Current Diagnosis & Treatment in Infectious Diseases

Section V - Bacterial Infections

68. Coxiella, Ehrlichia, & Rickettsia

Jeffery Loutit MB, ChB

Coxiella, Ehrlichia, and Rickettsia spp. are small, obligate intracellular bacteria that usually cause disease when they accidentally encounter a human host. Once inside a host cell, Coxiella and Ehrlichia spp. remain within a vacuole where they progress through distinct developmental stages; in contrast, the Rickettsia spp. escape the endocytic vacuole and replicate within the host cell cytoplasm. Ehrlichia and Rickettsia spp. are transmitted by arthropod vectors.

COXIELLA BURNETII INFECTION (Q FEVER)

Essentials of Diagnosis

Acute Infection

• Key symptoms and signs: fever, severe headache, myalgias, arthralgias, retrobulbar pain, cough; possible pneumonitis and hepatitis on examination.
• Predisposing factors: occupation as a dairy farmer, abattoir worker, or veterinarian; exposure to parturient or newborn animals, particularly cattle, sheep, and goats.
• Commonest environment for infection: a rural setting, but urban cases of Q fever also reported.
• Commonest infections: acute febrile illness, pneumonitis, and hepatitis.
• Key laboratory feature: positive antibodies to the phase-II antigens.

Chronic Infection

• Key symptoms and signs: fever and heart murmur.
• Predisposing factors: same as those for acute disease, plus prosthetic or abnormal heart valves.
• Commonest features: fever and endocarditis; echocardiogram rarely positive.
• Key laboratory features: levels of antibodies to phase-I antigens in excess of phase-II antigens.

General Considerations

Coxiella burnetii is the causative agent of Query or Q fever. This disease name originated with the description of a 1935 outbreak of a febrile illness of unknown etiology in nine abattoir workers in Brisbane, Australia. The disease agent, based on its morphology and obligate intracellular lifestyle, was originally classified as a member of the family Rickettsiaceae. However, molecular analysis and in particular ribosomal-DNA sequencing have revealed the relationships between C burnetii and the Legionella spp. within the gamma subdivision of the Proteobacteria, and its more distant relationships to the rickettsia and the alpha subdivision of Proteobacteria.

1. Epidemiology.Cattle, sheep, and goats are the primary reservoirs for C burnetii, although the organism is found in a wide variety of domesticated animals. Inhalation of aerosolized organisms and ingestion of unpasteurized milk or cheese are common mechanisms of transmission to humans. Infection of domestic livestock usually occurs via the aerosol route and fails to cause clinically apparent or significant disease. Persistence of C burnetiiin a latent phase in a host may be followed years later by reactivation and disease, especially during the late stages of pregnancy, because the organism exhibits tropism for the placenta. Many cases of human Q fever occur as a result of close association with animals at the time of parturition or soon thereafter, particularly sheep, cattle, cats, rabbits, and dogs. Ticks can also serve as transmission vehicles for C burnetii, but this mechanism is primarily involved in transmission of the organism to animals rather than humans.

Humans at risk for disease include dairy farmers and slaughterhouse and laboratory workers. Q fever is endemic throughout the world, except in New Zealand, but it is particularly common in the Middle East and Mediterranean regions. Although seemingly uncommon in the United States, Q fever is believed to be grossly underdiagnosed owing to its protean manifestations and to low clinical suspicion of Q fever as a probable disease; 70% of cases are reported from California and the western mountain states. Urban transmission has been described and is thought to result from close association with parturient animals.

1. Microbiology.C burnetiiis a short, pleomorphic gram-negative rod and an obligate intracellular pathogen.
2. Pathogenesis.C burnetiienters cells, allows the endocytic vacuole to fuse with lysosomes, multiplies within the acidic environment of the resulting phagolysosome, and ultimately destroys the host cell (Figure 68-1). Although the exact mechanisms by which C burnetii survives within the phagolysosome are unclear, it does require an acid environment at that point in its life cycle; in fact, pharmacologic strategies to block acidification of intracellular vacuoles, for example using chloroquine, are therapeutic (see Treatment section below). C burnetii also has the ability to form sporelike structures, enabling it to survive diverse environmental conditions. The organism exists in either of two antigenic phases (I or II), owing to variation in the expression of different membrane lipopolysaccharides and proteins. Fresh isolates exhibiting phase-I antigens are highly infectious. Conversion to phase II occurs after serial passage in the laboratory, although reversion to phase-I antigen occurs with passage through laboratory animals. The immune response to these phase-associated antigens is useful in the diagnosis of C burnetii infections. Antibodies to phase-II antigen are found in the blood of patients with acute disease, whereas antibodies to phase-I antigen are more often detected in patients with chronic disease, such as endocarditis. The virulence-associated mechanisms of this organism are poorly understood.

Tissues affected by Q fever reveal vascular injury and granulomatous inflammation along with hemorrhage and necrosis. Q fever is one of many causes of granulomatous hepatitis.

Clinical Findings

1. Acute infection.Seroepidemiologic studies indicate that ~ 50% of “cases” of Q fever in humans are asymptomatic. Symptomatic cases usually present with an acute febrile illness. Disease manifestations include a flulike illness, isolated fever, pneumonitis, hepatitis, exanthema with fever, pericarditis, myocarditis, and meningoencephalitis (Box 68-1). Most important in the diagnosis of acute Q fever is a history of contact with a newborn or parturient animal, which is found in two-thirds of all cases. There is marked geographic variation with respect to the clinical features of disease presentation; eg, hepatitis is seen more commonly in France than in Nova Scotia, and pneumonitis is more common in Nova Scotia than in France. The route of transmission does not seem to be a major factor in determining disease presentation.

Figure 68-1. Transmission electron micrograph of Coxiella burnetii within a phagocyte. (From Baca OC et al: Possible biochemical adaptations of Coxiella burnetii for survival within phagocytes: effect of antibody. In Schlessinger D: Microbiology 1984. American Society for Microbiology, 1984.)

38. The incubation period of Q fever ranges from 4 to 39 days, with an average of 14 days. Patients frequently present with an acute onset of fever >38.5°C, rigors, and a severe headache. Other symptoms may include retrobulbar pain, malaise, myalgias, arthralgias, neck stiffness, nausea, vomiting, cough, pleuritic chest pain, diarrhea, and jaundice. Hepatosplenomegaly may be found on examination, and a maculopapular rash is present in 20% of cases. Hepatic involvement may range from mild subclinical elevations of hepatic transaminase levels to marked enzyme and bilirubin elevations accompanied by typical clinical features of hepatitis. A patchy interstitial infiltrate, as seen with other causes of “atypical” pneumonia such as Mycoplasma pneumoniae, is often found on chest radiograph. The leukocyte count is usually normal, but thrombocytopenia may be seen on 25% of cases. The illness is usually self-limited and lasts 2–4 weeks.
39. Chronic Infection.Approximately 2% to 11% of patients with Q fever progress to a chronic infection, of which endocarditis accounts for 60–70% of cases. Q fever endocarditis develops almost exclusively in patients with previous valvular heart disease, in transplant recipients, and in patients with underlying immunosuppression. Aortic and prosthetic valves are most commonly involved. Vegetation is rarely seen on echocardiogram, and routine blood cultures are negative. A clue to the diagnosis of Q fever endocarditis is the finding of a systemic inflammatory syndrome or unexplained accelerated valve failure in a patient with a history of valvular heart disease. Manifestations of this disease may include hepatosplenomegaly, a purpuric rash, renal insufficiency, and embolic phenomena. Laboratory findings include leukocytosis (25% of patients), leukopenia (15%), increased hepatic transaminase levels (40–60%), thrombocytopenia (25–50%), anemia (40%), increased creatinine levels (65%), antinuclear antibodies (35%), and rheumatoid factor (60%). Another common presentation of chronic Q fever is fever of unknown origin. Bone and joint involvement due to Q fever are uncommon, but they have been reported in both children and adults. Chronic hepatitis is another uncommon manifestation of Q fever.

BOX 68-1 Q fever in Children and Adults

More Common · Flulike illness · Pneumonitis · Hepatitis Less Common · Chronic disease (ie, endocarditis or granulomatous hepatitis)

Diagnosis

The diagnosis of Q fever is based on an appropriate clinical history, along with a clear or possible history of animal exposure. The bacteria can be cultured from the blood, urine, and sputum by inoculation into chicken embryos or cultured human fibroblasts, but this procedure requires a specialized laboratory. In addition, the risk of transmission to laboratory workers is high; therefore, it should only be attempted in laboratories with considerable experience in handling this organism. The routine approach for the diagnosis of Q fever is a serological one, with detection of antibody to phase-I and -II antigens. Complement fixation, indirect fluorescent antibody (IFA), and enzyme-linked immunosorbent assays are available. Acute Q fever is diagnosed by a fourfold or greater increase in levels of antibodies directed against the C burnetii phase-II antigens. Titers become positive by 8–14 days after onset of the illness and peak at 4–8 weeks using IFA testing or at 12–13 weeks using complement fixation testing. Chronic disease, eg, endocarditis, is diagnosed by detecting levels of antibodies to C burnetii phase-I antigens in excess of levels of antibodies directed against the phase-II antigens. A complement fixation antibody titer against the phase-I antigens of >1:200 is considered also diagnostic.

BOX 68-2 Treatment of Acute Q Fever

Children Adults First Choice · Doxycycline, 100 mg twice daily for 15–21 days · Doxycycline 100 mg twice daily for 15–21 days Second Choice · Chloramphenicol, 50–100 mg in 4 doses/day · Chloramphenicol, 2–4 g/day Pediatric Considerations · Avoid tetracyclines unless disease is severe   Penicillin Allergic · As above · As above

Treatment

Acute Q fever is usually self-limited. However, antimicrobial agents are recommended to prevent the development of chronic infection and possibly to decrease the duration of symptoms (Box 68-2). Doxycycline is effective, provided that it is started early in the disease. Quinolones, because of their cerebrospinal fluid penetration, should be considered for the treatment of meningoencephalitis. Treatment of chronic Q fever has never been studied in a controlled setting. Recommended regimens include rifampicin or ciprofloxacin plus doxycycline (Box 68-3). The duration of therapy necessary for a cure is also unknown, but ≥12 months is required, and some experts recommend a minimum of 3 years. In many cases, lifelong treatment may be necessary. Current studies are assessing the use of hydroxychloroquine in conjunction with doxycycline and/or ciprofloxacin, since blockade of intracellular acidification with the former improves the bactericidal activity of the latter for C burnetii in vitro.

Prevention & Control

There is no currently available vaccine for the prevention of Q fever. Procedures should be in place to protect laboratory workers from being exposed to the organism and patients with the disease should be placed in standard-precaution isolation.

EHRLICHIA INFECTION (EHRLICHIOSIS)

Essentials of Diagnosis

• Key symptoms and signs: abrupt onset of high fever, headache, myalgias, chills 8–9 days after tick bite; rash (36% of human monocytic ehrlichiosis [HME] patients; only 2% of human granulocytic ehrlichiosis [HGE] patients); central nervous system involvement (20–25% of patients).

• Predisposing factors: tick and rural exposure (April through September).
• Presentation: most present as flu-like illness.
• Key laboratory features: thrombocytopenia, leukopenia, and elevated liver transaminases.
• Diagnosis: confirmed by a fourfold or greater rise in titers with an IFA.

BOX 68-3 Treatment of Chronic Q Fever

Children Adults First Choice · Doxycycline, 100 mg twice daily for 3 years, perhaps for life OR Doxycycline as above PLUS TMP/SMX OR Rifampicin OR Chloroquine · Doxycycline, 100 mg twice daily for 3 years, perhaps for life OR Doxycycline as above PLUS TMP/SMX OR Rifampicin OR Chloroquine Pediatric Considerations · Tetracycline should not be used in children <8 years old · Fluoroquinolones should not be used in children and adolescents <18 years old

General Considerations

Human ehrlichiosis was first recognized in the United States in 1986 as a life threatening tick-borne illness similar to Rocky Mountain spotted fever (RMSF), but with a much lower incidence of rash.

1. Epidemiology.Ehrlichiosis is not a reportable disease, so its true incidence is unknown. The majority of cases of HME have been reported from the south, central, and southeastern United States. Cases have also been reported from Western Europe, Scandinavia, and Africa. In contrast, most cases of HGE have been reported from the upper midwestern and northeastern United States. This difference in disease geography reflects the distinct habitats of the respective tick vectors. Amblyoma americanumtransmits HME and is found throughout the southeastern and south central United States. The white-tailed deer serves as a reservoir for the etiologic agent, E chaffeensis. The Ixodes species are the tick vectors of HGE (as well as Lyme disease and babesiosis), and they are found in the Northeast, upper Midwest, and Pacific Coast regions of the United States. The white-tailed deer is the primary host for adult Ixodes ticks, but small rodents—especially the white-footed mouse—play an important role in the deer-tick-rodent cycle and transmission of the agent of HGE to humans. Of infected humans, 80–100% report tick exposure within the 10 days preceding the onset of illness.

The median age of patients reported with HME is 44 years; 75% are male. The median age of HGE cases is 60 years, with a similar sex ratio. Cases of HME occur from April through December, but HGE cases are seen throughout the year, owing to the seasonal feeding patterns of the different tick vectors in different regions of the United States.

1. Microbiology.There are two forms of human ehrlichiosis in North America, HME and HGE; their clinical features are indistinguishable. The causative agent of HME, Ehrlichia chaffeensis, was the first member of this genus to be detected in humans in the United States; HGE was first recognized in 1994, and it is caused by an organism closely related to Ehrlichia equiand Ehrlichia phagocytophila. Ehrlichia sennetsu is the only other known pathogen for humans in this genus, but it has been reported only in Western Japan. Canine ehrlichiosis is caused by Ehrlichia canis and Ehrlichia ewingii, which infect macrophages and granulocytes, respectively. E phagocytophila is a pathogen of ruminants in Europe and exhibits tropism for neutrophils. E equi causes both equine and canine disease.
2. Pathogenesis.Ehrlichiaspecies are small, obligate intracellular organisms whose life cycle includes the formation of intraleukocytic inclusions, termed morulae. Replication and development of organisms within morulae lead to rupture and release of elementary bodies into the circulatory system and subsequent infection of other leukocytes. Recent data indicate that the granulocytic Ehrlichia species may enhance their survival within neutrophils by down-regulating expression of one component of the host NADPH oxidase enzyme complex, a critical feature of the oxidative burst machinery.

Clinical Findings

1. Signs and Symptoms.The symptoms and signs of human ehrlichiosis are nondescript, thereby making the diagnosis difficult. The median incubation period is 8–9 days after tick bite, with a range of 0–34 days. The clinical presentation characteristically includes an abrupt onset of high fever (>39°C), headache, myalgias, and shaking chills (Box 68-4). Other symptoms include malaise, confusion, rigors, sweats, nausea, vomiting, and abdominal pain. Rash is reported in 36% of patients with HME but only 2% of those with HGE.
2. Laboratory Findings.The laboratory findings of human ehrlichiosis are relatively consistent and include thrombocytopenia in 72–92% of patients, elevated liver transaminase levels in the serum in 85–90% of patients, and leukopenia in 50–75% of patients. These laboratory findings are most pronounced at the end of the first week of illness. Morulae are rarely seen on acute-phase peripheral blood smears of patients with HME but are seen more commonly in the peripheral blood smears of patients with HGE. Detection of morulae in peripheral blood smears remains an insensitive and time-consuming task, and, when found, morulae have been reported most often by clinical hematology laboratory technicians (Figure 68-2).
3. Differential Diagnosis.Diseases in the differential diagnosis include ehrlichiosis (see Diagnosis section), typhus, Q fever, tularemia, early Lyme disease, viral hepatitis, leptospirosis, influenza, and Colorado tick fever. Coinfection with other tick-borne agents must always be considered.
4. Complications.Central nervous system involvement is reported in 20–25% of patients, with symptoms ranging from confusion through coma. Other severe complications may occur, such as disseminated intravascular coagulation, respiratory failure, renal insufficiency, and opportunistic infections secondary to neutropenia. Most elderly patients with HME who have been reported have also been hospitalized. Case fatality rates are 2–5% for HME and 7–10% for HGE. However, it is also now clear from seroprevalence studies that many patients have mild or asymptomatic infection.

Figure 68-2. Granulocyte containing a morula from a patient with HGE. (Courtesy of Jesse Goodman.)

BOX 68-4 Ehrlichiosis in Children and Adults

More Common · Flulike illness · High fever, headache, chills, myalgias, arthralgias Less Common · Rash, diarrhea, abdominal pain, pulmonary infiltrates, respiratory failure, disseminated intravascular coagulation

Diagnosis

It is necessary and important to consider the diagnosis of ehrlichiosis based only on epidemiological and clinical features, to facilitate administration of empiric therapy, because there is no widely available rapid diagnostic test other than detection of visible morulae. Ehrlichiosis should be considered in any febrile patient in an endemic region with exposure to ticks within the preceding 3 weeks. The diagnosis becomes more likely if thrombocytopenia, elevated hepatic transaminases, or leukopenia is present. There are no absolute clinical criteria that distinguish ehrlichiosis from RMSF, although patients with ehrlichiosis are less likely to have a rash and more likely to have leukopenia and elevated hepatic transaminases. In addition to finding intraleukocytic morulae, serology offers a reliable but retrospective method for diagnosing Ehrlichia infection. Acute and convalescent titers are required. IFA detection assays are available for both HME and HGE. Although E chaffeensis and the agent of HGE can be cultured, this method of detection and PCR-based assays are not widely available.

Treatment

Doxycycline is the agent of choice for both HGE and HME (Box 68-5). The clinical response is rapid, usually within 24–48 h. Chloramphenicol has been used in younger children to prevent teeth discoloration secondary to tetracyclines; however, in vitro and in vivo failures have been described. Enhanced mortality and morbidity from ehrlichiosis are associated with delayed administration of appropriate therapy, advanced age, and a higher percentage of infected leukocytes. Although most patients respond to therapy within several days, most experts advocate a 14-day course of therapy, in part to treat more adequately for possible concomitant Borrelia burgdorferi infection.

BOX 68-5 Treatment of Ehrlichiosis

Children Adults First Choice · Doxycycline, 3 mg/kg/day in 2 divided doses for a minimum of 5–7 days · Doxycycline, 100 mg twice daily for 14 days (to treat possible concomitant Lyme disease) Second Choice · Chloramphenicol for HME, but it is ineffective against the human ehrlichiosis agent in vitro · Chloramphenicol for HME, but it is ineffective against the human ehrlichiosis agent in vitro Pediatric Considerations · Benefit of short-course doxycycline outweighs the potential risk of tooth staining

Prevention & Control

Preventive measures against tick exposure should be used to prevent transmission of ehrlichiosis. If tick exposure occurs, thorough whole-body examination for and prompt removal of attached ticks are important for prevention of transmission.

RICKETTSIAL INFECTIONS

The Rickettsia species are small, pleomorphic coccobacilli and obligate intracellular pathogens that depend on the host as a source of energy. Humans are only accidental hosts for these organisms and are usually infected by means of an arthropod vector. Rickettsia multiply at the bite site, invade the bloodstream, and establish infection by infecting endothelial cells throughout the microvasculature. Subsequent vascular lesions caused by damage to endothelial cells accounts for the pathologic changes that occur throughout the body. This damage is most marked in RMSF.

ROCKY MOUNTAIN SPOTTED FEVER

Essentials of Diagnosis

• Key symptoms and signs: abrupt onset of high fevers, headaches, myalgias, malaise, and a flu-like illness 3–12 days after tick bite; rash (80–90% of patients, initially maculopapular, then petechial, classically involving the palms and soles).
• Predisposing factors: tick exposure (April through September), pet owners, animal handlers, and outdoor activities.
• Commonest geographic location of infection: rural.
• Confirmatory serology via IFA.
• PCR with blood or skin biopsy: sensitive and specific but not widely available.

General Considerations

RMSF is caused by Rickettsia rickettsii and is an acute tick-borne illness occurring during seasonal tick activity. The disease is characterized by acute onset of fever, headache, and a rash of the extremities spreading to the trunk.

1. Epidemiology.Transmission of R rickettsiito humans by the Dermacentor tick occurs only if there is prolonged contact of at least several hours between the tick and the human host. RMSF is found only in the Western Hemisphere, with ~600 reported cases per year in the United States. Of those cases, ~50% occur in the mid-Atlantic states, but all states except Hawaii and Vermont have reported cases. Most (90%) of cases occur from April through September. Children in the 5- to 9-year age group have the highest incidence of infection. Another peak of disease incidence is observed among males >60 years of age.

Clinical Findings

1. Signs and Symptoms.Only 3% of cases present with the classic triad of fever, rash, and history of a tick bite. The incubation period is 3–12 days (average 7 days), which is then followed by abrupt onset of high fevers, headaches, malaise, and myalgias, followed by 1 to 2 days of a nonspecific flulike illness (Box 68-6). Early in the course of illness, chills, rigors, neck stiffness, anorexia, nausea, vomiting, and abdominal pain occur frequently. Conjunctival suffusion, photophobia, cough, and neurologic symptoms may also be present. In severe cases, mental confusion and obtundation may develop. Only 14% of patients with RMSF will have a rash on day 1, but, by day 3, 49% will have the characteristic rash. In 20% of cases, the rash occurs only after day 6, while 9–16% of patients will never develop a rash even though their illness is equally severe.

The initial rash of RMSF is erythematous and macular, involving the ankles and wrists. It then spreads to involve the palms, soles, trunk, and face. The rash becomes papular as local edema and perivascular inflammatory cell infiltrates accrue (Figure 68-3). The lesions are petechial in 41–59% of patients after day 6 of the illness if antibiotics are not administered early. The centripetal progression and the involvement of the palms and soles are the important diagnostic features. However, it is important to realize that, at day 3, at which time most people will present for care, the features considered most critical for rendering a diagnosis of RMSF are absent.

Figure 68-3. Petechial and hemorrhagic lesions on a boy with Rocky Mountain spotted fever. (From Woodward TE et al: Cutaneous manifestations of rickettsial infections. In Mandell GL, Stevens DL: Atlas of Infectious Diseases, Vol. II: Skin, soft tissue, bone and joint infections. Churchill Livingstone, 1995.)

Gastrointestinal manifestations such as nausea, vomiting, diarrhea, and abdominal pain occur in 39–63% of patients. Liver involvement is frequently manifested by mild to moderate elevations of hepatic enzymes. Pulmonary findings in RMSF are the most worrisome. The pathology of lung biopsy specimens from infected patients is characterized by widespread endothelial damage. Neurological involvement is the most significant cause of morbidity and mortality in RMSF. Clinically evident encephalitis is seen in ≤28% of cases. Symptoms vary from confusion, lethargy, stupor, delirium, and ataxia to coma and convulsions. Of all patients, 30% will have lymphohistiocytic meningitis. The course of untreated RMSF is marked by slowly advancing severity of illness, with high temperatures plus hemorrhagic and neurologic signs.

3. Laboratory Findings.The leukocyte count is usually slightly decreased or normal, but an elevated band count of >10% is seen in 69% of patients. Thrombocytopenia occurs in 52% of patients, and 32% will have platelet counts of <100,000/ml³. Other abnormalities include hyponatremia and elevated serum aminotransferase and bilirubin levels.
4. Imaging.Pneumonitis and capillary endothelial injury can result in life-threatening noncardiac pulmonary edema which may be seen on chest x-ray.
5. Differential Diagnosis.The differential diagnosis of RMSF includes influenza, enteroviral infection, typhoid fever, leptospirosis, infectious mononucleosis, viral hepatitis, and bacterial sepsis—especially meningococcemia, HME, and HGE.
6. Complications.Fulminant RMSF (>5 days from onset to death) is seen more commonly in black male patients with glucose-6-phosphate dehydrogenase deficiency and in the elderly. For those patients with RMSF who are hospitalized for >2 weeks, ~50% will have long-term neurologic complications.

BOX 68-6 Rocky Mountain Spotted Fever in Children and Adults

More Common · High fever, headaches, malaise · Chills, rigors, neck stiffness · Anorexia, nausea, vomiting, abdominal pain · Maculopapular rash of ankles, wrists, spreading to arms, legs, trunk, face, palms and soles · Rash becomes petechial Less Common · Conjunctival suffusion · Photophobia · Cough · Mental confusion, obtundation

Diagnosis

Confirmatory serology is retrospective in nature; therefore, the physician must have a high index of suspicion based on clinical findings to start therapy. There are no diagnostic laboratory tests other than specific serologic and PCR-based tests. The leukocyte count is usually slightly decreased or normal, but an elevated band count of >10% is seen in 69% of patients. Thrombocytopenia occurs in 52% of patients, and 32% will have platelet counts of <100,000/ml³. Other abnormalities include hyponatremia and elevated serum aminotransferase and bilirubin levels. A PCR assay for RMSF using whole blood is now available through state health departments or the Centers for Disease Control and Prevention. None of the currently available serologic tests are useful for diagnosis in the acute phase of illness. The most sensitive and specific serologic assay is an IFA test. A diagnostic titer of >64 is usually detectable between 7 and 10 days after the onset of symptoms. The less sensitive latex agglutination test is more widely available and will demonstrate a rise in titer to >128, 7–9 days after the onset of symptoms. Immunohistologic examination by immunofluorescence or immunoenzyme staining for R rickettsii in skin biopsy specimens can demonstrate the presence of the organism as early as days 3–8 of the illness and has a reported sensitivity and specificity of 70% and 100%, respectively.

Treatment

Doxycycline is the drug of choice for the treatment of RMSF, except in cases of pregnancy and drug allergy or in children <9 years of age (Box 68-7). Although chloramphenicol has been recommended in these groups, many experts feel that it is safe to give a short course of doxycycline for the treatment of a potentially life-threatening infection in children <9 years old. The likelihood of permanent tooth staining from a short course of doxycycline is very low. Although there are in vitro data indicating that fluoroquinolones may be efficacious, these agents have not been widely used in the treatment of RMSF and cannot be recommended at this time. Treatment is continued for ≥2 days after defervescence to reduce the risk of relapse. If therapy is started early, most patients defervesce within 48 to 72 h. Severely ill patients treated late in the course of disease may take considerably longer to recover.

Prevention

Avoidance of tick bites is the best method of prevention. Protective clothing, tick repellents, and careful total body inspection can reduce the risk of inoculation. Prompt removal of ticks with forceps by firm traction is the preferred method. It is essential not to crush the tick so as to prevent release of rickettsiae.

BOX 68-7 Treatment of Rocky Mountain Spotted Fever

Children Adults First Choice · Doxycycline, 100 mg twice daily for children over 100 lb.; 2 mg/lb., divided twice daily in children <100 lb. · Doxycycline, 100 mg twice daily for 7–10 days Second Choice · Chloramphenicol, 50–75 mg/kg/day divided into four daily doses · Tetracycline, 25–50 mg/kg/day divided into four daily doses · Chloramphenicol, 50–75 mg/kg/day divided four times a day · Tetracycline 2g/day divided four times a day Pediatric Considerations · In children <9 years of age, the risk of tooth staining with tetracycline and doxycycline must be considered

RICKETTSIALPOX

Essentials of Diagnosis

• Eschar at site of mite bite.
• Regional lymphadenopathy.
• Generalized erythematous papulovesicular eruption on the trunk, extremities, and mucous membranes 9–14 days after exposure.
• Systemic symptoms including chills, fever, myalgias, anorexia, and photophobia.
• Prediposing factors include urban dwelling in close proximity to house mice.
• Serology for R rickettsiiwill cross-react with antibodies to Rickettsia akari.

General Considerations

Rickettsialpox has been reported infrequently in the United States. This disease is a mild, self-limited illness caused by R akari and is transmitted to humans by a house mite. Both the house mouse and house mite are reservoirs for the organism.

Clinical Findings

A painless papule develops 7–14 days after the mite bite. The papule then becomes vesicular, dries, crusts over, and evolves into a black eschar. The onset of clinical illness, characterized by abrupt onset of high fever, sweats, headache, myalgias, and malaise, occurs 4–7 days after the appearance of the initial papule. The systemic symptoms are usually mild, but, if untreated, the patient will have daily temperature elevations up to 39–39.5°C for 7–10 days. A maculopapular rash appears at the onset of fever and quickly becomes vesicular. The vesicles are small and nonpruritic, and they may be numerous or few. Within a week, the vesicles crust over and disappear with no sequelae. The diagnosis is best established by the epidemiologic history, the presence of a primary eschar, and a serum IFA test. Therapy with doxycycline or chloramphenicol is effective (see Treatment section for Rocky Mountain spotted fever). Preventive steps involve eliminating house mice and their mites.

OTHER SPOTTED FEVERS

Other spotted fevers include Mediterranean spotted fever, South African tick bite fever, Siberian tick typhus, Queensland tick typhus, and Oriental spotted fever. All of these rickettsioses are associated with an eschar and regional adenopathy. A generalized maculopapular rash involving the palms and soles usually appears about 5 days into the illness. Fever lasts ~5 to 10 days if untreated. Diagnosis is based on epidemiology, clinical features including the presence of an eschar, and serology. Treatment with doxycycline is effective.

ENDEMIC (MURINE) TYPHUS

The organism principally responsible for endemic or murine typhus is Rickettsia typhi. More recently, Rickettsia felis has been characterized as a cause of endemic typhus in southern California and Texas. Transmission of these organisms to humans occurs via the flea. Clinical features include fever, headache, myalgias, and a maculopapular rash. Infected rats and opossums are the reservoirs for R typhi and R felis. The disease is endemic in the Southeast and Gulf states of the United States, especially Texas, and in southern California. During feeding on humans, when normal hosts are not available, the fleas deposit feces containing rickettsias. Humans become infected when the organisms are rubbed into the bite wound.

The incubation period for endemic typhus is 6–14 days. Initial symptoms include headache, malaise, backache, and chills. Severe shaking chills, fever, and a more severe headache soon follow. Symptoms last for 10–14 days if untreated. The rash appears at about the fifth day and comprises pink macules starting on the extremities, which then spread to the trunk but do not involve the palms and soles. The rash may become maculopapular but is not hemorrhagic, and in fact it is not seen at all in 20–46% of cases. Pulmonary manifestations are common, particularly a nonproductive cough. Although many patients will have a severe headache, analysis of cerebrospinal fluid is usually normal. Complement-fixing antibodies are important in making the diagnosis. Treatment with tetracycline, doxycycline, or chloramphenicol usually resolves symptoms within 24–48 h. Prevention of endemic typhus involves reduction of the rodent reservoir and control of the flea vector.

EPIDEMIC (LOUSE-BORNE) TYPHUS

The etiologic agent of epidemic typhus is Rickettsia prowazekii. Epidemic typhus is a severe acute disease characterized by high fever, intense headache, a macular skin rash, and diffuse vascular lesions. Although this organism was responsible for the deaths of millions of people during World Wars I and II, the disease is now most commonly reported from northeastern and central Africa. A large proportion of the population is usually louse infested before epidemic typhus occurs. An infected louse deposits infected feces at the feeding site. Scratching then distributes the organism into the broken skin. Typhus is spread from human to human only via the body louse. In the eastern United States, cases of R prowazekii infection have been reported in patients with no history of lice infestation. These patients all described contact with flying squirrels or their nests.

Epidemic typhus is far more severe than endemic typhus. After 7 days of incubation, patients develop sudden onset of severe headache, prostration, and high fever. A rash, appearing on the fifth day, consists of pink macules and is most common in the axillae. It occurs in 50–90% of patients. The rash coalesces, becomes petechial, and spreads to the trunk but usually does not involve the palms or soles. Conjunctival involvement is common. The disease is similar to RMSF, but the character and evolution of the rash, as well as the epidemiologic setting, distinguish the two diseases. An IFA test is the most sensitive and practical approach for diagnosing epidemic typhus. Chloramphenicol and tetracycline are effective therapies; patients usually become afebrile within 48 h. Relapse is rare if treatment is started early. A single 100-mg dose of doxycycline has also resulted in successful resolution of symptoms. Prevention requires mass delousing of the population at risk with permethrin or lindane.

SCRUB TYPHUS

Orientia tsutsugamushi causes scrub typhus; it is transmitted by the bite of an infected mite. The disease is found in Southeast Asia, India, and northeastern Australia. Symptoms and signs of disease consist of an eschar at the bite site, regional and then generalized adenopathy, high fever, and a macular rash on the trunk, which appears after 5 days. The rash becomes maculopapular as it spreads to the extremities. Serology is the most practical diagnostic approach. Chloramphenicol and doxycycline are the therapeutic agents of choice, with rapid resolution of symptoms after the onset of therapy. A recent report of doxycycline-resistant scrub typhus in northern Thailand was the first to describe drug resistance in a rickettsial organism.

 

REFERENCES

Coxiella burnetii Infection (Q Fever)

Heinzen RA, Hackstadt T, Samuel JE: Developmental biology of Coxiella burnetii. Trends Microbiol 1999; 7(4):149.

Maurin M, Raoult D: Q fever. Clin Microbiol Rev 1999; 12(4):518.

Raoult D et al: Treatment of Q fever endocarditis: comparison of 2 regimens containing doxycycline and ofloxacin or hydroxychloroquine. Arch Intern Med 1999;159(2):167.

Ehrlichia Infection (Ehrlichiosis)

Anderson BE et al: Ehrlichia chaffeensis, a new species associated with human ehrlichiosis. J Clin Microbiol 1991;29:2838.

Chen SM et al: Identification of a granulocytotropic Ehrlichia species as the etiologic agent of human disease. J Clin Microbiol 1994;32:589.

McQuiston JH et al: The human ehrlichioses in the United States. Emerg Infect Dis 1999;5(5):635.

Rocky Mountain Spotted Fever

Azad AF, Beard CB: Rickettsial pathogens and their arthropod vectors. Emerg Infect Dis 1998;4(2):179.

Thorner AR et al: Rocky Mountain spotted fever. Clin Infect Dis 1998;27(6):1353.

Rickettsialpox

Comer JA et al: Serologic evidence of rickettsialpox (Rickettsia akari) infection among intravenous drug users in inner-city Baltimore, Maryland. Am J Trop Med Hyg 1999;60(6):894.

Kass EM et al: Rickettsialpox in a New York City hospital, 1960–1989. N Engl J Med 1994;331:1612.

Endemic (Murine) Typhus

Higgins JA et al: Rickettsia felis: a new species of pathogenic rickettsia isolated from cat fleas. J Clin Microbiol 1996;34(3):671.

Epidemic (Louse-Borne) Typhus

Raoult D, Roux V: The body louse as a vector of reemerging human diseases. Clin Infect Dis 1999; 29(4):888.