infection), or the Mediterranean area although other pockets of infection are also known to occur in the Andes. In the United States, cases are mainly reported from Texas and Southern California.

Endemic typhus resembles recrudescent epidemic typhus in that it has a gradual onset, less severe symptoms, and a shorter duration of illness than epidemic typhus (7–10 days versus 14–21 days). The presentation is nonspecific, including fever, headache, and chills. Maculopapular rash occurs in around 50% of cases; it is concentrated on the trunk and fades fairly rapidly. Liver dysfunction occurs in the majority of cases. Peripheral facial paralysis and splenic infarction are reported to occur. Severe disease with mental confusion and signs of hepatic, cardiac, renal, and pulmonary involvement may develop. Postinfectious optic neuritis is rare and may occur weeks after successful treatment. Rare complications include a respiratory distress syndrome and a hemophagocytosis syndrome. Jaundice, bradycardia, and the absence of a headache are correlated with a delayed defervescence (in both epidemic and endemic typhus).

The most common entity in the differential diagnosis is Rocky Mountain spotted fever, usually occurring after a rural exposure and with a different rash (centripetal versus centrifugal for epidemic or endemic typhus). Serologic confirmation may be necessary for differentiation, with complement-fixing or immunofluorescent antibodies detectable within 15 days after onset, with specific R typhi antigens. A fourfold rise in serum antibody titers between the acute and the convalescence phase is diagnostic.

Antibiotic treatment is the same as for epidemic typhus (see above). Ciprofloxacin (500–750 mg orally twice a day) and ampicillin (500 mg orally three times a day) are reportedly successful in pregnant women. Mortality is usually low with (1%) or without (4%) appropriate antibiotics. Preventive measures are directed at control of rats and ectoparasites (rat fleas) with insecticides, rat poisons, and rat-proofing of buildings.

Anyfantakis D et al. Liver function test abnormalities in murine typhus in Greece: a retrospective study of 165 cases. Infez Med. 2013 Sep;21(3):207–10. [PMID: 24008853]

Badiaga S et al. Murine typhus in the homeless. Comp Immunol Microbiol Infect Dis. 2012 Jan;35(1):39–43. [PMID: 22093517]

Raby E et al. Endemic (murine) typhus in returned travelers from Asia, a case series: clues to early diagnosis and comparison with dengue. Am J Trop Med Hyg. 2013 Apr;88(4):701–3. [PMID: 23358638]

  1. Scrub Typhus (Tsutsugamushi Fever)

 ESSENTIALS OF DIAGNOSIS

 Exposure to mites in endemic area of Southeast Asia, the western Pacific (including Korea), and Australia.

 Black eschar at site of the bite, with regional and generalized lymphadenopathy.

 High fever, headache, myalgia, and a short-lived macular rash.

 Frequent pneumonitis, encephalitis, and cardiac failure.

 General Considerations

Scrub typhus is caused by Orientia tsutsugamushi, which is principally a parasite of rodents and is transmitted by larval trombiculid mites (chiggers). The disease is endemic in Korea, China, Taiwan, Japan, Pakistan, India, Thailand, Malaysia and Queensland, Australia (Table 32–3), which form an area known as the “tsutsugamushi triangle”. Transmission is often more common at higher altitudes. The mites live on vegetation but complete their maturation cycle by biting humans who come in contact with infested vegetation. Therefore, the disease is more common in rural areas within these countries. Vertical transmission occurs, and blood transfusions may transmit the pathogen as well. Rare occupational transmission via inhalation is documented among laboratory workers.

 Clinical Findings

  1. Symptoms and Signs

After a 1- to 3-week incubation period, malaise, chills, severe headache and backache develop. At the site of the bite, a papule evolves into a flat black eschar, a finding which is usually helpful for diagnosis. The regional lymph nodes are commonly enlarged and tender, and sometimes a more generalized adenopathy occurs. Fever rises gradually during the first week of infection and the rash is usually macular and primarily on the trunk area. The rash can be fleeting or more severe, peaking at 8 days but lasting up to 21 days after onset of infection. The patient may become obtunded. Gastrointestinal symptoms including nausea, vomiting, and diarrhea occur in nearly two-thirds of patients and correspond to the presence of superficial mucosal hemorrhage, multiple erosions, or ulcers in the gastrointestinal tract. Both acalculous cholecystitis and acute abdominal attacks are reported. Transient parkinsonism, opsoclonus, or myoclonus may occur. Severe complications, such as pneumonitis, myocarditis and heart failure, encephalitis or meningitis, acute abdominal pain, peritonitis, granulomatous hepatitis, disseminated intravascular coagulation, cerebrovascular hemorrhage or infarction, ARDS, hemophagocytosis, or acute kidney disease may develop during the second or third week. An attack confers prolonged immunity against homologous strains and transient immunity against heterologous strains. Heterologous strains produce mild disease if infection occurs within a year after the first episode.

  1. Laboratory Findings

Thrombocytopenia and elevation of liver enzymes, bilirubin, and creatinine are common. Serologic testing with immunofluorescence and immunoperoxidase assays or commercial dot-blot ELISA dipstick assays are convenient diagnostic aids, but a conclusive diagnosis requires documentation of a fourfold increase between acute and convalescence titers of antibodies. An indirect immunofluorescence assay is the mainstay of serologic diagnosis and titers quickly lose sensitivity so should be read as soon as possible after collection. A rapid immunochromatographic test for IgM and IgG detection is more sensitive and specific than the standard immunofluorescence assay. PCR (from the eschar or blood) may be the most sensitive diagnostic test but remains positive even after the initiation of treatment. Culture of the organism (by mouse inoculation) from blood obtained in the first few days of illness is another diagnostic modality but requires a specialized BioSafety Level 3 laboratory. Filter paper immunofluorescent assays are as sensitive and specific as paired sera and may be especially useful in field settings.

 Differential Diagnosis

Leptospirosis, typhoid, dengue, malaria, Q fever, hemorrhagic fevers, and other rickettsial infections should be considered. The headache may mimic trigeminal neuralgia. Scrub typhus is a recognized cause of obscure tropical fevers, especially in children.

 Treatment & Prognosis

Without treatment, fever subsides spontaneously after 2 weeks, but the mortality rate may be 10–30%. Empiric treatment for 3 days with doxycycline, 100 mg orally twice daily, or with minocyline, 100 mg intravenously twice daily, or for 7 days with chloramphenicol, 25 mg/kg/d orally or intravenously in four divided doses, eliminates most deaths and relapses. Chloramphenicol- and tetracycline-resistant strains have been reported from Southeast Asia, where azithromycin or roxythromycin may become the drug of choice for children, pregnant women, and patients with refractory disease. Rifampin reduces the duration of fever by 1 day when used with doxycycline.

Poor prognostic factors include requiring care in an ICU, high APACHE-II scores, age over 60 years, absence of an eschar (making the diagnosis difficult) and laboratory findings such as leukocytosis or hypoalbuminemia. HIV infection does not appear to influence the severity of scrub typhus.

 Prevention

Repeated application of long-acting miticides can make endemic areas safe. Insect repellents on clothing and skin as well as protective clothing are effective preventive measures. For short exposure, chemoprophylaxis with doxycycline (200 mg weekly) can prevent the disease but permits infection. No effective vaccines are available.

Chiou YH et al. Scrub typhus associated with transient parkinsonism and myoclonus. J Clin Neurosci. 2013 Jan;20(1):182–3. [PMID: 23010430]

Chung JH et al. Scrub typhus and cerebrovascular injury: a phenomenon of delayed treatment? Am J Trop Med Hyg. 2013 Jul;89(1):119–22. [PMID: 23716407]

Lee CH et al. Peritonitis in patients with scrub typhus. Am J Trop Med Hyg. 2012 Jun;86(6):1046–8. [PMID: 22665616]

Silpasakorn S et al. Development of new, broadly reactive, rapid IgG and IgM lateral flow assays for diagnosis of scrub typhus. Am J Trop Med Hyg. 2012 Jul;87(1):148–52. [PMID: 22764306]

SPOTTED FEVERS

  1. Rocky Mountain Spotted Fever

 ESSENTIALS OF DIAGNOSIS

 Exposure to tick bite in an endemic area.

 An influenza-like prodrome followed by chills, fever, severe headache, and myalgias; occasionally, delirium and coma.

 Red macular rash appears between the second and sixth days of fever, first on the wrists and ankles and then spreading centrally; it may become petechial.

 Serial serologic examinations by indirect fluorescent antibody confirm the diagnosis retrospectively.

 General Considerations

Despite its name, most cases of Rocky Mountain spotted fever (RMSF) occur outside the Rocky Mountain area. Passive surveillance data from 2002 to 2007 reported cases from 46 states and the District of Columbia. More than half (64%) of these cases were from only five states: North Carolina, Tennessee, Oklahoma, Missouri, and Arkansas. RMSF is endemic in Central and Southern America with a small fatal familiar cluster reported from Panama (Table 32–3). Native American residents are at high risk for infection. The causative agent, R rickettsii, is transmitted to humans by the bite of ticks, including the Rocky Mountain wood tick, D andersoni, in the western United States, and the American dog tick, Dermacentor variabilis, in the eastern United States. Several hours of contact between the tick and the human host are required for transmission. The brown dog tick, Rhipicephalus sanguineus, is a vector in eastern Arizona and responsible for many Native American cases. Other hard ticks transmit the organism in the southern United States and in Central and South America and are responsible for transmitting it among rodents, dogs, porcupines, and other animals. There are 25 genotypes of R rickettsii in four different groups, and potential genomic-clinical correlations are underway.

In the United States, the estimated annual incidence of RMSF is increasing to as high as seven cases per million persons (primarily occurring from April through September), with a higher incidence among children and men. Better diagnostic capacity and improved surveillance are thought responsible for the changing epidemiology.

 Clinical Findings

  1. Symptoms and Signs

RMSF can cause severe multiorgan dysfunction and fatality rates of up to 73% if left untreated, making it the most serious rickettsial disease. Two to 14 days (mean, 7 days) after the bite of an infectious tick, symptoms begin with the abrupt onset of high fevers, chills, headache, nausea and vomiting, myalgias, restlessness, insomnia, and irritability. The characteristic rash (faint macules that progress to maculopapules and then petechiae) appears between days 2 and 6 of fever. It initially involves the wrists and ankles, spreading centrally to the arms, legs, and trunk over the next 2–3 days. Involvement of the palms and soles is characteristic. Facial flushing, conjunctival injection, and hard palatal lesions (Figure 32–6) may occur. In about 10% of cases, however, no rash or only a minimal rash is seen. Cough and pneumonitis may develop and delirium, lethargy, seizures, stupor, and coma may also appear in more severe cases. Splenomegaly, hepatomegaly, jaundice, myocarditis (which may mimic an acute coronary syndrome), adrenal hemorrhage, or uremia are occasionally present. ARDS and necrotizing vasculitis, when present, are of greatest concern.

 Figure 32–6. Hard palate lesion caused by Rocky Mountain spotted fever. (Public Health Image Library, CDC.)

  1. Laboratory Findings

Thrombocytopenia, hyponatremia, elevated aminotransferases, and hyperbilirubinemia are common. Cerebrospinal fluid may show hypoglycorrhachia and mild pleocytosis. Disseminated intravascular coagulation is observed in severe cases. Diagnosis during the acute phase of the illness can be made by immunohistologic (including PCR) demonstration of R rickettsiae in skin biopsy specimens (or cutaneous swabs of eschars or skin lesions), but sensitivity is maximized by performing such studies as soon as skin lesions become apparent and before antibiotics commence. Isolation of the organism using the shell-vial technique is available in some laboratories but is hazardous.

Serologic studies confirm the diagnosis, but most patients do not mount an antibody response until the second week of illness. The indirect fluorescent antibody test is most commonly used. No commercial PCR technique is validated for serologic use.

 Differential Diagnosis

The diagnosis is challenging because early symptoms resemble those of many other infections. The classic triad of fever, rash, and tick bite is rarely recognized, with up to 40% of patients not recalling a tick bite. Moreover, the rash may be confused with that of measles, typhoid, and ehrlichiosis, or—most importantly—meningococcemia. Blood cultures and examination of cerebrospinal fluid establish the latter. Some spotted fever rickettsioses may also mimic RMSF.

 Treatment & Prognosis

Treatment with doxycycline at similar doses and duration as for epidemic typhus (100 mg orally twice daily for 4–10 days) is recommended, including for children. Similarly, chloramphenicol (50–100 mg/kg/d in four divided doses, orally or intravenously for 4–10 days) is the preferred alternative during pregnancy. Patients usually defervesce within 48–72 hours and therapy should be maintained for at least 3 days after defervescence occurs. Mild cases in low-risk individuals may be observed without treatment.

The reported mortality rate in the United States is about 3–5%. The following features are associated with increased mortality: (1) infection in very young children, the elderly, or Native Americans; (2) the presence of atypical clinical features (absence of headache, no history of tick attachment, gastrointestinal symptoms) and underlying chronic diseases; (3), and a delay in initiation of appropriate antibiotic therapy. The usual cause of death is pneumonitis with respiratory or cardiac failure. Sequelae may include seizures, encephalopathy, peripheral neuropathy, paraparesis, bowel and bladder incontinence, cerebellar and vestibular dysfunction, hearing loss, and motor deficits.

 Prevention

Protective clothing, tick-repellent chemicals, and the removal of ticks at frequent intervals are helpful measures. Prophylactic therapy after a tick bite is not currently recommended.

Dahlgren FS et al. Fatal Rocky Mountain spotted fever in the United States, 1999–2007. Am J Trop Med Hyg. 2012 Apr;86(4):713–9. [PMID: 22492159]

Mosites E et al. Knowledge, attitudes, and practices regarding Rocky Mountain spotted fever among healthcare providers, Tennessee, 2009. Am J Trop Med Hyg. 2013 Jan;88(1):162–6. [PMID: 23243110]

Woods CR. Rocky Mountain spotted fever in children. Pediatr Clin North Am. 2013 Apr;60(2):455–70. [PMID: 23481111]

  1. Rickettsialpox

Rickettsialpox is an acute, self-limiting, febrile illness caused by Rickettsia akari, a parasite of mice, transmitted by the mite Liponyssoides sanguineus (Table 32–3). Infections are reported globally. Seroprevalence studies done on injection drug users in inner Baltimore showed antibody positivity as high as 16%. The illness has also been found in farming communities. Crowded conditions and mouse-infested housing allow transmission of the pathogen to humans. The primary lesion is a painless red papule that vesiculates and forms a black eschar followed by an incubation period of 7–12 days. Onset of symptoms is sudden, with chills, fever, headache, photophobia, and disseminated aches and pains. Two to 4 days later, a widespread papular eruption appears. The rash becomes vesicular and forms crusts that are shed in about 10 days. Early lesions may resemble those of chickenpox (typically vesicular versus papulovesicular in rickettsialpox). Pathologic findings include dermal edema, subepidermal vesicles, and at times a lymphocytic vasculitis.

Transient leukopenia and thrombocytopenia and acute hepatitis can occur. A fourfold rise in serum antibody titers to rickettsial antigen, detected by complement fixation or indirect fluorescent assays, is diagnostic. Conjugated anti-rickettsial globulin can identify antigen in punch biopsies of skin lesions. PCR detection of rickettsial DNA in fresh tissue also appears of value. R akari can reportedly also be isolated from eschar biopsy specimens.

Treatment consists of oral doxycycline (200 mg/d) for 7 days. The disease is usually mild and self-limited without treatment, but occasionally severe symptoms may require hospitalization. Control requires the elimination of mice from human habitations and insecticide applications.

Eremeeva ME et al. Investigation of an outbreak of rickettsial febrile illness in Guatemala, 2007. Int J Infect Dis. 2013 May;17(5):e304–11. [PMID: 23266334]

Renvoisé A et al. A case of rickettsialpox in Northern Europe. Int J Infect Dis. 2012 Mar;16(3):e221–2. [PMID: 22257655]

  1. Tick Typhus (Rickettsial Fever)

The term “tick typhus” denotes a variety of spotted rickettsial fevers, often named by their geographic location (eg, Mediterranean spotted fever, Queensland tick typhus, Oriental spotted fever, African tick bite fever, Siberian tick typhus, North Asian tick typhus), or by morphology (eg, boutonneuse fever). These illnesses are transmitted by tick vectors of the rickettsial organisms R africaeR australis, R conorii, R japonica, R massiliae, R parkeri, and R sibirica (Table 32–3). Dogs and wild animals, usually rodents and even reptiles, may serve as reservoirs. Travel is a risk factor for disease, particularly among elderly ecotourists. In a series of 280 international travelers with rickettsial disease, the most common cause was spotted fever rickettsiosis (231 cases, 82.5% of the total) followed by scrub typhus (16, 5.7%). The pathogens usually produce an eschar or black spot (tâche noire) at the site of the tick bite that may be useful in diagnosis, though spotless boutonneuse fever occurs. Symptoms include fever, headache, myalgias, and rash. Rarely, papulovesicular lesions may resemble rickettsialpox. Endothelial injury produces perivascular edema and dermal necrosis. Regional adenopathy, disseminated lesions, kidney disease, splenic rupture, and focal hepatic necrosis may occur. Neurologic manifestations, including encephalitis, internuclear ophthalmoplegia, coronary involvement, and the hemophagocytic syndrome, are rare.

The diagnosis is clinical, with serologic or PCR (culture can be used but is less sensitive than either) used for confirmation, and treatment should be started upon clinical suspicion since delayed therapy is the usual cause of increased morbidity. Oral treatment with doxycycline (200 mg/d) or chloramphenicol (50–75 mg/kg/d in four divided doses) for 7–10 days is indicated. Caution is advised with the use of ciprofloxacin because it is associated with a poor outcome and increases the severity of disease in Mediterranean spotted fever. The combination of azithromycin and rifampin is effective and safe in pregnancy. Prevention entails protective clothing, repellents, and inspection for and removal of ticks.

Formerly classified as an endemic or murine typhus, the cat-flea typhus, caused by Rickettsia felis is now more properly classified as a spotted fever. The causative agent has been linked to the cat flea and opossum exposure. Most cases in the United States (southern Texas and California, and possibly Hawaii) occur in the spring and summer. Treatment is the same as for other rickettsial fevers.

A rickesttsial infection recognized as a cause of eschar-associated illness was recognized in northern California and is referred to as the spotted fever group rickettsia 364D.

Angelakis E et al. Comparison of real-time quantitative PCR and culture for the diagnosis of emerging Rickettsioses. PLoS Negl Trop Dis. 2012;6(3):e1540. [PMID: 22413026]

Blanton LS. Rickettsial infections in the tropics and in the traveler. Curr Opin Infect Dis. 2013 Oct;26(5):435–40. [PMID: 23842049]

Wilson PA et al. Queensland tick typhus: three cases with unusual clinical features. Intern Med J. 2013 Jul;43(7):823–5. [PMID: 23841762]

OTHER RICKETTSIAL & RICKETTSIAL-LIKE DISEASES

  1. Ehrlichiosis & Anaplasmosis

 ESSENTIALS OF DIAGNOSIS

 Infection of monocyte or granulocyte by tick-borne gram-negative bacteria.

 Nine-day incubation period, with variable clinical illness, ranging from asymptomatic to persistent or life threatening.

 Common symptoms are malaise, nausea, fever, and headaches.

 US cases are largely in elderly white men in the summer.

 Excellent response to therapy with tetracyclines.

 General Considerations

Ehrlichiae and anaplasmae are small tick-borne gram-negative obligate intracellular bacteria that infect monocytes or granulocytes. Human monocytic ehrlichiosis is caused by Ehrlichia chaffeensis (Table 32–3). Human granulocytic anaplasmosis is caused by Anasplasma phagocytophilium. Ehrlichia ewingii (infecting primarily dogs) can rarely cause human granulocytic ehrlichiosis (also referred to as E ewingii ehrlichiosis) similar to human granulocytic anaplasmosis. A third Ehrlichia species that infects humans appears to be related to Ehrlichia muris. An Ehrlichia-like organism, Neorickettsia sennetsu, is the etiologic agent of sennetsu fever, which is confined to western Japan.

Human monocytic ehrlichiosis is seen primarily in the South Central states (especially Arkansas, Missouri, and Oklahoma) of the United States, although cases are also recognized in Israel, Japan, Mexico, South America, and Europe. Human granulocytic anaplasmosis is more frequent in the upper Midwestern United States; but infections in Europe and China are also well documented. Human infection with E ewingii is limited to Missouri, Oklahoma, and Tennessee and occurs mainly among the immunocompromised. In North America, the major vectors for these pathogens are the Lone Star tick (Amblyomma americanus for E chaffeensis and E ewingii), the western black-legged tick (Ixodes pacificus, for E chaffeensis), and Ixodes scapularis (the same vector for Lyme disease) and babesiosis for A phagocytophilium). Reported incidences of both human monocytic and granulocytic ehrlichiosis are increasing and both are now at about 3 per million, respectively, with higher rates in the summer among whites and among men. Up to 4.9% of Amblyomma americatus and D variabilis ticks are seropositive for Ehrlichia.

The principal reservoirs for human monocytic ehrlichiosis and human granulocytic anaplasmosis are the white tail deer and the white footed mouse, respectively. Other mammals are implicated as well. A nosocomial outbreak was reported from China (where nine patients had exposure to body fluids and none reported tick bites). Perinatal and blood product transmission of human granulocytic anaplasmosis is also documented.

 Clinical Findings

  1. Symptoms and Signs

Clinical disease of human monocytic ehrlichiosis ranges from mild to life threatening. Typically, after about a 9-day incubation period and a prodrome consisting of malaise, rigors, and nausea, worsening fever and headache develop. A pleomorphic rash may occur. Presentation in immunosuppressed patients (including transplant patients) and the elderly tends to be more severe. Serious sequelae include acute respiratory failure and ARDS, encephalopathy, and acute kidney disease, which may mimic thrombotic thrombocytopenic purpura.

The symptoms of human granulocytic ehrlichiosis and E ewingii infection are similar to those seen with human monocytic ehrlichiosis. Rash, however, is infrequent in human granulocytic ehrlichiosis and should prompt the consideration of other infections (eg, Lyme disease). Persistent fever and malaise are reported to occur for 2 or more years.

The clinical manifestations of anaplasmosis are similar to those of ehrlichiosis. Coinfection with anaplasmosis and Lyme disease or babesiosis may occur, but the clinical manifestations (including fever and cytopenias) are greater with anaplasmosis than with Lyme disease. A newly discovered spirochete, Borrelia miyamotoi, may mimic anaplasmosis in its clinical manifestations.

  1. Laboratory Findings

Diagnosis can be made by the history of tick exposure followed by a characteristic clinical presentation. Leukopenia, absolute lymphopenia, thrombocytopenia, and transaminitis occur often. Thrombocytopenia occurs more often than leukopenia in human granulocytic ehrlichiosis. Examination of peripheral blood with Giemsa stain may reveal characteristic intraleukocytic vacuoles (morulae). An indirect fluorescent antibody assay is available through the CDC and requires acute and convalescent sera. A PCR assay, if available, is a rapid diagnostic tool, especially for early disease.

 Treatment & Prevention

Treatment for all forms of ehrlichiosis is with doxycycline, 100 mg twice daily (orally or intravenously) for at least 10 days or until 3 days of defervescence. Rifampin is an alternative in pregnant women and children. Treatment should not be withheld while awaiting confirmatory serology when suspicion is high. Lack of clinical improvement and defervescence 48 hours after doxycycline initiation suggests an alternate diagnosis. Tick control is the essence of prevention.

Chowdri HR et al. Borrelia miyamotoi infection presenting as human granulocytic anaplasmosis: a case report. Ann Intern Med. 2013 Jul 2;159(1):21–7. [PMID: 23817701]

Dahlgren FS et al. Increasing incidence of Ehrlichia chaffeensis and Anaplasma phagocytophilum in the United States, 2000–2007. Am J Trop Med Hyg. 2011 Jul;85(1):124–31. [PMID: 21734137]

Fritzen CM et al. Infection prevalences of common tick-borne pathogens in adult lone star ticks (Amblyomma americanum) and American dog ticks (Dermacentor variabilis) in Kentucky. Am J Trop Med Hyg. 2011 Oct;85(4):718–23. [PMID: 21976578]

Horowitz HW et al. Lyme disease and human granulocytic anaplasmosis coinfection: impact of case definition on coinfection rates and illness severity. Clin Infect Dis. 2013 Jan;56(1):93–9. [PMID: 23042964]

Pritt BS et al. Emergence of a new pathogenic Ehrlichia species, Wisconsin and Minnesota, 2009. N Engl J Med. 2011 Aug 4;365(5):422–9. [PMID: 21812671]

  1. Q Fever

 ESSENTIALS OF DIAGNOSIS

 Exposure to sheep, goats, cattle, or their products; some infections are laboratory acquired.

 An acute or chronic febrile illness with severe headache, cough, prostration, and abdominal pain.

 Extensive pneumonitis, hepatitis, or encephalopathy; less often, endocarditis, vascular infections, or chronic fatigue syndrome.

 A common cause of culture-negative endocarditis.

 General Considerations

Q fever (for “query” in view of its formerly unknown cause), a reportable disease in the United States, is caused by Coxiella burnetii, an organism previously classified as a rickettsia but now considered a proteobacteria. Unlike rickettsiae, C burnetii is usually transmitted to humans not by arthropods but by inhalation or ingestion. Coxiella infections occur globally, mostly in cattle, sheep, and goats, in which they cause mild or subclinical disease (Table 32–3). In these animals, reactivation of the infection occurs during pregnancy and causes abortions or low birth weight offspring. Coxiella is resistant to heat and drying and remains infective in the environment for months.

Humans become infected by inhalation of aerosolized bacteria (in dust or droplets) from feces, urine, milk (in particular raw milk), or products of conception of infected animals. Ingestion and skin penetration are other recognized routes of transmission. Outbreaks associated with other mammals such as cats and dogs are also described. A major outbreak in Netherlands that began in 2007 was thought to be due to exposure to aborting ruminants and was associated with over 3000 cases through 2010. There is a known occupational risk for animal handlers, slaughterhouse workers, veterinarians, laboratory workers, and other workers exposed to animal products. Outbreaks in military personnel returning from Iraq and Afghanistan were described. Transmission through aerosols is possible in that Coxiella can be pathogens of other organisms (free living amoebae), which are transmitted through air ducts.

Endocarditis, an uncommon but serious form of Coxiella infection, is linked to preexisting valvular conditions, immunocompromised states, urban residence, and raw milk ingestion. Horizontal spread from one human to another does not seem to occur even in the presence of florid pneumonitis, but maternal–fetal infection can occur.

 Clinical Findings

  1. Symptoms and Signs

Asymptomatic infection is common. For the remaining cases, a febrile illness develops after an incubation period of 2–3 weeks, usually accompanied by headache, relative bradycardia, prostration, and muscle pains. The clinical course may be acute, chronic (duration ≥ 6 months), or relapsing. Pneumonia and granulomatous hepatitis are the predominant manifestation in the acute form, whereas other less common manifestations include skin rashes (maculopapular or purpuric), fever of unknown origin, myocarditis, pericarditis, aseptic meningitis, encephalitis, hemolytic anemia, orchitis, acute kidney disease, spondylodiscitis, tenosynovitis, and regional (mediastinal) or diffuse lymphadenopathies. Cases of Q fever mimicking autoimmune and systemic inflammatory disease are reported. The most common presentation of chronic Q fever is culture-negative endocarditis, which occurs in < 1% of infected individuals. It is found mainly in the setting of preexisting valve disease. Vascular infections, particularly of the aorta (causing mycotic aneurysms), are the second most common form of Q fever and are associated with a high mortality (25%). A post-Q fever chronic fatigue syndrome (1 year after acute infection with chronic symptoms not explained by chronic Q fever) is controversial and of unknown pathophysiology although the basis may be immunogenetic.

Reactivation of Q fever in pregnant women may cause spontaneous abortions, intrauterine growth retardation, intrauterine fetal death, premature delivery, and oligamnios.

  1. Laboratory Findings

Laboratory examination during the acute phase may show elevated liver function tests and occasional leukocytosis. Patients with acute Q fever usually produce antibodies to C burnetii phase II antigen. A fourfold rise between acute and convalescent sera by indirect immunofluorescence is diagnostic. Realtime PCR for C burnetii DNA is helpful only in early diagnosis of Q fever with C burnetii DNA becoming undetectable in serum as serologic responses develop. The positive predictive value of antibodies to phase II antigens in acute disease is at most 65%.

While chronic Q fever can be diagnosed on the basis of serologic tests done at 3- and 6-month intervals (with an IgG titer against phase I antigen of 1:1600 or greater), it is now recommended that clinical criteria be used for diagnosis of chronic disease. Diagnosis is often made at the time of valve replacement with PCR of tissue samples. C burnetti may also be isolated from affected valves using the shell-vial technique. The organism is highly transmissible to laboratory workers and culture techniques require a biosafety level 3 setting. In one series, at 6 years after infection, reversion to seronegativity occurred in 7 of 38 patients, and none showed the organism in peripheral blood mononuclear cells. Antiphospholipid antibodies and anti-ADAMTS 13 antibodies may be present and account for thrombotic and other clinical symptoms.

  1. Imaging

Radiographs of the chest show patchy pulmonary infiltrates, often more prominent than the physical signs suggest.

 Differential Diagnosis

Viral, mycoplasmal, and bacterial pneumonias, viral hepatitis, brucellosis, Legionnaire disease, Kawasaki disease, tuberculosis, psittacosis, and other animal-borne diseases must be considered. Q fever should be considered in cases of unexplained fevers with negative blood cultures in association with embolic or cardiac disease.

 Treatment & Prognosis

For acute infection, treatment with doxycycline (100 mg orally twice daily) for 14 days or at least 3 full days after defervescence is recommended. Even in untreated patients, the mortality rate is usually low, except when endocarditis develops.

For chronic infection, there is no agreement on the type and duration of antimicrobial therapy. Most experts recommend a combination oral therapy with doxycycline (100 mg twice a day) plus ciprofloxacin (typically 750 mg twice a day) or rifampin (300 mg twice a day) or hydroxychloroquine (200 mg three times a day) for approximately 2 years or more for the treatment of endocarditis. A study reported in 1999 of 35 patients with Q fever endocarditis showed favorable outcomes with oral doxycycline (100 mg twice a day) plus oral hydroxychloroquine (200 mg three times a day) for 18 months for native valves and 24 months for prosthetic valves. A randomized study assessing antibiotics and cognitive therapy in chronic Q fever is underway in the Netherlands.

Serologic responses can be monitored during and after completion of therapy and treatment extended in the absence of favorable serologic response (considered a titer of 1:1600 or greater to phase I antigen). The general variability of serologic data, however, limits their usefulness and providers usually rely on clinical criteria. Patients should be monitored for at least 5 years due to risk of relapse. Heart valve replacement may be necessary in refractory disease. Given the difficulty in treating endocarditis, transthoracic echocardiography is recommended for all patients with acute Q fever, and the same aforementioned therapy for 1 year should be offered in the presence of valvulopathy.

Because of the obstetric complications (which appear to have a strain specificity) that occur among pregnant women in whom Q fever develops, a regimen of long-term trimethoprim-sulfamethoxazole (320/1600 mg orally for the duration of pregnancy) should be given to all infected pregnant women. However, a randomized controlled study of pregnant women in Holland did not show that serologic surveillance and treatment of seropositive women were effective in preventing obstetric complications. Other data from Denmark among pregnant women exposed in the past to Coxiella also suggest the risk of obstetric complications may not be high. The official recommendations nonetheless remain as stated.

 Prevention

Prevention is based on detection of the infection in livestock, reduction of contact with infected and, in particular, parturient animals or contaminated dust, special care when working with animal tissues, and effective pasteurization of milk. No vaccine is approved for use in the United States, although a whole-cell Q fever vaccine, with a 5-year efficacy of > 95%, is available in Australia for persons with high-risk exposures where some seroprevalence studies show 7% seropositivity.

C burnetii is a category B bioterrorism agent. In the setting of a bioterrorist attack, postexposure prophylaxis with doxycycline (100 mg orally twice daily) for 5 days should be started 8–12 days after exposure.

Pregnant women should take trimethoprim-sulfamethoxazole (160 mg/800 mg orally twice daily) for the duration of the pregnancy.

Anderson A et al. Diagnosis and management of Q fever—United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013 Mar 29;62(RR-03):1–30. Erratum in: MMWR Recomm Rep. 2013 Sep 6;62(35):730. [PMID: 23535757]

Gunn TM et al. Cardiac manifestations of Q fever infection: case series and a review of the literature. J Card Surg. 2013 May;28(3):233–7. [PMID: 23574261]

Keijmel SP et al. The Qure study: Q fever fatigue syndrome—response to treatment; a randomized placebo-controlled trial. BMC Infect Dis. 2013 Mar 27;13:157. [PMID: 23536997]

Munster JM et al. Routine screening for Coxiella burnetii infection during pregnancy: a clustered randomised controlled trial during an outbreak, the Netherlands, 2010. Euro Surveill. 2013 Jun 13;18(24). [PMID: 23787163]

Nielsen SY et al. No excess risk of adverse pregnancy outcomes among women with serological markers of previous infection with Coxiella burnetii: evidence from the Danish National Birth Cohort. BMC Infect Dis. 2013 Feb 17;13:87. [PMID: 23413787]

van der Hoek W et al. Follow-up of 686 patients with acute Q fever and detection of chronic infection. Clin Infect Dis. 2011 Jun 15;52(12):1431–6. [PMID: 21628483]

KAWASAKI DISEASE

 ESSENTIALS OF DIAGNOSIS

 Fever, conjunctivitis, oral mucosal changes, rash, cervical lymphadenopathy, peripheral extremity changes.

 Elevated erythrocyte sedimentation rate and C-reactive protein levels.

 General Considerations

Kawasaki disease is a worldwide multisystemic disease initially described by Tomisaku Kawasaki in 1967. It is also known as the “mucocutaneous lymph node syndrome.” It occurs mainly in children between the ages of 3 months and 5 years but can occur occasionally in adults as well. Kawasaki disease occurs significantly more often in Asians or native Pacific Islanders than in whites. It is an acute, self-limiting, mucocutaneous vasculitis characterized by the infiltration of vessel walls with mononuclear cells and later by IgA secreting plasma cells that can result in the destruction of the tunica media and aneurysm formation. Several infectious agents (New Haven coronavirus, parvovirus, bocavirus, CMV, Yersinia pseudotuberculosis, meningococcus), bacterial superantigens, and genetic polymorphisms (confirmed in whole genome analysis) in components of the immune system (interleukin 10 and 18) are implicated in its pathogenesis. A “new” RNA virus was considered a trigger of the disease, based on the finding of intracytoplasmic inclusion bodies in ciliated bronchial epithelium of Kawasaki patients. Epidemiologic studies from Seattle show an increased risk with advanced maternal age, mother of foreign birth, maternal group B streptococcus colonization, and early infancy hospitalization. Whole genomic analysis, mostly from China, is identifying target gene products.

 Clinical Findings

A clinical diagnosis of “complete” Kawasaki disease requires, in the absence of other processes, explaining the current illness of fever and four of the following criteria for at least 5 days: bilateral nonexudative conjunctivitis, mucous membrane changes of at least one type (injected pharynx, erythema, swelling and fissuring of the lips, strawberry tongue), peripheral extremity changes of at least one type (edema, desquamation, erythema of the palms and soles, induration of the hands and feet, Beau lines [transverse grooves of the nails]), a polymorphous rash, and cervical lymphadenopathy > 1.5 cm (most worrisome when retropharyngeal with edema is present). An “incomplete” form is diagnosed when only two criteria are met. The classic syndrome is often preceded by nonspecific symptoms including irritability, vomiting, anorexia, cough, and diarrhea for up to 10 days.

Major complications include arteritis and aneurysms of the coronary vessels, occurring in about 25% of untreated patients (and slightly over 10% of treated patients in a recent Danish review), on occasion causing myocardial infarction. The “incomplete” form appears more frequently to result in cardiac complications. The pathogenesis of infarction is often thrombus formation, vasospasm, stenosis, or aneurysm rupture. Coronary complications are more common among patients older than 6 years or younger than 1 year of age. Noninvasive diagnosis of coronary complications can be made with CT coronary angiography (preferred in one series to MR), magnetic resonance angiography or transthoracic echocardiography (advocated for early screening). Other factors associated with the development of coronary artery aneurysms are male sex, relentless fever (even after the administration of IVIG), high C-reactive protein, urticarial exanthems, anemia, hypoalbuminemia, hyponatremia, and thrombocytopenia. Pericardial effusions, myocarditis, and mitral regurgitation (usually mild) are also common. Coronary artery fistulas occur in up to 5% of patients and diastolic dysfunction is also reported. Arteritis of extremity vessels, peripheral gangrene, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and the hemophagocytic syndrome are also reported. Cases of pancreatitis and bile duct stenosis due to underlying vasculitis are reported. Cerebrospinal fluid pleocytosis is found in one-third of cases and encephalitis is rarely reported. Other CNS complications include seizures, oculomotor palsies, and sensorineural hearing loss which, when sought, can be found in as many as 55% of cases. Rare case reports of atypical presentations (eg, retropharyngeal abscess) are described.

Differentiation from disseminated adenovirus infection is important and can be performed with rapid adenovirus assays.

 Treatment & Prevention

Every patient with a clinical diagnosis of Kawasaki disease (complete or incomplete) should be treated. IVIG (2 g/kg over 10–12 hours) is given within the first 10 days of illness. Patients in whom persistent fever, ongoing systemic inflammation, or aneurysm formation presents later should be offered IVIG as well. Concomitant aspirin should be started at 80–100 mg/kg/d orally (divided into four doses and not exceeding 4 g/d) until the patient is afebrile for 48 hours and then reduced to 3–5 mg/kg/d until markers of acute inflammation normalize. Aspirin therapy is continued if coronary aneurysm develops. If fevers persist beyond 36 hours after the initial IVIG infusion, a second dose of IVIG at 2 g/kg should be given if no other source of fever is found. Rare cases of aseptic meningitis are reported with IVIG, and this complication may be hard to distinguish from the occasional CNS disease associated with Kawasaki syndrome itself although the time course and the cerebrospinal fluid differential (more polymorphonuclear with IVIG, more lymphocytic with Kawasaki syndrome) may help differentiate the two. Methylprednisolone (30 mg/kg/d intravenously if possible for a maximum of 3 days) followed by tapering dose of corticosteroids in addition to IVIG administration improve coronary artery outcomes in severe Kawasaki disease. Routine childhood vaccinations should be given and live vaccines (eg, MMR) should be delayed for at least 9 months only if IVIG was administered (IVIG can block the immune response to live vaccines). If vaccine preventable disease endemicity requires urgent vaccination, it is prudent to revaccinate 11 months after the IVIG and first vaccination were given.

Further options for refractory cases include TNF blockers (infliximab or etanercept), cyclophosphamide or cyclosporine, methotrexate, and plasmapheresis, but not further pulse corticosteroid or IVIG. Abciximab therapy may be associated with coronary vessel remodeling in large coronary artery aneurysms. An echocardiogram is essential in the acute phase of illness and 6–8 weeks after onset. Anticoagulation with warfarin or low-molecular-weight heparin (the latter is preferable for children where dosage adjustments are difficult using warfarin) is indicated along with aspirin, 81 mg orally daily, in patients with aneurysms > 8 mm in diameter. If myocardial infarction occurs, therapy with thrombolytics, percutaneous coronary intervention, coronary artery bypass grafts, and even cardiac transplantation should be considered. Manifestation of coronary artery aneurysms can occur as late as in the third or fourth decade of life with a study showing a prevalence of 5% coronary sequelae from Kawasaki disease among young adults evaluated with angiography. Data are equivocal on the development of accelerated atherosclerosis among those with a history of Kawasaki disease.

While secondary prevention of complications entails the modalities described above, primary prevention is difficult in the absence of a clear explanation for the disease.

 Prognosis

Cases that develop recurrent disease tend to more often show cardiac complications. Patients with a parental history of Kawasaki disease show more recurrent disease and more cardiac complications. The long-term prognosis for adults with a history of Kawasaki disease but without coronary artery aneurysms is excellent. A heart-healthy lifestyle, however, is essential. The prognosis of patients with a history of cardiac complications requires regular follow-up with risk stratification based on published guidelines and under cardiologic supervision. Children with Kawasaki disease show an increased risk for subsequent allergic diseases.

 When to Refer

All cases of Kawasaki disease merit referral to specialists.

Dominguez SR et al. Advances in the treatment of Kawasaki disease. Curr Opin Pediatr. 2013 Feb;25(1):103–9. [PMID: 23283289]

Hayward K et al. Perinatal exposures and Kawasaki disease in Washington State: a population-based, case-control study. Pediatr Infect Dis J. 2012 Oct;31(10):1027–31. [PMID: 22653485]

Kobayashi T et al. Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial. Lancet. 2012 Apr 28;379(9826):1613–20. [PMID: 22405251]

Patel A et al. Evaluation of clinical characteristics of Kawasaki syndrome and risk factors for coronary artery abnormalities among children in Denmark. Acta Paediatr. 2013 Apr;102(4):385–90. [PMID: 23278838]

Punnoose AR et al. JAMA patient page. Kawasaki disease. JAMA. 2012 May 9;307(18):1990. [PMID: 22570468]

Selamet Tierney ES et al. Vascular health in Kawasaki disease. J Am Coll Cardiol. 2013 Sep 17;62(12):1114–21. [PMID: 23835006]

Teraguchi M et al. Steroid pulse therapy for children with intravenous immunoglobulin therapy-resistant Kawasaki disease: a prospective study. Pediatr Cardiol. 2013 Apr;34(4):959–63. [PMID: 23184018]

1 A general guide for vaccine preventable diseases is available at www.who.int/vaccines-documents/