ACP medicine, 3rd Edition

Infectious Disease

Infections Due to Rickettsia, Ehrlichia, and Coxiella

Daniel J. Sexton MD, FACP1

1Professor, Department of Medicine, Duke University School of Medicine

The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

August 2004

Taxonomy

Like other gram-negative bacteria, Rickettsia and Ehrlichia are members of the alpha group of purple bacteria. In the past, the family Rickettsiaceae was divided into three tribes: Ehrlichiae, Rickettsiae, and Wolbachia. The tribe Ehrlichiae was divided into three genera:Ehrlichia, Cowdria, and Neorickettsia. A new taxonomy of existing organisms has been proposed [see Figure 1] that is based on genetic analysis and divides the order Rickettsiales into two families, Rickettsiaceae and Anaplasmataceae; however, this taxonomy is still controversial and is likely to change in the future. The family Rickettsiaceae contains the genera Orientia and Rickettsia. The genusRickettsia is divided into the typhus and spotted-fever groups, which in turn contain numerous species. For example, over 15 different spotted-fever-group rickettsial species have been named. The family Anaplasma taceae is divided into a complex number of Anaplasma andEhrlichia genera. Some organisms previously considered to be Ehrlichia have been renamed Anaplasma.

 

Figure 1. Taxonomy of the Rickettsias

Taxonomy of the rickettsias.

Although the term ehrlichiosis is generally used by clinicians to describe tick-borne diseases caused by organisms in the genera Ehrlichiaand Anaplasma, some organisms that were previously considered to be (and are still widely considered to be) Ehrlichia have been assigned to the genus Anaplasma. For example, the agent of human granulocytic ehrlichiosis (HGE) has been renamed A. phagocytophilum (some sources list this as A. phagocytophilia or A. phagocytophila). Although this chapter uses the old term, HGE, some authors now call this disease human granulocytic anaplasmosis. Moreover, some authors now use the term anaplasmosis instead of ehrlichiosis to describe infection by agents in the family Anaplasmataceae. To make taxonomic matters even more complicated, a surprising number of new spotted-fever-group rickettsial species have been discovered over the past 10 years. Additionally, previously recognized spotted-fever-groupRickettsia species (e.g., R. parkeri) that were thought not to cause human disease were recently confirmed to be human pathogens.1

Biology and Ecology

Rickettsia are gram-negative bacteria that are difficult to see in tissue without the use of special stains. Rickettsia can usually be visualized using Gimenez or special immunoperoxidase stains or can be detected in tissue by the use of direct fluorescent antibody staining techniques.

Rickettsia organisms cannot be propagated on cell-free media, but they can be grown in tissue cultures or in the yolk sacs of developing chick embryos. Members of the spotted-fever group, such as R. rickettsii, grow in both the nucleus and the cytoplasm of host cells, whereas typhus-group Rickettsia organisms grow only in the cytoplasm of infected host cells. Rickettsial cell walls contain lipopolysaccharides and outer-membrane proteins (rOmps). These rOmps are capable of eliciting a protective immune response in animals. Their exact function in arthropods and mammalian cells is uncertain.

Ehrlichia and Anaplasma organisms may infect monocytes (in human monocytic ehrlichiosis [HME]) or granulocytes (in HGE). Ehrlichiaorganisms replicate in the phagosomes of the host cell. Like Rickettsia organisms, Ehrlichia organisms have distinct ribosomes and are surrounded by an outer and inner membrane. Ehrlichia organisms can be detected by light microscopy when they exist as single organisms and can be stained with Gram, Giemsa, Wright, or silver stains. Ehrlichia organisms cannot be grown on cell-free media and thus far have been cultured only in eukaryotic cells and in yolk sacs.

Most Rickettsia and Ehrlichia organisms cycle between arthropod vectors and small mammals, infecting humans only as an incidental host. A notable exception to this pattern is R. prowazekii, which is primarily maintained in a human-louse cycle.

Pathophysiology

After inoculation into humans, Rickettsia organisms proliferate intracellularly and then spread throughout the body via the bloodstream or lymphatics. Spotted-fever-group Rickettsia species, such as R. rickettsii, have a specific and characteristic tropism for endothelial cells. After attachment to the host endothelial cell plasma membrane via a cholesterol-containing receptor, these organisms enter the cell via pinocytosis and then escape from phagosomes into the cytosol. R. rickettsii divides by binary fission and then spreads cell to cell via filopodia derived from host cell membranes.

The hallmark of most rickettsial diseases is cell injury or death associated with an intense vasculitis. Widespread Rickettsia-induced vasculitis in humans leads to minute focal areas of hemorrhage and edema (as a result of increased vascular permeability), along with activation of the humoral immune response, inflammation, and coagulation. Vasculitis from rickettsial infection may result in hypotension, shock, widespread organ dysfunction, and death. Although the histopathologic and clinical features of rickettsial infection have been well characterized, the precise cellular mechanism by which most Rickettsia organisms produce cell damage to small blood vessels is unknown.

Individual Ehrlichia and Anaplasma species infect hosts ranging from humans to dogs, sheep, and horses. Four species are known to infect humans: E. chaffeensis (the organism responsible for human monocytic ehrlichiosis), A. phagocytophilum (the agent of HGE), E. sennetsu, and E. ewingii.

Ehrlichia organisms enter host cells by phagocytosis and then grow and divide while in the host cell phagosome. After a few days, tightly packed clusters of organisms are observable as intracellular inclusions. Later, additional growth and replication of Ehrlichia organisms result in large, mature inclusions called morulae. In vitro growth of Ehrlichia and Anaplasma in tissue culture or yolk cell systems takes 8 to 36 days. Only a few isolates of E. chaffeensis and A. phagocytophilum have been cultured from humans, because in vitro cultivation of these organisms from clinical specimens is extremely difficult.

There is no serologic cross-reactivity between Ehrlichia and Rickettsia, although some cross-reactivity exists between E. chaffeensis, E. ewingii, and A. phagocytophilum. In animals, both experimentally induced and naturally acquired Ehrlichia infections may result in antibody responses, but these responses may not be protective. The relationship between humoral antibody responses and immunity in human ehrlichiosis is still not understood.

How Ehrlichia produces human disease is also poorly understood. Ehrlichia does not cause vasculitis, nor do human tissues infected withEhrlichia demonstrate cell necrosis, abscess formation, or a severe inflammatory response. Patients infected with Ehrlichia may develop lymphadenopathy and perivascular lymphohistiocytic infiltrates without apparent endothelial injury or thrombosis. Some patients with A. phagocytophilum infection contract secondary opportunistic fungal infections. There is also no understanding of the mechanism for the thrombocytopenia that occurs, predictably and early, in most forms of ehrlichiosis. Studies in animal models have shown that decreased hematopoietic production, immune-mediated platelet destruction, and splenic sequestration are unlikely to be the primary mechanism for this thrombocytopenia.2

Rocky Mountain Spotted Fever

EPIDEMIOLOGY

Rocky Mountain spotted fever (RMSF) is an acute tick-borne illness caused by R. rickettsii. RMSF occurs widely in the Western Hemisphere, from southern Canada to Mexico. RMSF also occurs in Central America and has been described in Colombia and Brazil. The primary vectors of RMSF are the Rocky Mountain wood tick in the western United States and the American dog tick in the eastern United States. Other tick vectors are responsible for transmission in Mexico, Central America, and South America. Ticks represent both the reservoir and the vector of RMSF. R. rickettsii normally cycles between ticks and small mammals such as moles and rodents; humans are only an incidental host.

Although RMSF occurs sporadically in most of the continental United States in rural, suburban, and urban locations, it is most often reported from the southeastern and south central United States. Cases of RMSF have been reported from Central Park in New York City and from suburban areas such as Long Island, New York. Over 90% of all cases of RMSF occur from early spring to early autumn.

Up to one third of patients with proven RMSF cannot recall a history of tick bite or recent tick contact. Rickettsial transmission in such cases presumably occurs through inapparent or unrecognized tick bite or through contact with infected tick tissues.

DIAGNOSIS

Clinical Manifestations

RMSF typically begins abruptly. The incubation period after tick bite or tick exposure ranges from 2 to 12 days. The early phases of illness are usually marked by nonspecific symptoms such as fever, headache, malaise and myalgias, and nausea and vomiting. Some patients, especially children, have prominent abdominal pain; this pain may be severe enough to mimic an acute surgical abdomen. Rarely, gastrointestinal involvement in the early phases of RMSF leads to an erroneous diagnosis, such as acute appendicitis, cholecystitis, or even bowel obstruction. Hepatic involvement in severe cases can result in jaundice, which may be striking.

The skin rash that gives RMSF its name may begin as a macular or maculopapular eruption and evolve into a generalized petechial rash [seeFigure 2]. Generalized ecchymosis and even gangrene of the digits, genitals, ears, and nose may rarely occur in severe cases.3 The rash typically develops on the third to the fifth day of illness. Appearance of the rash may be delayed, however; and in a small percentage of patients, the rash does not develop at all. Delay or absence of the rash greatly complicates clinical diagnosis. In one study, only 14% of RMSF patients had a rash on the first day of illness and fewer than 50% developed a rash in the first 72 hours of illness.4 Absence of rash does not correspond to milder disease; a small percentage of patients with so-called spotless RMSF have fatal illness.5 Moreover, the characteristic skin rash of RMSF may be overlooked in dark-skinned patients.

 

Figure 2. Rocky Mountain Spotted Fever

Purpuric macules on the palm and wrist of a patient with Rocky Mountain spotted fever.

Patients with RMSF may occasionally present with a wide variety of neurologic symptoms ranging from confusion to seizures and encephalopathy. Some patients with RMSF have focal neurologic signs that lead to misdiagnoses. Neurologic symptoms may persist after recovery of acute illness in some patients.6 Other atypical and uncommon presenting features of RMSF include periorbital edema (especially in children) and cough.

The diagnosis of RMSF is notoriously difficult, even for experienced physicians in highly endemic areas. In the first few days of illness, particularly when the characteristic rash is absent, RMSF may mimic an array of nonspecific viral diseases. If early RMSF is mistaken for a bacterial illness and if β-lactams or other antibiotics ineffective against R. rickettsii are given, the subsequent appearance of a rash may be tragically mistaken for a drug eruption and lifesaving therapy may be omitted or delayed. RMSF has been confused with measles, staphylococcal bacteremia, hepatitis, leptospirosis, meningococcemia, and infectious mononucleosis.7 The clinical features of RMSF and ehrlichiosis are often similar [see Table 1]. Even experienced physicians cannot always distinguish the two diseases, although the presence of severe leukopenia and the absence of rash favor the diagnosis of ehrlichiosis.8

It is axiomatic that the diagnosis of RMSF must be based on the clinical features and an appropriate epidemiologic setting rather than on any single laboratory test. There is no completely reliable diagnostic test for RMSF in the early phases of illness; thus, therapy should always begin before laboratory confirmation is obtained.

Table 1 Diagnosis of Diseases Caused by Rickettsia, Ehrlichia, and Coxiella Species

Disease
(Pathogen)

Rocky Mountain
  Spotted Fever

    (Rickettsia
     rickettsii)

Rickettsialpox
  (Rickettsia
      akari)

TIBOLA

Murine Typhus
  (Rickettsia
      typhi)

Epidemic
  Typhus

(Rickettsia
prowazekii)

Scrub Typhus
    (Orientia
tsutsugamushi)

Ehrlichial
 Diseases

Q Fever
(Coxiella
burnetii)

Animal
Reservoir

Rocky Mountain
  wood tick (western
  U.S.), American
  dog tick
  (eastern U.S.)

House mouse via
  bloodsucking
  mite

Tick (Dermacentor
    marginatus
)

Rat, cat, or
  mouse flea

Human body
  louse (squirrel
  lice and fleas
  in sylvatic
  form)

Mite (Pacific rim)

White-tailed
  deer, rodents

Cattle, goat,
  sheep, cats,
  dogs, ticks

Transmission

Tick bite

Mite bite

Tick bite

Flea bite

Louse or flea
  bite

Mite bite

Tick bite

Airborne,
   direct contact,
   infected milk

Incubation
Period (Range)

2–12 days

2–12 days

3–10 days

8–16 days

7–10 days

7–10 days

3–12 days

29 days (range,
    10–39 days)

Clinical Manifestations

Fever, headache,
    malaise,
    myalgias,
    nausea/vomiting;
    abdominal pain;
    rash on days
    3–5 in most but
    not all cases;
jaundice

Eschar at bite
  site, then severe
  headache, fever,
  chills, myalgias,
  papulovesicular
rash

Localized lesion
  at bite site; cervical
  or regional
  lymphadenopathy;
  fever
  and rash in <
  10% of cases;
  alopecia may
  occur and persist
  at site of
  local lesion

Fever, chills,
  headache,
  myalgias, GI
  symptoms;
  rash at end of
  first week beginning
  on
  trunk, spreading
  to extremities;
  cough,
  dyspnea in
  severe illness

Acute severe infection,
  fever,
  headache, myalgias,
  cough, abdominal
  pain,
  GI symptoms,
  jaundice; red
  macular/maculopapular
  rash on trunk
  spreading to
  extremities;
  neurologic
  symptoms
  may occur

Necrotic eschar at
  bite site; fever,
  headache, anorexia,
  malaise,
  chills; macular/
  maculopapular
  rash in half of
  patients, usually
  sparing the face;
  generalized lymphadenopathy;
  respiratory symptoms;
  neurologic
  symptoms may
  occur

Headache,
  fever, anorexia,
  malaise,
  cough, nausea
  and vomiting;
  rash
  uncommon

Fever, headache,
  myalgias, anorexia,
  malaise,
  chills; chest pain,
  cough, rales,
  pneumonia;
  hepatitis; chronic
  disease in immunocompromised
  patients;
  may cause
  endocarditis

Laboratory Test Results

Thrombocytopenia,
  elevated
  plasma aminotransferase,
  elevated bilirubin,
  elevated
  serum creatinine,
  positive
  serology, positive
  PCR; culture
  difficult

Thrombocytopenia,
  mild elevations
  in plasma
  aminotransferases;
  positive
  serology

Thrombocytopenia,
  positive
  serology, positive
  PCR

Thrombocytopenia;
  positive
  serology

Elevated aminotransferases,
    thrombocytopenia;
    positive
    serology

Serology not
    reliable in early
    phases; antibodies
    present
    10–20 days after
    onset

Serology not
    reliable in
    early phases,
    antibodies
    present 10–20
    days after
    onset; positive
    PCR; culture
    difficult

Elevated antibody
    titer,
    positive PCR

PCR—polymerase chain reaction  TIBOLA—tick-bite-associated lymphadenopathy

Laboratory Studies

The white blood cell count remains normal in most patients with RMSF. In some cases, however, the WBC may be low or elevated. Thrombocytopenia generally occurs in severe cases and is a helpful diagnostic finding. The low platelet count may be accompanied by reduced fibrinogen concentrations and elevated levels of fibrin split products. Other characteristic laboratory abnormalities in patients with RMSF include elevated blood levels of aminotransferases, bilirubin, and creatinine.

Diagnostic proof of RMSF can be obtained by direct immunofluorescent or immunoenzyme staining of skin biopsy samples or, in the convalescent phase of the disease, by the detection of characteristic antibodies. These antibodies typically do not appear before day 8 to 10 of illness; thus, serologic testing has no role in the initial diagnosis of acutely ill patients with suspected RMSF.

Culture of Rickettsia from blood samples can be done only in specialized laboratories and the delay in obtaining a result makes positive cultures useful only in retrospect. Polymerase chain reaction technology has been applied to the diagnosis of RMSF, but such testing is neither sensitive nor widely available. Because some patients die before generating an antibody increase against R. rickettsii antigen, the diagnosis in fatal cases may be completely missed unless immunohistochemical staining is performed on tissues obtained at autopsy.9

TREATMENT

Tetracyclines and chloramphenicol are the only antibiotics known to be effective against R. rickettsii. Doxycycline is the preferred agent in all patients except pregnant women, for whom chloramphenicol remains the agent of choice. Therapy should be initiated as early as possible in the course of RMSF. Therapy started more than 5 days after onset is much less likely to be effective than therapy given earlier.10

The usual dosage of doxycycline is 200 mg a day in two divided doses. The same dosage can be administered intravenously or orally. Intravenous therapy is preferred for patients who are seriously ill or who are experiencing nausea or vomiting. Children with RMSF should be given doxycycline at a dosage of 2.5 to 3 mg/kg/day in two divided doses. Chloramphenicol given at an initial loading dose of 50 mg/kg, followed by 50 mg/kg/day in four divided doses, is an appropriate alternative for patients who cannot tolerate tetracyclines or who are pregnant [see Table 2].

Table 2 Treatment of Diseases Caused by Rickettsia, Ehrlichia, and Coxiella Species

Infection

Drug

Dosage

Relative Efficacy

Cost*

Comments

Rocky Mountain spotted
  fever, rickettsialpox, murine typhus, infections due to other spotted-fever-group
  Rickettsia species

Doxycycline

100 mg q. 12 hr I.V. or p.o
    for 5–7 days

First choice

Oral, $6–8

I.V. preferred for adult and pediatric patients who are seriously ill or who have nausea or vomiting

Chloramphenicol

50 mg/kg initial loading dose, then 50 mg/kg/day in 4 divided doses

For pregnant women and those who cannot tolerate tetracycline

Epidemic typhus

Doxycycline

Single dose of 200 mg; repeat weekly for prophylaxis

First choice

$1

Chloramphenicol

50 mg/kg initial loading dose, then 50 mg/kg/day in four divided doses for 5–7 days

For pregnant women and those who cannot tolerate tetracycline

Scrub typhus

Doxycycline plus
  rifampin

Doxycycline, 100 mg q.
  12 hr I.V. or p.o. for
  3–7 days; rifampin, 600
  mg/day for 5–7 days

First choice

Oral doxycycline,
  $3–8; rifampin, $20–28

This regimen may not be effective in geographic areas where strains with reduced susceptibility to tetracyclines have been documented (see text for details)

Azithromycin or
  rifampin

Azithromycin, 500 mg/day
  for 5–7 days; rifampin,
  600 mg/day for 5–7 days

Azithromycin, $75–105;
  rifampin, $20–28

For use in areas with strains
  with reduced susceptibility
  to tetracycline; for
  pregnant women

Ehrlichia, Anaplasma
  phagocytophilia
infection

Doxycycline

100 mg q. 12 hr I.V. or p.o.
  for 5–7 days

First choice

Oral, $6–8

Chloramphenicol

50 mg/kg initial loading
  dose, then 50 mg/kg/day
  in four divided doses for
  5–7 days

Efficacy unproven; for
    pregnant women and
    those who cannot tolerate
    tetracyclines

Q fever (acute disease)

Tetracycline

500 mg, p.o., q. 6 hr for 14
  days

Equally effective

$15

Doxycycline

100 mg, p.o., q. 12 hr for 14
  days

Equally effective

$15

Ciprofloxacin

500 mg, p.o., q. 12 hr for 14
  days

Equally effective

$131

*Rounded to nearest dollar. Costs are derived from online pharmaceutical sources and are intended to indicate relative costs of available therapies.
For recommendations on treatment of chronic Q fever, see text.

Unfounded fears about the risk of tetracycline therapy in children with suspected rickettsial disease may unnecessarily delay the institution of potentially lifesaving therapy.11 Because RMSF can normally be cured with a short course of doxycycline therapy, concerns about staining of the teeth should not prohibit the use of doxycycline in young children with suspected RMSF; indeed, such therapy may be lifesaving, and it is considerably safer than therapy with chloramphenicol. In addition to antimicrobial therapy, treatment should include measures to correct associated complications, such as hypotension, heart failure, and electrolyte disturbances. Glucocorticoid therapy has never been shown in a controlled study to be useful in the treatment of RMSF, and it is not recommended.

PREVENTION

The prevention of RMSF relies on avoidance of tick-infested areas or the use of protective clothing and tick repellent while in such areas. Prompt removal of ticks after attachment is particularly important. Ticks should be removed using tweezers, tissue, or cloth to protect the fingers, because crushed tick tissues can be infectious.

PROGNOSIS

In consequence of the difficulty in making a conclusive diagnosis of RMSF in the early phases of illness, delays in the initiation of therapy are common. Such delays are often associated with fatal outcome if they exceed 5 days. A number of host factors have been associated with severe or fatal RMSF, including increasing age, male gender, and the presence of glucose-6-phospate dehydrogenase (G6PD) deficiency. Black race and alcohol use have also been associated with more severe disease and a higher fatality, but it is difficult to exclude the role of delay in seeking or receiving antimicrobial therapy in these patients. The biologic causes for the worse outcomes seen in patients older than 40 years and in male patients remain poorly understood. Patients with abnormal renal function at the time of presentation have a worse prognosis than those with normal renal function.12

Rickettsialpox

Rickettsialpox is an uncommon mite-borne rickettsial disease caused by R. akari. The disease's name is derived from its clinical resemblance to chickenpox.

EPIDEMIOLOGY

  1. akariis transmitted to the house mouse by a blood-sucking mite (Liponyssoides sanguineus). The mouse serves as a reservoir for the disease, and as with RMSF, humans are only an incidental host. When mouse populations are reduced by vermin-eradication programs, L. sanguineuswill bite humans and transmit rickettsialpox. Initially, rickettsialpox was recognized only in urban areas such as New York City, Pittsburgh, Cleveland, and Boston. However, cases have now been described in rural areas and in areas outside the previously recognized geographic range for the disease, including North Carolina, the Ukraine, Croatia, Turkey, and the Yucatan region of Mexico.13

DIAGNOSIS

Rickettsialpox is usually recognized by the appearance of one or more characteristic skin lesions (eschars) at the site of the bite, followed soon thereafter by the abrupt onset of headache, fever, chills, and myalgias and a papulovesicular rash. Most patients with rickettsialpox are only mildly ill and recover without treatment after 10 to 14 days of illness. Headache is characteristically severe. The skin rash of rickettsialpox can be distinguished from that of chickenpox by the fact that it typically begins as a maculopapular eruption that quickly evolves into a papulovesicular eruption. Most patients with vesicular lesions also have a primary eschar at the site of their mite bite. Lesions in rickettsialpox are often scant, characteristically scab, and resolve without scarring. Unlike the rash of chickenpox, the rash of rickettsialpox does not appear in crops or clusters, nor do the vesicular lesions of rickettsialpox have the characteristic dew-drop appearance of chickenpox lesions. Certain other rickettsial diseases that produce eschars and vesicular rashes can mimic rickettsialpox [seeOther Spotted-Fever-Group Rickettsial Infections, below].

The diagnosis of rickettsialpox is typically confirmed by serologic testing. However, biopsy of the eschar or the rash can be diagnostic if special fluorescent antibody reagents are available to demonstrate R. akari in tissue.

TREATMENT

Treatment for rickettsialpox is identical to that for RMSF (see above).

Other Spotted-Fever-Group Rickettsial Infections

Other tick-borne spotted-fever-group rickettsial infections include Mediterranean spotted fever, African tick-bite fever, Queensland tick typhus, Siberian tick typhus, Japanese spotted fever, Flinders Island spotted fever, tick-borne lymphadenopathy (TIBOLA), and R. parkeriinfection. All of these illnesses respond to treatment with tetracyclines or chloramphenicol. Most are milder in course and severity than RMSF, although Mediterranean spotted fever may, in rare cases, be fatal.

In addition to rickettsialpox, six spotted-fever-group rickettsioses are characterized by localized eschars (Mediterranean spotted fever, African tick-bite fever, R. parkeri infection, Queensland tick typhus, and Siberian tick typhus). TIBOLA is not usually associated with a generalized rash; rather, this unusual rickettsiosis is characterized by a localized area of scalp alopecia. The alopecia typically follows the development of a crusted lesion at the site of a resolving tick bite. Localized hair loss may be prolonged. Cervical or regional lymphadenopathy is common in TIBOLA. Only a minority of TIBOLA patients have fever, and rash occurs in fewer than 10% of patients.14

Infection with a newly recognized rickettsial agent, R. mongolotimonae, has been seen in southern France. In the few cases reported to date, clinical manifestations have typically been similar to those of Mediterranean spotted fever.15

A recent report of human infection with R. parkeri suggested that some cases of apparent RMSF in the United States, especially those in which an eschar was present at the site of a tick bite, may in fact be infection with the spotted-fever-group agent R. parkeri.16

Murine Typhus

EPIDEMIOLOGY, ETIOLOGY, AND PATHOGENESIS

Murine typhus occurs worldwide. It is caused by Rickettsia typhi, which is transmitted to humans by the bite of an infected flea. Although house mice, domestic cats, and shrews may be occasional hosts for infected fleas, the principal reservoir of R. typhi is the rat. In addition to serving as hosts for infected fleas, rats may become rickettsemic after contact with such fleas and then transmit organisms to other, simultaneously feeding fleas. When such fleas happen to bite humans, murine typhus may result. Murine typhus is uncommon in the United States, although a relatively large number of cases have been reported in southern Texas during the past 20 years. A total of 47 cases of murine typhus were reported in Hawaii during 2003, which is a remarkable increase from previous numbers, and serologic evidence of R. typhi infection has been demonstrated in a variety of rodent species in Hawaii.17

DIAGNOSIS

Clinical Manifestations

Onset of murine typhus is typically abrupt, occurring after an incubation period ranging from 8 to 16 days. Early manifestations of illness are nonspecific, typically comprising fever, chills, headache, and myalgias. In addition, many patients have gastrointestinal complaints, including nausea, vomiting, abdominal pain, and diarrhea. Rash typically occurs near the end of the first week of illness. The rash is classically described as beginning on the trunk and spreading to the extremities. Rash may be faint or difficult to see, and in some patients, it does not occur at all. Murine typhus is usually a mild illness; even in untreated cases, deaths are rare. However, severe disease with mental confusion, encephalopathy, renal dysfunction, and severe thrombocytopenia can occur. Patients with severe illness may develop cough and dyspnea. As in other rickettsial diseases, the presence of G6PD deficiency and advanced age appear to be associated with more severe or fatal disease.

Laboratory Studies

Thrombocytopenia is present in most cases of murine typhus and is an important laboratory clue to the diagnosis. As in other rickettsial diseases, serology is the most reliable and widely available diagnostic method. Convalescent antibodies typically appear after 8 to 10 days of illness. In severely ill patients with pulmonary manifestations, chest x-rays may show interstitial infiltrates or changes suggestive of pneumonia or pulmonary edema.

TREATMENT

As in other rickettsial diseases, the only effective agents for treatment of murine typhus are tetracyclines and chloramphenicol, with doxycycline the preferred choice in most patients. The dosages of doxycycline in the treatment of murine typhus are the same as those in the treatment of RMSF [see Table 2].

Epidemic (Louse-Borne) Typhus

EPIDEMIOLOGY, ETIOLOGY, AND PATHOGENESIS

Louse-borne, or epidemic, typhus, caused by R. prowazekii, killed millions of people in Eastern Europe and Russia during the periodic wars that devastated this geographic area during the past 2 centuries. Fortunately, epidemic typhus is now a rare disease. However, sporadic outbreaks still occur in parts of Russia, Algeria, and Burundi and in the Andes Mountains of South America.18 War, famine, and human cruelty can result in epidemics; for example, more than 45,000 cases of epidemic typhus occurred in Burundi after the 1993 civil war in that country.19

Until 25 years ago, epidemic typhus was thought to involve an exclusive cycle between the body louse and infected humans. However, a sylvatic cycle of infection with R. prowazekii is now known to be endemic in the eastern United States. This sylvatic cycle of infection involves flying squirrels (Glaucomys volans) and their ectoparasites, but secondary transmission in humans has been recognized when lice that normally infest squirrels seek a host in humans.20 A case report of epidemic typhus in a patient from the southwestern United States (an area outside the known geographic range of the flying squirrel) suggests the existence of additional vectors or wild-animal reservoirs forR. prowazekii.21

The principal vector for epidemic typhus is the human body louse (Pediculus humanus corporis), although occasionally, the head louse (P. humanus capitis) can also transmit infection [see 2:VIII Parasitic Infestations]. Both the squirrel flea (Orchopeas howardi) and the squirrel louse (Neohaematopinus sciuropteri) also act as vectors for R. prowazekii in the sylvatic cycle of infection. Infected fleas and lice are capable of producing a rickettsemia in flying squirrels and thus allowing propagation of infection to additional generations of ectoparasites.

In its classic epidemic form, typhus is transmitted by body lice. While taking a blood meal from humans, body lice defecate and regurgitate infective gastrointestinal contents; these highly infective substances are then inoculated into the skin when the person scratches the pruritic feeding site. Lice feces remain infectious for as long as 100 days. Thus, human-to-human transmission of R. prowazekii can occur via the sharing of clothes or via transfer of infected lice feces from one human to another.

Transmission of the sylvatic form of epidemic typhus to humans occurs only when humans have direct contact with infected squirrels or when squirrels nesting in the attics of homes are removed or killed, leaving the lice that infested their nests to seek an alternative (human) host.

PATHOPHYSIOLOGY

After entering the human body, R. prowazekii spreads via the bloodstream and lymphatics to produce a generalized vasculitis. The precise mechanism by which R. prowazekii produces cellular injury is poorly understood, but the net effect of this infection is widespread endothelial injury. This rickettsial vasculitis may produce diffuse myocarditis, along with macroscopic and microscopic damage to muscles and neural tissue, the spleen, kidneys, and other internal organs. Central nervous system involvement may result in so-called typhus nodules, which comprise perivascular infiltrates consisting of lymphocytes, macrophages, and plasma cells.

DIAGNOSIS

Clinical Manifestations

  1. prowazekiiinfection produces two distinct clinical syndromes. The most common is an acute, severe infection that occurs 7 to 10 days after exposure to infected lice and may result in death. A second, recrudescent form, called Brill-Zinsser disease, may occur from 1 to 5 decades after a primary infection.

Patients with acute epidemic typhus infection typically become abruptly ill with fever, headache, and myalgias. Other nonspecific symptoms, such as cough, abdominal pain, nausea, and diarrhea, are common. Skin rash in patients with epidemic typhus classically begins several days after the onset of symptoms as a red macular or maculopapular eruption on the trunk that then spreads to the extremities. Although skin rash is classically described as sparing the palms and soles, exceptions to this rule occur. In severe cases of epidemic typhus, skin rash may become petechial; rarely, gangrene of the extremities has been described.

In humans, the clinical features of the sylvatic form of typhus are similar to those of the epidemic form. In one series, however, only half of the patients with the sylvatic form of R. prowazekii infection had a skin rash.

Patients with epidemic typhus often have neurologic symptoms that may range from mild confusion and drowsiness to coma, seizures, and focal neurologic findings. As in other rickettsial diseases, jaundice and myocarditis may occur in severe cases.

Recrudescent R. prowazekii infection (Brill-Zinsser disease) is generally a much milder illness than acute epidemic typhus. The onset of Brill-Zinsser disease is often abrupt, with chills, fever, and headache. Skin rash typically begins 4 to 6 days after the onset of symptoms, and it is often scant or evanescent. Because patients with Brill-Zinsser disease are often elderly or have other chronic medical conditions, their symptoms (e.g., confusion, dyspnea, and lethargy) may be incorrectly attributed to preexisting or coexisting cardiac, cerebrovascular, or pulmonary disease.

Laboratory Studies

Both forms of R. prowazekii infection are best diagnosed by serologic testing. The indirect immunofluorescent antibody (IFA) test and an immunoblot technique are reliable serologic methods. A fourfold rise in antibody titers 10 to 21 days after onset of symptoms is considered diagnostic in both forms of R. prowazekii infection, although only an IgG antibody response is elicited in Brill-Zinsser disease.

Common accompanying laboratory findings in acute epidemic typhus include increased plasma aminotransferase levels and thrombocytopenia. Patients with severe involvement may have pulmonary infiltrates and other laboratory evidence of myocarditis.

TREATMENT

Tetracyclines and chloramphenicol are effective treatments for both acute and recrudescent R. prowazekii infections, but the drug of choice is doxycycline. In one study, 35 of 37 patients with epidemic typhus were cured with a single 200 mg dose of doxycycline.22 However, the two remaining patients had a relapse 6 and 7 days after initial response. Patients with R. prowazekii infection characteristically improve within 48 hours of initiation of antirickettsial therapy. In severe cases, supportive care with vasopressors, intravenous fluids, oxygen, and even dialysis may be necessary.

PREVENTION

Efficacy of prophylaxis for epidemic typhus is directly related to the efficacy of prophylactic measures against lice infestation. Because humans who have contacts with other lice-infested humans can secondarily acquire lice even if they have good hygiene, all louse-infested persons and workers in close contact with such persons should use long-acting topical insecticides such as malathion, lindane, or a pyrethroid (permethrin). Fabrics and clothing treated with permethrin remain toxic to lice even after 20 washings.23

In epidemic settings, the use of chloramphenicol or tetracycline for prophylaxis of R. prowazekii infection is highly effective. Even a single 200 mg dose of doxycycline taken once weekly by travelers or health care workers in areas where epidemic typhus is present has been shown to protect against infection. Prophylaxis should be continued for 1 week after leaving an endemic or epidemic area.24

Inactivated vaccines have been shown to confer protection against experimental R. prowazekii infections.24 Such vaccines are not currently commercially available nor are they likely to become available, in view of the effectiveness of both prophylactic antibiotics and other preventive measures.

PROGNOSIS

In the preantibiotic era, higher mortality from epidemic typhus was associated with older age and male gender. With prompt institution of antimicrobial therapy, however, mortality is now rare.

Scrub Typhus

Scrub typhus is a mite-borne disease, caused by Orientia tsutsugamushi, that was first described by Chinese physicians in the third century. Widespread outbreaks of scrub typhus in Allied soldiers in the Pacific theater of World War II led to investigations by military physicians that provided much of our current understanding of the clinical features, diagnosis, and prevention of this highly geographically focal disease.

EPIDEMIOLOGY

  1. tsutsugamushiis distributed throughout the Pacific rim and is endemic in Korea, China, Taiwan, Japan, Pakistan, India, Thailand, Malaysia, and northern Australia. Most cases of scrub typhus occur in rural areas, but cases may also occur in suburban areas, such as those around Bangkok, where the seroprevalence in the general population may be as high as 20%.25

The reservoir and vector of scrub typhus are trombiculid mites of the genus Leptotrombidium. Larval mites (known as chiggers) maintain the infection in successive generations via transovarial transmission. Because the geographic distribution of mites is often highly focal, areas as small as a few hundred square meters of scrub vegetation may contain enormous numbers of infected chiggers. The risk of disease transmission by these chiggers may be extremely high in humans who enter these focal areas (also called mite islands). Because of the ease of air travel and the long incubation period of scrub typhus (up to 2 weeks), tourists to endemic areas may fall ill after returning home to regions where the illness is not familiar to physicians. Numerous cases of scrub typhus have been described in tourists returning to the United States, Europe, and Canada from endemic regions.

BIOLOGY AND PATHOPHYSIOLOGY

  1. tsutsugamushiis distinct serologically and epidemiologically from typhus-group Rickettsia. However, this organism shares many of the microbiologic characteristics of typhus and spotted-fever-group Rickettsia, such as inability to be propagated on cell-free media. Unlike other Rickettsiaspecies, O. tsutsugamushi has a trilaminar outer membrane. O. tsutsugamushi is also unique in that it is released from infected cells by a peculiar budding process involving the plasma membrane of host cells. Once released from the infected cell, organisms are in turn phagocytosed by adjacent cells and eventually disseminate widely throughout the body.

There are three strains of O. tsutsugamushi: Karp, Gilliam, and Kato. Infection with one strain does not preclude infection with a different strain.

DIAGNOSIS

Clinical Manifestations

Onset of scrub typhus typically occurs 7 to 10 days after the person is bitten by an infected mite. The illness may begin gradually or abruptly. In either case, headache, anorexia, malaise, chills, and fever are prominent early symptoms. Approximately one half of patients with scrub typhus develop a characteristic macular or maculopapular rash. In severe cases, this rash may become petechial. Rash from scrub typhus typically spares the face.

A localized necrotic skin lesion or eschar is a hallmark of scrub typhus [see Figure 3]. Eschars typically occur at the site of the infected chigger bite and may appear before the onset of systemic symptoms. Some patients have multiple eschars. In various case series, eschars have occurred in as few as 40% and as many as 88% of patients with scrub typhus.26

 

Figure 3. Eschar in Scrub Typhus

Eschar at the site of a mite bite in a patient with scrub typhus.

Generalized lymphadenopathy occurs in most patients with scrub typhus; some patients also have splenomegaly. Respiratory involvement occurs more often in scrub typhus than in other rickettsial diseases, and cough may be present in as many as one half of patients. As in other rickettsial diseases producing vasculitis, scrub typhus may be marked by neurologic involvement, which may manifest as aseptic meningitis, seizures, or focal neurologic abnormalities. In some patients, neurologic abnormalities are the dominant symptoms.

DIAGNOSIS

The initial diagnosis of scrub typhus must be based on clinical and epidemiologic features, because serologic testing is not reliably positive in the early phases of illness. Convalescent antibodies, which are best detected by an IFA technique, occur in the majority of patients between 10 and 20 days after onset of illness. Because more than one strain of O. tsutsugamushi is capable of causing scrub typhus, a battery of antigens should be used to detect convalescent antibodies. In addition to IFA testing, an enzyme-linked immunosorbent assay (ELISA) and a dot-blot immunoassay have been developed to diagnose scrub typhus.

Although not commonly done, biopsy of the generalized rash or the eschar can help establish the diagnosis of scrub typhus. Examination of the biopsy sample will reveal vasculitis with a perivascular collection of lymphocytes and macrophages.

Culture of O. tsutsugamushi can be performed in specialized centers with the necessary laboratory facilities and diagnostic reagents; a PCR-based test has also been developed. However, such tests are rarely available in regions of the world where scrub typhus is endemic.

DIFFERENTIAL DIAGNOSIS

Scrub typhus is one of the classic causes of tropical fever in the Pacific Rim, where it is well known to be easily confused with malaria, dengue, or typhoid fever. Coinfection with scrub typhus and leptospirosis has been described in agricultural workers in Thailand. One of these workers, who was treated with penicillin only, died of respiratory failure attributed to untreated scrub typhus infection.27

TREATMENT

The treatment of scrub typhus is the same as that of most other rickettsial diseases [see Table 2]. Doxycycline is typically the agent of choice. Regimens of doxycycline as short as 1 day have been advocated for the therapy of scrub typhus, but a small number of patients treated with this short course suffer relapse.28,29 To prevent relapse, most experts recommend a 3- to 7-day course of therapy with doxycycline.

In the mid-1990s, strains of O. tsutsugamushi with reduced susceptibility to tetracycline were reported in Thailand.30 Azithromycin may be effective against strains with reduced susceptibility to tetracycline and, therefore, may be selected for therapy in areas where such strains are known or suspected to exist. However, there is little clinical experience, as well as few in vitro susceptibility data, to support this choice. Azithromycin may also be used to treat pregnant woman infected with typhus.

A randomized trial in northern Thailand compared the efficacy of doxycycline alone with the combination of doxycycline and rifampin for scrub typhus. The median duration of fever was significantly shorter in patients treated with the combined regimen.31

PREVENTION

Although there is no vaccine available to prevent the transmission of scrub typhus, several studies have demonstrated that doxycycline is highly effective for prophylaxis when used by nonimmune persons living and working in areas where scrub typhus is highly endemic. A weekly dose of 200 mg of doxycycline has been shown to be reasonably effective in preventing transmission.

Human Monocytic Ehrlichiosis

EPIDEMIOLOGY

The principal vector of HME is the Lone Star tick (Amblyomma americanum) The causative agent of HME, E. chaffeensis, was first isolated from a soldier at Fort Chaffee, Arkansas, in 1990. Since then, HME has been recognized as endemic throughout the southeastern and south central United States. In addition, a few cases of HME have been recognized in New England and the Pacific Northwest, and isolated cases have been reported in Europe, Africa, and Mexico.32

In some locations, HME is probably more common than RMSF. In a prospective study of 35 consecutive patients from North Carolina who presented to outpatient facilities with fever and a recent history of tick bite, 26% had HME, 17% had RMSF, and one patient was coinfected with R. rickettsii and E. chaffeensis. Most of these patients received outpatient treatment with doxycycline, and all of them recovered quickly.33

Estimates of the incidence of HME have varied widely. A prospective study of febrile patients hospitalized in southeast Georgia in the United States showed that the prevalence of HME was 5.7 cases per 100,000 population.34 A remarkably higher incidence was described in a golf-oriented retirement community in Tennessee, in which the annual incidence of disease was 660 per 100,000.35 A serosurvey in the same community revealed that 12.5% of the residents had serologic evidence of past infection. Tick bites, exposure to wildlife, and golfing were associated with an increased risk of infection.

White-tailed deer are thought to be the principal animal reservoirs for E. chaffeensis infection. A study from Georgia found serologic evidence of E. chaffeensis infection in 27 of 35 deer and isolated E. chaffeensis from five of them, confirming that deer are naturally infected in endemic areas.36 Although the role of wild canids and domestic dogs in the epidemiology of HME is uncertain, in one study 15 of 21 coyotes trapped in Oklahoma were found to be infected with E. chaffeensis 37

DIAGNOSIS

As with other tick-borne diseases, the diagnosis of HME is usually based on the recognition and synthesis of characteristic clinical and laboratory features in patients who reside in a geographic location where ehrlichiosis is known to occur during a time of year when tick exposure is likely or known. In other words, a history of tick bite or tick exposure during the spring or summer months in a resident of an endemic area, coupled with the presence of leukopenia or thrombocytopenia and abnormal liver function test results, provides strong circumstantial evidence for the diagnosis of HME. Even the presence of some of these findings is sufficient justification for the initiation of therapy.

Clinical Manifestations

After an incubation period of 5 to 14 days, patients with HME typically develop fever along with malaise and headache. Chills occur in approximately two thirds of patients, and gastrointestinal symptoms, including nausea and vomiting, may occur in up to one half of patients. Cough may also be a prominent symptom of HME, leading to diagnostic confusion with a host of respiratory illnesses. Although HME usually presents as an acute illness, subacute infection from E. chaffeensis has been described. In one study, for example, six of 41 patients with HME diagnosed at a medical center in Missouri during a 4-year period had protracted fever, ranging in duration from 17 to 51 days.38 In addition, rare cases of subclinical or self-limiting infection with E. chaffeensis have been described.

Skin rash is uncommon in patients with HME, but when present, it may be macular, maculopapular, or petechial. Although skin rash was reported in 36% of cases in one case series of 211 patients with HME, skin rash has been less common in the experience of many clinicians working in HME-endemic regions.39 The clinical features of HME are highly variable. Some patients present only with headache, anorexia, and malaise, whereas other patients have prominent neurologic symptoms that may include mental-status changes and stiff neck.

Laboratory Studies

The most common laboratory abnormalities seen in patients with HME are leukopenia (often accompanied by a left shift), thrombocytopenia, and elevated levels of aminotransferases (transaminases), lactate dehydrogenase, and alkaline phosphatase. Anemia and an elevated plasma creatinine concentration also may be seen. Later in the course of illness or during recovery, a striking atypical lymphocytosis may occur.

Abnormalities of the cerebrospinal fluid are common in patients in whom a lumbar puncture is performed because of neurologic symptoms. Lymphocytic pleocytosis and elevated CSF protein levels were found in 21 of 38 patients with E. chaffeensis infection in one study.40

The detection of morulae in lymphocytes in smears of the peripheral blood or buffy coat can occasionally be useful and even diagnostic. Unfortunately, morulae are seen in only a small minority of patients with HME. Thus, such testing has a low sensitivity, even though the finding of morulae is highly specific.

HME can be confirmed serologically with an IFA test using E. chaffeensis as the test antigen. IFA tests can be obtained through all state health departments. The current case definition of HME used by the Centers for Disease Control and Prevention requires at least a fourfold rise or fall in IFA titer against E. chaffeensis between the acute stage and convalescent stage, with a minimum titer of 1:64.41 An important limitation of this test is that antibodies first become detectable 2 to 3 weeks after the onset of the illness. Thus, as with RMSF, serology is useful only in confirming infection, not in the decision to initiate therapy

Culture of Ehrlichia is extremely difficult. Only a few isolates of E. chaffeensis have been made from humans, and in such cases, detection required over 30 days of cultivation.42 PCR-based testing is available for the diagnosis of HME, but such testing is performed only in special laboratories and remains mostly a research tool.

DIFFERENTIAL DIAGNOSIS

Ehrlichiosis may be easily confused with RMSF, a wide number of common viral illnesses (e.g., mononucleosis), thrombotic thrombocytopenic purpura, hematologic malignancy, cholangitis, the early phases of hepatitis A infection, and community-acquired pneumonia.

TREATMENT

The treatment of HME is the same as that of HGE (see below).

PROGNOSIS

Estimated mortality for patients with HME has ranged from 2% to 5%. The available mortality data are limited and are based on small case series, which may overestimate the actual risk.

Human Granulocytic Ehrlichiosis (Anaplasmosis)

EPIDEMIOLOGY

First described in 1994 in patients from the north central United States, HGE is now known to occur in Wisconsin, Minnesota, Connecticut, New York, Massachusetts, California, and Florida, as well as in western Europe.43 A population-based surveillance study from northwestern Wisconsin reported an incidence of 9.5 HGE cases per 100,000 population in an area where the incidence of Lyme disease was 57 cases per 100,000 population.44 Epidemiologic serosurveys have demonstrated that 3% to 15% of asymptomatic persons living in endemic areas may have antibodies to the HGE agent.45

  1. phagocytophilum, the causative agent of HGE, is primarily transmitted by Ixodes scapularis, the tick that is also the vector of Lyme disease and babesiosis. I. pacificus, the black-legged tick, is the primary vector of HGE in the western United States, and I. ricinisis the presumed vector in Europe.

DIAGNOSIS

The diagnosis of HGE must sometimes be made on a circumstantial basis, by synthesis of the history and the clinical and epidemiologic features of an individual case. Clinicians should consider HGE as a possible diagnosis in any patient with a nonspecific febrile illness who becomes ill in the spring or summer months, who inhabits or has visited an endemic region, or who has a history of recent tick bite or tick exposure. Laboratory studies can support, and sometimes confirm, the diagnosis. However, the absence of such findings—in particular, the failure to detect morulae in leukocytes—should not dissuade clinicians when the overall picture suggests HGE.

Clinical Manifestations

The incubation period (5 to 14 days) and clinical features of HGE are similar to those of HME. Most patients with HGE have nonspecific symptoms such as malaise, myalgia, headache, nausea, vomiting, arthralgias, and cough. In a study of 18 adults with HGE, symptoms appeared an average of 5.5 days after a tick bite was noted.46

Clinically, HGE can range from mild to severe. Fatal HGE has been documented: a retrospective case study of 41 patients with laboratory-diagnosed HGE infection found a case-fatality rate of 4.9%.47 Many of the patients who died had secondary opportunistic infections, such as fungal pneumonia. However, other studies have estimated that the mortality for HGE may actually be less than 1%.43

Laboratory Studies

The diagnosis of HGE can be confirmed by finding characteristic intraleukocytic morulae in the peripheral blood [see Figure 4] or buffy coat, by serology (using IFA testing), or by PCR testing.

 

Figure 4. Blood Smear in Ehrlichiosis

In a peripheral blood smear from a patient with human granulocytic ehrlichiosis, a typical round ehrlichial morula is seen at the center of the neutrophil, adjacent to the nuclear lobes (arrow). Two platelets can be seen below and to the right of the neutrophil, for comparison. Wright-Giemsa stain was used; original magnification: x 370.

The frequency of detecting morulae in the peripheral smears of patients with HGE has varied in different case series. In one report, typical morulae were found in the peripheral smear in 28 of 35 patients with laboratory-confirmed HGE infection.47 The percentage of infected neutrophils ranged from 1% to 44% (median, 5%). In another study of patients with HGE, from the upper Midwest and New York, morulae were visible in neutrophils in 86 of 141 patients (61%).48

The most characteristic laboratory abnormality in patients with HGE is thrombocytopenia. In addition, patients with HGE typically manifest relative and absolute lymphopenia during the early phases of their infection, and significant increases in the band neutrophil counts occur during the first week of illness.48 It is important to emphasize that automated blood counts are unable to distinguish between band and normal neutrophils or to detect morulae. Therefore, a manual differential WBC should be ordered whenever HGE is suspected.

Diagnosis of Coinfection with Borrelia burgdorferi

Because the agent of Lyme disease and HGE are transmitted by the same vector, it is not surprising that a number of reports have described patients who were coinfected with B. burgdorferi and A. phagocytophilum.49 In studies of I. scapularis ticks from different locales, 2.2% to 26% of ticks were infected with both pathogens.50 The diagnosis of HGE can easily be missed in such patients because the typical rash of early Lyme disease (erythema migrans) may mislead the clinician into failing to consider the possibility of coinfection with A. phagocytophilum. Such coinfection should be suspected when patients with presumed Lyme disease also have some or many of the following findings: leukopenia, thrombocytopenia, cough, high fever, or abnormal liver enzyme test results. Similarly, when rash is present in a patient with known or presumed HGE, the possibility of coinfection with B. burgdorferi should be suspected.

TREATMENT

As with HME, treatment should be initiated in all patients suspected of having HGE. The drug of choice is doxycycline, given orally or intravenously at a dosage of 200 mg/day in two divided doses. Intravenous therapy is preferred for patients who are seriously ill or experiencing nausea or vomiting. Children should be given doxycycline at a dosage of 2.5 to 3 mg/kg/day in two divided doses. There is no consensus on the use of chloramphenicol; many experts advise against its use for any form of ehrlichiosis. Patients who have intolerance or allergy to tetracyclines can be treated with rifampin for 7 to 10 days, but such patients require careful follow-up and monitoring, because there is only anecdotal information on the efficacy of this therapy in patients with HGE (and even less information on its efficacy in HME).43

At present, there are no guidelines for the treatment of ehrlichiosis in pregnancy. However, a report describing the successful treatment of two cases of HGE using rifampin suggests that other Ehrlichia species (e.g., E. chaffeensis) may be susceptible to rifampin as well.51

In one study, A. phagocytophilum was susceptible in vitro to fluoroquinolones and rifampin. However, the most active fluoroquinolone was trovafloxacin, which is not in general use because of concerns about hepatic toxicity.52

Even without treatment, most patients with ehrlichiosis probably make a full recovery. There is no evidence that untreated ehrlichiosis produces a chronic illness such as that which occurs with Lyme disease. However, infection may not confer long-lasting immunity. One report describes a patient who experienced two episodes of HGE spaced 2 years apart. At the onset of the second infection, the antibody titer to A. phagocytophilum had fallen from 1,280 to 80.53

Q Fever

EPIDEMIOLOGY AND ETIOLOGY

Q fever (the Q stands for “query”) was first described in 1935 by Edward Derrick, after he investigated an outbreak of febrile illness involving abattoir workers in Queensland, Australia. Q fever is now known to be a worldwide zoonosis with highly variable clinical features. The causative organism, Coxiella burnetii, is a strictly intracellular pathogen that replicates and persists in cells in phagolysosomes. Microbial products, including acid phosphatase, help the organism resist the acidic and presumably harsh vacuolar environment.54 In addition, vegetative C. burnetii cells form endogenous sporelike structures that resist extreme environmental conditions; spore formation has been observed in infected cardiac valves.55 Because of these microbiologic characteristics, C. burnetii is capable of surviving prolonged drying in dust and excreta and can remain viable for months in water and milk. C. burnetii can be grown in cultured mammalian cells and in small animals but is not able to replicate on cell-free media.

The most common reservoirs for C. burnetii are cattle, goats, and sheep. Animals infected with C. burnetii are rarely symptomatic, but they shed organisms in their milk, urine, feces, and placentas. Infected placental tissue, postpartum discharges, and feces are presumed to be the principal sources of transmission to other animals and to humans. Domestic cats and dogs may also acquire C. burnetii and become sources for zoonotic transmission to humans.56 Numerous tick species are also naturally infected with C. burnetii. Such infected ticks may transmit C. burnetii to other generations of ticks transovarially and via tick bites to wild rodents. Livestock sometimes acquire C. burnetiiinfections from infected ticks, but most often, they become infected by inhalation of contaminated dust.

Dairy and slaughterhouse workers are at increased risk for acquiring Q fever. However, sporadic cases of Q fever may occur in humans who acquire infection via infectious aerosols that were generated at relatively long distances from the site of acquisition. Infected milk may also account for some outbreaks of the disease in humans. Human infection from tick bites is extremely rare. C. burnetii is highly infectious in the laboratory, and outbreaks have occurred in researchers. Transmission between humans is rare, but transmission during delivery (to an obstetrician)57 and sexual transmission58 have been described. Exposure to wild rabbits, parturient cats, and products of feline parturition may lead to Q fever pneumonia in humans, sometimes by an indirect route (e.g., from contaminated clothing). Such cases illustrate an important clinical point: Q fever may occur in urban dwellers without obvious or direct contact with animals.

Q fever is endemic throughout the six populated continents, but it is particularly common in the Mediterranean and Persian Gulf regions. The diagnosis of Q fever should be considered in travelers and military personnel who return to the United States from endemic areas. In the United States and Canada, Q fever still occurs sporadically, particularly in areas where cattle, sheep, and goats are raised. Because of the difficulty in diagnosis and because spontaneous improvement occurs in many patients who do not receive effective antimicrobial therapy, the true prevalence of Q fever in the United States is unknown.

DIAGNOSIS

Clinical Manifestations

Q fever is usually classified into acute and chronic forms. Asymptomatic infection is also common. Acute Q fever may manifest as a self-limiting febrile illness, an influenzalike lower respiratory tract infection, hepatitis, or pneumonia. A small number of well-documented cases of meningoencephalitis from C. burnetii infection have also been described.59 Patients with chronic C. burnetii infection may develop granulomatous hepatitis with prolonged fever, myocarditis, pericarditis, or endocarditis.

The incubation period of Q fever ranges from 10 to 39 days, with an average duration of 20 days.60 The initial manifestations of acute C. burnetii infection are systemic and nonspecific—headache, chills, fever, myalgias, anorexia, and malaise. Skin rash does not occur in patients with Q fever. High fevers and headache often persist, and after 4 or 5 days of fever, patients typically manifest pneumonia, cough, chest pain, and inspiratory rales. In most cases, chest radiographs show focal areas of pneumonitis. Radiologic changes may be more marked than symptoms or physical findings. A minority of patients with Q fever pneumonia develop pleural effusions, hemoptysis, and even respiratory failure.61 Pulmonary involvement occurs in about 50% of patients, but the incidence of this complication may vary with geographic location. In certain parts of the world, hepatitis may be more common than pneumonia in patients with acute Q fever.62 Hepatitis in patients with acute Q fever usually lasts for 1 to 2 weeks and follows a benign, self-limited course. Complications are rare. However, granulomatous hepatitis with hepatosplenomegaly, jaundice, and abnormal liver function test results can also persist along with fever for up to 3 or 4 weeks.

In approximately 2% to 11% of infected persons, a chronic form of Q fever will develop insidiously a few months to as long as 20 years after the acute illness. Risk factors for chronic Q fever include underlying valvular heart disease and an immunocompromised state.63 Infective endocarditis caused by C. burnetii is a common feature of the chronic syndrome.64 The disease may affect healthy valves, previously damaged native valves, or prosthetic valves. Q fever endocarditis is sometimes insidious in onset and is often accompanied by granulomatous hepatitis. Other forms of endovascular infection with C. burnetii also occur, including infections of aneurysms and grafts.

Laboratory Studies

The diagnosis of acute Q fever is usually established by demonstration of a fourfold or greater rise in complement-fixing antibody titer against C. burnetii phase II antigen.65,66 IFA techniques and ELISA offer greater sensitivity than complement-fixation methods. IFA techniques for the early detection of specific IgM antibody are the serodiagnostic method of choice. The diagnosis of chronic Q fever or Q fever endocarditis is established by detecting elevated titers (i.e., > 1:200) of IgG or IgA antibodies against C. burnetii phase I antigen or by a ratio of anti-phase I antibody to anti-phase II antibody of 1 or greater.

  1. burnetiican be isolated from blood, sputum, or urine by intraperitoneal inoculation in guinea pigs, inoculation into chick embryos, or inoculation of cultured human fetal diploid fibroblasts. Because this organism is so highly contagious in the laboratory, attempts at isolation should be made only in a special biologic containment facility.

Echocardiography may not be diagnostic in Q fever endocarditis. A study that examined the heart valves removed from 28 patients with Q fever endocarditis showed that infected valves were usually fibrotic and calcified but that most had only slight inflammation. Only two of 16 patients with native Q fever endocarditis and two of 10 patients with bioprosthetic Q fever endocarditis had macroscopic vegetations, yet C. burnetii was isolated by culture in 64% of these patients and identified by PCR in 75%.67

DIFFERENTIAL DIAGNOSIS

Early in its course, Q fever resembles a variety of acute febrile illnesses, including an array of viral respiratory infections, viral hepatitis, and infectious mononucleosis. In patients with a history of contact with livestock, other zoonoses (e.g., brucellosis and leptospirosis) should be considered along with Q fever. In patients who present with pneumonia, infection with Mycoplasma pneumoniae, Chlamydia pneumoniaeand C. psittaci, Legionella pneumophila, Histoplasma capsulatum, and the agents causing viral pneumonia should also be considered in the differential diagnosis. When hepatitis is present and noncaseating granulomas are found on liver biopsy, a host of causes of granulomatous hepatitis (e.g., tuberculosis, sarcoidosis, brucellosis, and histoplasmosis) must be considered. Q fever should always be considered when the clinical features of endocarditis are present but blood cultures are negative.

TREATMENT AND PREVENTION

Effective treatment for acute Q fever is tetracycline, 500 mg orally every 6 hours; doxycycline, 100 mg orally every 12 hours; or ciprofloxacin, 500 mg orally every 12 hours. Most patients treated early in the course of the infection recover rapidly; however, acute Q fever is usually self-limited.

If left untreated, Q fever endocarditis is fatal. Valve replacement is often necessary, in addition to prolonged antimicrobial therapy. Prolonged antibiotic therapy is necessary both for those who have valve surgery and for those in whom medical therapy alone is used. A study of cardiac valves in patients with Q fever endocarditis found that histologic, microbiologic, or molecular detection of C. burnetii was possible in more than 80% of patients who had been treated for less than 1 year; cultures and PCR tests were still positive in 22% and 33% of patients, respectively, who were treated for more than 1 year before valve excision.67

Medical regimens employing different antimicrobial agents, either alone or in combination, have been tried with variable success in Q fever endocarditis.68,69 Some experts recommend treatment with doxycycline plus rifampin or with doxycycline plus a fluoroquinolone for at least 3 years.70 Chloroquine has been also used as adjunctive therapy because of its ability to block intracellular vacuole acidification and, hence, growth of C. burnetii.

Patients with Q fever need not be isolated, because secondary cases do not occur. Killed vaccines made from C. burnetii grown in chick embryo cultures are immunogenic and can provide protection for persons at high risk, such as dairy and slaughterhouse workers, woolsorters, tanners, and laboratory workers. However, vaccines against C. burnetii are not commercially available for human use in the United States.

Acknowledgments

Figure 2 Slide courtesy of Dr. Mark Lebwohl, Mount Sinai Medical Center, New York.

Figure 4 Slide courtesy of Dr. P. Joanne Cornbleet, Stanford University School of Medicine, Stanford, California.

References

  1. Paddock CD, Sumner JW, Comer JA, et al: Rickettsia parkeri: a newly recognized cause of spotted fever rickettsiosis in the United States. Clin Infect Dis 38:805, 2004
  2. Borjesson DL, Simon SI, Tablin F, et al: Thrombocytopenia in a mouse model of human granulocytic ehrlichiosis. J Infect Dis 184:1475, 2001
  3. Kirkland KB, Marcom K, Sexton DJ, et al: Rocky Mountain spotted fever complicated by gangrene: report of six cases and review of the literature. Clin Infect Dis 16:629, 1993
  4. Kirkland KB, Wilkinson WE, Sexton DJ: Therapeutic delay and mortality in cases of Rocky Mountain spotted fever. Clin Infect Dis 20:1118, 1995
  5. Sexton DJ, Corey GR: Rocky Mountain “spotless” and “almost spotless” fever: a wolf in sheep's clothing. Clin Infect Dis 15:439, 1992
  6. Archibald LK, Sexton DJ: Long-term sequelae of Rocky Mountain spotted fever. Clin Infect Dis 20:1122, 1995
  7. Kirk J, Fine DJ, Sexton DJ, et al: Rocky Mountain spotted fever: a clinical review based upon 48 confirmed cases 1943–1986. Medicine (Baltimore) 69:35, 1990
  8. Carpenter C, Gandhi TK, Kong LK, et al: The incidence of ehrlichial and rickettsial infection in patients with unexplained fever and recent history of tick bite in central North Carolina. J Infect Dis 180:900, 1990
  9. Paddock CD, Greer PW, Ferebee TL, et al: Hidden mortality attributable to Rocky Mountain spotted fever: immunohistochemical detection of fatal, serologically unconfirmed disease. J Infect Dis 179:1469, 1999
  10. Kirkland KB, Wilkinson WE, Sexton DJ: Therapeutic delay and mortality in cases of Rocky Mountain spotted fever. Clin Infect Dis 20:1118, 1995
  11. Purvis JJ, Edwards MS: Doxycycline use for rickettsial diseases in pediatric patients. Pediatr Infect Dis J 19:871, 2000
  12. Conlon PJ, Procop G, Fowler V, et al: Predictors of prognosis and acute renal failure in patients with Rocky Mountain spotted fever. Am J Med 101:621, 1996
  13. Krussell A, Comer JA, Sexton DJ: Rickettsialpox in North Carolina: a case report. Emerg Infect Dis 8:727, 2002
  14. Raoult D, Roux V: Rickettsioses as paradigms of new or emerging infectious diseases. Clin Microbiol Rev 10:694, 1997
  15. Fournier P-E, Tissot-Dupont H, Gallais H, et al: Rickettsia mongolotimonae: a rare pathogen in France. Emerg Infect Dis 6:290, 2000
  16. Paddock CD, Sumner JW, Comer JA, et al: Rickettsia parkeri: a newly recognized cause of spotted fever rickettsiosis in the United States. Clin Infect Dis 38:805, 2004
  17. Murine typhus—Hawaii 2002. MMWR Morb Mortal Wkly Rep 52:(50):1224, 2002
  18. Walker DH, Barbour AG, Oliver JH, et al: Emerging bacterial zoonotic and vector-borne diseases: ecological and epidemiological factors. JAMA 275:463, 1996
  19. Raoult D, Ndihokubwayo JB, Tissot-Dupont H, et al: Outbreak of epidemic typhus associated with trench fever in Burundi. Lancet 357:353, 1998
  20. Duma RJ, Soneshine DE, Bozeman FM, et al: Epidemic typhus in the United States associated with flying squirrels. JAMA 245:2318, 1981
  21. Massung RF, Davis LE, Slater K, et al: Epidemic typhus meningitis in the southwestern United States. Clin Infect Dis 32:979, 2001
  22. Huys J, Kayihigi J, Freyens P, et al: Single-dose treatment of epidemic typhus with doxycycline. Chemotherapy 18:314, 1973
  23. Sholdt LL, Rogers EJ Jr, Gerberg EJ, et al: Effectiveness of permethrin-treated military uniform fabric against human body lice. Mil Med 154:90, 1989
  24. Kazar J, Brezina R: Control of rickettsial diseases. Eur J Epidemiol 7:282, 1991
  25. Strickman D, Tanskul P, Eamsila C, et al: Prevalence of antibodies to rickettsiae in the human population of suburban Bangkok. Am J Trop Med Hyg 51:149, 1994
  26. Sheehy TW, Hazlett D, Turk RE: Scrub typhus: a comparison of chloramphenicol and tetracycline in its treatment. Arch Intern Med 132:77, 1973
  27. Watt G, Jjongsakul K, Suttinont C: Possible scrub typhus coinfections in Thai agricultural workers hospitalized with leptospirosis. Am J Trop Med Hyg 68:89, 2003
  28. Song JH, Lee C, Chang WH, et al: Short-course doxycycline treatment versus conventional tetracycline therapy for scrub typhus: a multicenter randomized trial. Clin Infect Dis 21:50, 1995
  29. Brown GW, Saunders JP, Singh S, et al: Single dose doxycycline therapy for scrub typhus. Trans R Soc Trop Med Hyg 72:412, 1978
  30. Strickman D, Sheer T, Salata K, et al: In vitro effectiveness of azithromycin against doxycycline-resistant and -susceptible strains of Rickettsia tsutsugamushi, etiologic agent of scrub typhus. Antimicrob Agents Chemother 39:2406, 1995
  31. Watt G, Kantipong P, Jongsakul K, et al: Doxycycline and rifampicin for mild scrub-typhus infections in northern Thailand: a randomised trial. Lancet 356:1057, 2000
  32. Gongora-Biachi RA, Zavala-Velazquez J, Castro-Sansores CJ, et al: First case of human ehrlichiosis in Mexico. Emerg Infect Dis 5:481, 1999
  33. Carpenter C, Gandhi TK, Kong LK, et al: The incidence of ehrlichial and rickettsial infection in patients with unexplained fever and recent history of tick bite in central North Carolina. J Infect Dis 180:900, 1999
  34. Fishbein DB, Kemp A, Dawson JE, et al: Human ehrlichiosis: prospective active surveillance in febrile hospitalized patients. J Infect Dis 160:803, 1989
  35. Standaert SM, Dawson JE, Schaffner W, et al: Ehrlichiosis in a golf-oriented retirement community. N Engl J Med 333:420, 1995
  36. Lockhart JM, Davidson WR, Stallknecht DE, et al: Isolation of Ehrlichia chaffeensis from wild white-tailed deer (Odocoileus virginianus) confirms their role as natural reservoir hosts. J Clin Microbiol 35:1681, 1997
  37. Kocan AA, Levesque GC, Whitworth LC, et al: Naturally occurring Ehrlichia chaffeensis infection in coyotes from Oklahoma. Emerg Infect Dis 6:477, 2000
  38. Roland WF, McDonald G, Caldwell CW, et al: Ehrlichiosis a cause of prolonged fever. Clin Infect Dis 20:821, 1995
  39. Fishbein DB, Dawson JE, Robinson LE: Human ehrlichiosis in the United States, 1985 to 1990. Ann Intern Med 120:736, 1994
  40. Ratnasamy N, Everett ED, Roland WE, et al: Central nervous system manifestations of human ehrlichiosis. Clin Infect Dis 23:314, 1996
  41. Dawson JE, Fishbein DG, Eng TR, et al: Diagnosis of human ehrlichiosis with the indirect fluorescent antibody test: kinetics and specificity. J Infect Dis 162:91, 1990
  42. Dumler JS, Bakken JS: Ehrlichial diseases of humans: emerging tick-borne infections. Clin Infect Dis 20:1102, 1995
  43. Bakken JS, Dumler JS: Human granulocytic ehrlichiosis. Clin Infect Dis 31:554, 2000
  44. Belongia EA, Gale CM, Reed KD, et al: Population-based incidence of human granulocytic ehrlichiosis in northwestern Wisconsin, 1997–1999. J Infect Dis 184:1470, 2001
  45. Walder G, Tiwald G, Dierich MP, et al: Serological evidence for human granulocytic ehrlichiosis in Western Austria. Eur J Clin Microbiol Infect Dis 22:543, 2003
  46. Aguero-Rosenfeld ME, Horowitz HW, Wormser GP, et al: Human granulocytic ehrlichiosis: a case series from a medical center in New York state. Ann Intern Med 125:904, 1996
  47. Bakken JS, Krueth J, Wilson-Noldskog C, et al: Clinical and laboratory characteristics of human granulocytic ehrlichiosis. JAMA 275:199, 1996
  48. Bakken JS, Aguero-Rosenfeld ME, Tilden RL, et al: Serial measurements of hematologic counts during the active phase of human granulocytic ehrlichiosis. Clin Infect Dis 32:862, 2001
  49. Nadelman RB, Horowitz HW, Hsieh TC, et al: Simultaneous human granulocytic ehrlichiosis and Lyme borreliosis. N Engl J Med 337:27, 1997
  50. Schwartz I, Fish D, Daniels TJ: Prevalence of the rickettsial agent of human granulocytic ehrlichiosis in ticks from a hyperendemic focus of Lyme disease (letter). N Engl J Med 337:49, 1997
  51. Buitrago MI, Ijdo JW, Rinaudo P, et al: Human granulocytic ehrlichiosis during pregnancy treated successfully with rifampin. Clin Infect Dis 27:213, 1998
  52. Klein MB, Nelson CM, Goodman JL: Antibiotic susceptibility of the newly cultivated agent of human granulocytic ehrlichiosis: promising activity of quinolones and rifamycins. Antimicrob Agents Chemother 41:76, 1997
  53. Horowitz HW, Aguero-Rosenfeld ME, Dumler JS, et al: Reinfection with the agent of human granulocytic ehrlichiosis. Ann Intern Med 129:461, 1998
  54. Baca OG, Li YP, Kumar H: Survival of the Q fever agent Coxiella burnetii in the phagolysosome. Trends Microbiol 2:476, 1994
  55. McCaul TF, Dare AJ, Gannon JP, et al: In vivo endogenous spore formation by Coxiella burnetii in Q fever endocarditis. J Clin Pathol 47:978, 1994
  56. Marrie TJ, Raoult D: Q fever: a review and issues for the next century. Int J Antimicrob Agents 8:145, 1997
  57. Stein A, Raoult D: Q fever during pregnancy: a public health problem in southern France. Clin Infect Dis 27:592, 1998
  58. Milazzo A, Hall R, Storm PA, et al: Sexually transmitted Q fever. Clin Infect Dis 33:399, 2001
  59. Bernit E, Pouget J, Jambon F, et al: Neurological involvement in acute Q fever: a report of 29 cases and review of the literature. Arch Intern Med 162:693, 2002
  60. Spelman DW: Q fever: a study of 111 consecutive cases. Med J Aust 1:547, 1982
  61. Sampere M, Font B, Font J, et al: Q fever in adults: review of 66 clinical cases. Eur J Clin Microbiol Infect Dis 22:108, 2003
  62. Tissot-Dupont H, Raoult D, Brouqui P, et al: Epidemiologic features and clinical presentation of acute Q fever in hospitalized patients: 323 French cases. Am J Med 93:427, 1992
  63. Brouqui P, Tissot-Dupont H, Drancourt M, et al: Chronic Q fever: ninety-two cases from France, including 27 cases without endocarditis. Arch Intern Med 153:642, 1993
  64. Tobin MJ, Cahill N, Gearty G, et al: Q fever endocarditis. Am J Med 72:396, 1982
  65. Soriano F, Camacho MT, Ponte C, et al: Serological differentiation between acute (late control) and endocarditis Q fever. J Clin Pathol 46:411, 1993
  66. Fournier P-E, Marrie TJ, Raoult D: Diagnosis of Q fever. J Clin Microbiol 36:1823, 1998
  67. Lepidi H, Houpikian P, Liang Z, et al: Cardiac valves in patients with Q fever endocarditis: microbiological, molecular, and histologic studies. J Infect Dis 187:1097, 2003
  68. Tobin MJ, Cahill N, Gearty G, et al: Q fever endocarditis. Am J Med 72:396, 1982
  69. Stein A, Raoult D: Detection of Coxiella burnetii by DNA amplification using polymerase chain reaction. J Clin Microbiol 30:2462, 1992
  70. Levy PY, Drancourt M, Etienne J, et al: Comparison of different antibiotic regimens for therapy of 32 cases of Q fever endocarditis. Antimicrob Agents Chemother 35:533, 1991

Editors: Dale, David C.; Federman, Daniel D.