Rickettsial Infections

1954

CHAPTER 335  RICKETTSIAL INFECTIONS  

335  RICKETTSIAL INFECTIONS DIDIER RAOULT

DEFINITION

Rickettsioses are emerging infectious diseases. Because of better diagnostic tools and changes in tick exposure, many new rickettsial diseases have been described in the past 20 years. Three families of diseases are grouped under this name: rickettsioses, ehrlichioses and anaplasmoses, and Q fever.

The Pathogens

The agents of rickettsial diseases (formerly grouped in the order Rickettsiales) are small gram-negative bacteria that grow within eukaryotic cells. They have never been grown in axenic media thus far and for culture require living hosts such as cell cultures, embryonated eggs, or susceptible animals. With the exception of Rickettsia prowazekii, the agent of epidemic typhus, these bacteria infect humans incidentally and are mainly animal pathogens. On the basis of molecular phylogeny, the bacteria causing rickettsial diseases have been reclassified into three phyla (Table 335-1). Because of their difficult growth in vitro, the main diagnostic tool for rickettsioses is serology. Serologic evaluation is frequently hampered by late positivity and cross-reactivity. The development of direct staining in blood

1955

CHAPTER 335  RICKETTSIAL INFECTIONS  

TABLE 335-1 GENETIC CLASSIFICATION OF RICKETTSIALES Rickettsiae

GENUS Rickettsia

GROUP Typhus

SPECIES R. prowazekii

Spotted fever

R. conorii

SUBSPECIES

FIRST YEAR OF ISOLATION OR DISCOVERY 1916

R. typhi

1920 conorii

1932

israeli

1974

caspia

1991

indica

2001

R. rickettsii R. sibirica

Coxiellae

mongolotimonae

1996 1997

R. honei

1991

R. japonica

1992

R. parkeri

2003

R. massiliae

2006

R. monacencis

2007

R. heilongjiangensis

1998

R. aeschlimannii

2001

R. helvetica

2000

R. australis

1950

R. felis

2001

R. akari

1946

R. raoultii

2008

O. tsutsugamushi

1920

E. chaffeensis

1991

E. ewingii

1999

E. canis

1996

Anaplasma

A. phagocytophilum

1992

Neorickettsia

N. sennetsu

1957

Wolbachia

W. pipientis

2001

Coxiella

C. burnetii

1931

Ehrlichia

Scrub typhus

smears or skin biopsy samples as well as polymerase chain reaction (PCR) amplification of DNA in blood samples or biopsy specimens has considerably helped identification at the species level and led to the description of emerging pathogens.

RICKETTSIOSES (DISEASES CAUSED BY RICKETTSIA SPECIES AND ORIENTIA TSUTSUGAMUSHI) DEFINITION

1946

R. slovaca

Orientia Ehrlichiae

1919 sibirica

Rickettsia spp are small gram-negative bacteria that multiply free in the cytoplasm of their host cells. The target cells in humans are endothelial cells or monocytes, and vasculitis is the most prominent clinical manifestation. These bacteria invade cells by phagocytosis and escape the phagosome vacuole. The genome of Rickettsia is small, between 1.1 and 1.6 Mb; some have plasmids and potential for conjugation. These bacteria have a family of outer membrane proteins of the surface cell antigen family, including rOmpA (lacking in typhus group) and rOmpB. These proteins are major antigens that help identify the rickettsial species, and their encoding genes are used for amplification and sequencing for diagnostic or taxonomic purposes. Among rickettsiae, two subgroups, the typhus group and the spotted fever group, were identified on the basis of growth conditions and antigenicity. A specific group antigen, determined to be lipopolysaccharide, has been identified. The optimal growth temperature is 37° C for the typhus group and 32° to 35° C for the spotted fever group. The complete genome sequencing of R. prowazekii (from the typhus group) showed that it is mainly a subset of Rickettsia conorii (a member of the spotted fever group).

Tick-Borne Rickettsioses ROCKY MOUNTAIN SPOTTED FEVER EPIDEMIOLOGY

Rocky Mountain spotted fever (RMSF), the most severe of the rickettsioses, is caused by Rickettsia rickettsii (Table 335-2). It is the major tick-transmitted rickettsiosis (Chapter 367) recognized in America, with Rickettsia africae in the West Indies, Rickettsia parkeri in the southern states of the United States, and, perhaps, Rickettsia amblyommii. It was described first in the 19th century in the western United States. RMSF is prevalent in at least 44 states in the United States (Fig. 335-1) and in Central and South America (Argentina, Brazil, Colombia, Costa Rica, Mexico, and Panama). Rickettsia is transmitted transovarially to tick progeny from one generation to the next. The infecting ticks are mainly Dermacentor andersoni (a wood tick) in the western United States; Dermacentor variabilis (the American dog tick) in the East, the Midwest, and the South; and Rhipicephalus sanguineus in Arizona. In Central and South America, Amblyomma cajennense is the major vector. Humans are infected through infected saliva after a tick bite. The duration of attachment is critical in any tick-borne rickettsiosis, and transmission is unlikely when the tick feeds for less than 20 hours. The tick bite is painless and frequently unnoticed. Rarely, an eschar at the site of the tick bite is observed in RMSF. The epidemiology of RMSF undergoes largely unexplained yearly variations. This temporal repartition is determined by tick activity and human encounter. More than 500 cases occur each year, and more than 90% are reported from April to September. The disease is more prevalent in children younger than 10 years. A recent increase has been reported, but the current

1956

CHAPTER 335  RICKETTSIAL INFECTIONS  

TABLE 335-2 RICKETTSIAL DISEASES IN HUMAN BEINGS DISEASE

ORGANISM

ARTHROPOD HOST

GEOGRAPHIC AREA

RASH

ESCHAR TACHE NOIRE

REGIONAL LYMPH NODE

HIGH FEVER

FATALITY RATE

TICK-TRANSMITTED SPOTTED FEVERS Rocky Mountain spotted fever

R. rickettsii

Mediterranean R. conorii spotted fever, Astrakhan fever, Israeli spotted fever

Dermacentor andersoni Dermacentor variabilis Rhipicephalus sanguineus Amblyomma cajennense

America (North, Yes, may be Central, and South) purpuric

Very rare

No

Yes

High

Rhipicephalus sanguineus

Mediterranean, India, Caspian Sea, Africa

Yes, papular; may be purpuric

Yes

No

Yes

Moderate

African tick bite fever

R. africae

Amblyomma hebraeum Amblyomma variegatum

Sub-Saharan Africa, West Indies

Yes, half of cases may be vesicular

Yes (frequently multiple)

Yes

No

Low

Queensland tick typhus

R. australis

Ixodes holocyclus

Eastern Australia

Yes, may be vesicular

Yes

?

Yes

Moderate

Siberian tick typhus

R. sibirica

Dermacentor nuttallii

Siberia, China, Mongolia

Yes

Yes

No

Yes

Low

Scalp eschar, neck lymphadenopathy after tick bite (SENLAT)

R. slovaca or R. raoultii Dermacentor marginatus Europe, Pakistan Dermacentor reticulatus

Very rare

Yes, may be Yes (painful) erythematous

No

Low

Lymphangitisassociated rickettsiosis (LAR)

R. sibirica mongolotimonae

Yes

Yes

Yes

Low

Hyalomma asiaticum

Mongolia, Africa, Europe

Yes

Unnamed

R. aeschlimannii

Hyalomma sp

Mediterranean, Africa

Yes

Yes

Yes

Yes

Unknown

Flinders Island spotted fever

R. honei

Ixodes granulosus

Flinders Island, eastern Australia

Yes

Yes

Yes

Yes

Low

Japanese spotted fever

R. japonica

Ixodes ricinus

Japan, Korea (China?)

Yes

Yes

No

Yes

Low

Unnamed

R. parkeri

Amblyomma maculatum

America

Yes

Yes

No

Yes

Unnamed

R. helvetica R. massiliae

Ixodes ricinus Rhipicephalus sanguineus Ixodes ricinus

Europe, Asia Europe, United States

No Yes

Yes Yes

No No

No Yes

Unknown

Europe

Yes

Yes

No

Yes

Unknown

R. monacencis FLEA-TRANSMITTED DISEASES Murine typhus

R. typhi

Xenopsylla cheopis Ctenocephalides felis

Worldwide

Yes

No

No

Yes

Low

Flea-borne spotted fever

R. felis

Ctenocephalides felis

Worldwide

Sometimes

Sometimes

Unknown

Yes

Unknown

LOUSE-TRANSMITTED DISEASE Epidemic typhus

R. prowazekii

Pediculus humanus corporis Amblyomma ticks (?)

Worldwide

Yes

No

No

Yes

High

American sylvatic typhus

R. prowazekii

Flying squirrel ectoparasites

United States

Yes

No

No

Yes

Low

Brill-Zinsser disease (relapse of epidemic typhus)

R. prowazekii

Worldwide

Yes, could lack

No

No

No

Low

MITE-TRANSMITTED DISEASE Rickettsialpox

R. akari

Liponyssoides sanguineus Worldwide

Yes, vesicular

Yes

Yes

Yes

Low

Scrub typhus

Orientia tsutsugamushi

Leptotrombidium sp (chiggers)

Yes

Yes

Yes

Yes

High, may relapse

Central and eastern Asia, Australia

diagnostic tools do not allow discrimination between RMSF and other rickettsioses.

CLINICAL MANIFESTATIONS

Two to 14 days after the tick bite, fever and headaches appear. The fever is high (temperature >102° F) and associated with nonspecific symptoms, including malaise, myalgias, nausea, vomiting, anorexia, and diarrhea. At this stage, RMSF is not frequently diagnosed, but during the “tick season,” patients with high fever who live in or have a history of travel to an endemic

location and, possibly, a history of tick bite should be considered as possibly having RMSF. The most characteristic feature is a rash. However, the classic triad of fever, headache, and rash is present in only 44% of confirmed cases. Rash is found in 14% of cases on the first day of disease and in less than 50% in the first 3 days. The rash is macular; it appears first on the ankles and wrists and then generalizes. Spots are 1 to 5 mm in diameter and can evolve from pink to purpuric. A rash can appear later or even not at all; Rocky Mountain “spotless” fever represented 34% of cases in a series from the Centers for Disease

CHAPTER 335  RICKETTSIAL INFECTIONS  

1957

40 161 7

200 148

62

1,260 364

401

FIGURE 335-1.  Number of reported cases of Rocky Mountain spotted fever by region,

1994 to 1998.

Control and Prevention (CDC). Involvement of the palms and soles theoretically differentiates the typhus diseases (in which it is absent) from the spotted fevers. Untreated patients worsen progressively. The disease is associated in various degrees with general manifestations related to vascular inflammation and increased vascular permeability and with multiple organ involvement that can lead to multiple organ dysfunction syndrome (MODS). In severe forms, patients suffer from edema, hypovolemia, hypoalbuminemia, and hypotension leading to shock. In very severe cases, necrosis and gangrene of the extremities occur. In some instances, noncardiogenic pulmonary edema develops; pulmonary involvement leading to respiratory distress can cause death. Renal failure can result either from hypovolemia and shock and be reversible or from acute tubular necrosis and require hemodialysis. The usual neurologic symptoms are confusion, lethargy, and stupor. In severe cases, delirium, coma, and seizures are observed. Cerebrospinal fluid (CSF) sampling exhibits meningitis in a third of cases; in general, a few monocyte cells (10 to 100) are observed, along with increased protein but normal glucose levels. Heart involvement can cause arrhythmia. Liver involvement is manifested as an increase in transaminases in a third of patients and jaundice in 8%. Jaundice can also reflect hemolysis. Intestinal tract involvement is manifested as abdominal pain, diarrhea, vomiting, and severe bleeding (upper gastrointestinal hemorrhage can cause death). Ocular involvement consists of conjunctivitis and retinal abnormalities, including hemorrhages, papilledema, and arterial occlusion. The blood cell count shows a normal number of white blood cells but often immature myeloid cells. Thrombocytopenia is observed in 30 to 50% of cases and may be marked in severe cases. Anemia develops in 30% of patients. Coagulopathy with decreases in clotting factors (including fibrinogen) and prolonged coagulation times may contribute to bleeding; albuminemia may be low and proteins of the acute phase response increased (C-reactive protein, ferritin, fibrinogen). Hyponatremia and hypocalcemia may be noted and correlate with severity, as with an increase in creatininemia. Increased concentrations of serum enzymes such as aminotransferases (aspartate [AST] and alanine [ALT] aminotransferase), lactate dehydrogenase (LDH), and creatine kinase usually reflect the severity of organ involvement, including the lung, heart, and liver and multifocal rhabdomyolysis.

DIAGNOSIS

The diagnosis of RMSF should be based on clinical and epidemiologic findings and lead to early use of doxycycline. The most important clue is unexplained fever in a patient with a history of tick exposure in an endemic area. When a rash is present, RMSF should be suspected and the patient treated accordingly unless another cause is demonstrated. The differential diagnosis includes other rickettsioses (such as those caused by R. parkeri in southeastern states), meningococcemia, enterovirus infections, typhoid, leptospirosis, ehrlichiosis, gonococcemia, toxic shock syndrome, syphilis, rubella, measles, and the Kawasaki syndrome. Drug hypersensitivity, especially after antimicrobial use for febrile illness, is sometimes confused with RMSF. The main diagnostic test relies on serology, and treatment should never be delayed to obtain diagnostic confirmation. Criteria for laboratory confirmation include a fourfold or greater change in antibody titer determined by

FIGURE 335-2.  Tick removal technique.

serology (measured by immunofluorescence assay [IFA], complement fixation, or latex agglutination) and direct detection of the bacterium by demonstration of specific antigens by immunodetection, genomic amplification by PCR, or culture. A biopsy specimen of a skin lesion is the best sample for this purpose. Culture of Rickettsia takes 3 to 7 days and is restricted to specialized laboratories. It is performed on cell lines such as Vero, L929, or HEL cells. Immunodetection by IFA or immunohistochemistry is sensitive and specific. It can be performed with frozen or fixed and paraffin-embedded material and allows retrospective diagnosis. PCR amplification and identification give promising results in rickettsioses in general but have not been properly evaluated for diagnosis of RMSF. Skin biopsy and direct detection in removed ticks yield the best results because blood contains inhibitors and only few copies of rickettsial DNA. Two serum samples should be tested (early and convalescent). The early serum is usually negative because patients seroconvert between the 7th and 15th days. IFA is highly sensitive and specific. A cutoff value of 1/64 for total immunoglobulin and 1/32 for IgM antibodies is required for diagnosis. The latex agglutination cutoff is 1/64 or 1/128. Cross-reactive antibodies have been reported with infections caused by other rickettsioses, Ehrlichia, Bartonella, Legionella, and Proteus. False-positives, including IgM, may be observed when rheumatoid factor is present in serum and in patients with viral infection generating nonspecific B-lymphocyte proliferation (cytomegalovirus, Epstein-Barr virus). Complement fixation (which lacks sensitivity) and the Weil-Felix test (using antibodies that cross-react with Proteus strains) should not be used.

TREATMENT  The prognosis for patients with RMSF depends on the timing of antimicrobial treatment. Doxycycline saves patients with RMSF. The recommended dose is 100 mg two times a day, and treatment should be continued for at least 3 days after the fever resolves. Oral treatment is effective, but in patients with gastric intolerance or coma, the intravenous route is advised. Several antimicrobials are effective in vitro against R. rickettsii, including fluoroquinolones, rifampin, and new macrolide antimicrobials (but not erythromycin), but lack of clinical experience precludes their use for RMSF. β-Lactam antimicrobials, aminoglycosides, and cotrimoxazole are not effective. Severely ill patients should be treated in intensive care units and fluid administration carefully monitored. Mechanical ventilation is used in case of respiratory distress, hemodialysis in patients with renal insufficiency, and antiseizure drugs in patients with seizures. Anemia and coagulation abnormalities may also be corrected. For patients with gangrene of the extremities, amputation may be necessary. Glucocorticoids have not proved useful.

PREVENTION

Prevention is based on avoidance of tick bites (Chapter 367) by use of repellents, protective garments, or both. To discourage tick attachment, repellents containing permethrin can be sprayed on boots and clothing and will last for several days. Repellents containing DEET (N,N-diethyl-m-toluamide) can be applied to the skin but will last only a few hours before reapplication is necessary. It is also useful to check for ticks after exposure. Careful examination of the scalp, groin, and axillae is recommended. The tick can be removed by forceps, and the skin should be disinfected (Fig. 335-2).

PROGNOSIS

The evolution of RMSF depends strongly on the timing of diagnosis and antimicrobial treatment. The current fatality rate is 2.4% on the basis of a 4-year national survey in the United States (27 deaths were attributable to

1958

CHAPTER 335  RICKETTSIAL INFECTIONS  

R. sibirica mongolitimonae

R. helvetica

R. slovaca

R. conorii caspia

R. sibirica mongolotimonae R. sibirica sibirica

R. japonica R. conorii conorii R. conorii indica

R. parkeri R. rickettsii

R. conorii israeli R. conorii conorii R. australis R. aeschlimannii

R. honei

R. africae FIGURE 335-3.  Geographic distribution of tick-borne rickettsioses.

RMSF during this period). This rate is currently lowering, but this may result from reporting of confounding rickettsial diseases. No significant difference in outcome was observed between blacks and whites, but the case-fatality rate was highest in people older than 70 years (9%). Patients with glucose-6phosphate dehydrogenase (G6PD) deficiency were more susceptible to severe infection. Chloramphenicol was associated with a poorer outcome than treatment with doxycycline. Recovery from RMSF is usually complete, but neurologic sequelae can remain, and amputation of extremities may be necessary after gangrene.

OTHER TICK-BORNE RICKETTSIOSES EPIDEMIOLOGY

Like other tick-transmitted diseases (Chapter 367), rickettsioses have a limited geographic distribution that is determined mainly by the tick vector ecology (Fig. 335-3). R. parkeri has recently been identified in the United States and South America. R. conorii is found in Europe around the Mediterranean and Caspian seas (caspia subspecies); Rickettsia slovaca, Rickettsia raoultii, and possibly Rickettsia helvetica in western and central Europe; and Rickettsia sibirica mongolotimonae in France and Greece. Elsewhere, a number of specific agents of rickettsial disease have been identified (see Table 335-2).

CLINICAL MANIFESTATIONS

R. conorii comprises different but closely related subspecies. Many names are given to the infection caused by R. conorii: Mediterranean spotted fever (MSF), boutonneuse fever, Marseilles fever, Kenya tick typhus (caused by the subspecies R. conorii conorii), Astrakhan fever (caused by R. conorii caspia), Israeli spotted fever (caused by R. conorii israeli), and Indian tick typhus (caused by R. conorii indica). R. conorii is closely related to R. rickettsii, with which it shares many common antigens that generate cross-reactive antibodies. MSF resembles RMSF but has several specificities. The spontaneous evolution is milder, but a fatality rate of 1.5 to 2.5% in hospitalized patients is still observed. A malignant form of the disease that includes purpuric rash, shock, and MODS has been described in alcoholic, diabetic, human immunodeficiency virus (HIV)–infected, and old or debilitated patients. The typical clinical manifestation is that of a patient with fever, a rash, and a tache noire (i.e., a black eschar at the site of the tick bite). A tache noire is found in 50 to 80% of cases. Multiple lesions do not occur because the dog tick vector, R. sanguineus, seldom bites humans. The rash is frequently clearly papular, which led to one of the names of the disease, boutonneuse

fever. Israeli tick bite fever and Astrakhan fever appear to be milder than typical MSF, and tache noire is usually lacking. R. africae, which causes African tick bite fever, may be responsible for most of the rickettsioses worldwide. It is extremely common in travelers visiting southern Africa. It is transmitted by African ticks, Amblyomma hebraeum and Amblyomma africanum. These ticks are often infected; as many as 60% can harbor R. africae. They usually feed on ungulates but attack human beings in groups and cause a high prevalence of infection in rural Africa (60% of tested patients exhibit antibodies) and in travelers. The tick attacks typically generate clusters of cases in Safari tourists. The disease differs from MSF in that it is much milder, fever is frequently absent, a rash is observed in only half the patients, and the rash may be vesicular (which has never been reported in confirmed MSF). Moreover, several taches noires are frequently observed. They are prevalently found on the lower limbs and often associated with draining lymphadenopathy in the groin. Japanese spotted fever (caused by Rickettsia japonica) and Siberian tick typhus (caused by R. sibirica) resemble MSF. Infections caused by R. sibirica mongolitimonae resemble MSF but in some cases exhibit specific clinical features, including a tache noire, groin lymphadenopathy, and lymphangitis joining these two lesions. The disease has recently been named lymphangitisassociated rickettsiosis. Rickettsia australis (Queensland tick typhus) and Rickettsia honei (Flinders Island spotted fever) cause diseases resembling MSF, but their rash can be vesicular. R. slovaca and R. raoultii cause a disease apparently common in Europe named scalp eschar and neck lymphadenopathy transmitted by ticks (Hungary, Germany, France, Spain). Its tick vectors, Dermacentor marginatus and Dermacentor reticulatus, preferentially bite in cold months and bite the scalp because they prefer hairy prey. In contrast to other tick-borne rickettsioses, the disease is more prevalent in children and women. It is rarely exanthematic; the typical clinical picture consists of an erythematous skin lesion at the site of the tick bite on the scalp that ranges from 2 to 8 cm in diameter and a draining neck lymphadenopathy (which may be painful). Rarely, patients may exhibit fever and a rash. Deep postinfectious asthenia and residual alopecia at the site of the tick bite can be observed. The occurrence of this rickettsiosis without rash may stimulate research on other new rickettsial diseases with only localized manifestations.

DIAGNOSIS

The diagnosis of other tick-borne rickettsioses is similar to that of RMSF, mainly by serology (IFA; see earlier). An exception is R. slovaca infection, in which the serologic response is weak, possibly because of its lack of general

CHAPTER 335  RICKETTSIAL INFECTIONS  

infection; in this case, PCR of a skin lesion sample by a swab or a lymph node aspirate is the best solution. In R. africae infection, the serologic response occurs later than in RMSF and MSF, and late serum samples are therefore recommended.

TREATMENT  Doxycycline (100 mg twice daily for adults or 4.4 mg/kg body weight per day in two divided doses for children under 45.4 kg [100 lb]) is the drug of choice for treatment. A single day of therapy usually suffices, but in adults with more severe disease, it should be administered until the patient is afebrile for 24 hours. In pregnant women, josamycin, a macrolide antimicrobial, has proved efficient at a dose of 3 g daily for 7 days for MSF; quinolones and newer macrolide antimicrobials give results comparable to those of doxycycline but with longer regimens.

Flea-Transmitted Diseases

Fleas (Chapter 367) can harbor two rickettsial species: Rickettsia typhi, the agent of murine typhus; and Rickettsia felis, the agent of flea-borne spotted fever. Both rickettsiae can be transmitted transovarially in the flea. Vectors are Xenopsylla cheopis and Pulex irritans but also Ctenocephalides felis, a cat flea. Rats, cats, opossums, and dogs can propagate infected fleas. These reservoirs and vectors are distributed worldwide, and thus these diseases have a global distribution. Fleas can be infected by both species at the same time.

MURINE TYPHUS DEFINITION Fleas are usually infected by R. typhi when feeding on apparently healthy rats that have blood-borne infection. Humans and other mammals are infected through autoinoculation by scratching a fleabite that is contaminated with feces from an infected flea. Murine typhus, because of its cycle, is more prevalent in hot and humid areas, when rats proliferate.

EPIDEMIOLOGY

In the United States, 50 to 100 cases are reported yearly, mainly in southern California and southern Texas. In California, a transmission cycle involving opossums and cat fleas has been demonstrated. Murine typhus is extremely common in Southeast Asia and North Africa and is a common cause of fever in travelers.

CLINICAL MANIFESTATIONS

On the basis of studies of infected volunteers, the incubation period is generally 8 to 16 days. The disease begins with abrupt fever, nausea, vomiting, myalgias, arthralgias, and headache. A rash is observed in 40 to 50% of patients about 6 days after the onset. It is detected even less frequently in patients with dark skin. The rash begins as pink maculae that can evolve to be maculopapular. It is often discrete, starting in the axilla; it generalizes to the trunk but does not usually involve the face, palms, and soles. In severe cases, it can become purpuric. The most frequently involved organ is the lung. A third of patients have a cough, and in a fourth, a nonspecific interstitial pneumonia develops that is sometimes associated with a pleural effusion. In severe forms, respiratory failure occurs. In patients with severe disease, neurologic symptoms range from confusion and stupor to coma and seizures. Cerebral hemorrhages may occur. Digestive involvement can be manifested as vomiting, abdominal pain, jaundice, and, in severe cases, hematemesis. The white blood cell count shows leukopenia and then leukocytosis. Thrombocytopenia can be noted as well as anemia, specifically when hemolysis is observed (frequently in patients with G6PD deficiency). A moderate increase in serum liver enzymes is common. In patients with severe disease, hyponatremia and hypoalbuminemia are observed.

DIAGNOSIS

The diagnosis of murine typhus is based mainly on serology (IFA) with titers similar to those of RMSF. On serologic evaluation, R. typhi cross-reacts with R. prowazekii; it can be differentiated either by comparing titers (two dilutions or more if IgG and IgM titers are discriminative) or by cross-adsorption. In this technique, the serum is absorbed with either antigen and then retested, and the causative agent is that removing antibodies to both bacteria. Skin biopsies and blood samples for culture and PCR may be valuable.

1959

TREATMENT  Treatment is the same as that for RMSF.

PROGNOSIS

The prognosis is usually favorable, but 10% of patients require intensive care and 1% die. Older patients and those with G6PD deficiency (Chapter 164) or chronic debilitating conditions are at higher risk.

FLEA-BORNE SPOTTED FEVER CAUSED BY RICKETTSIA FELIS

R. felis is mainly transmitted transovarially. Its genome comprises one or two plasmids, one being apparently conjugative. This is a new, incompletely defined disease. The bacterium is found in fleas in the Americas, Asia, Europe, Africa, and New Zealand. Isolated cases have been reported from Texas, Mexico, Brazil, France, and Germany. Reported cases all exhibited fever, a rash in six of seven cases, and inoculation eschar in some cases. The diagnosis can be based on serologic evaluation using specific R. felis antigen or PCR of blood or skin biopsy samples. Treatment has not been established, but the bacterium is highly susceptible to doxycycline and resistant to erythromycin.

Louse and Mite Infections EPIDEMIC LOUSE-BORNE TYPHUS EPIDEMIOLOGY

The human body louse (Chapter 367) lives in clothes and multiplies rapidly when cold weather and lack of hygiene allow it to. The body louse transmits three bacterial diseases: trench fever (caused by Bartonella quintana), relapsing fever (caused by Borrelia recurrentis), and exanthematic typhus (caused by R. prowazekii). The name typhus is derived from the Greek tuphos, which describes the neurologic condition associated with this disease and with typhoid. The body louse is prevalent during war, in poor countries, and in the homeless population of rich countries, including the United States and Europe. A 100,000-person outbreak of typhus was reported during the civil war in Burundi in 1997, and cases were reported in Russia, Peru, the United States, Algeria, and France in the 1990s. Louse-transmitted diseases killed more people than weapons did during central and eastern European wars in the 19th and 20th centuries. The epidemiology of R. prowazekii is mainly related to humans as reservoirs and lice as vectors. In the United States, the eastern flying squirrel (Glaucomys volans volans) is also a reservoir, and its fleas, lice, and mites can be infected. R. prowazekii has also been found in Amblyomma ticks, but their role is not known. The louse is infected when feeding on blood, which it does five times a day. R. prowazekii multiplies in the gut of the louse and is released in feces; after a few days, it destroys intestinal epithelium, which causes bright red blood to spread from the gut (typhus was also named the red louse disease). The patient is usually contaminated by infected feces (in which R. prowazekii survives for weeks), through aerosols, or by skin autoinoculation after scratching. Patients who recover from typhus may harbor the bacterium in a dormant form and suffer relapses under stressful conditions years later; this relapsing form is called Brill-Zinsser disease. During the relapse, a bacteremia occurs that may allow the start of a new outbreak if lice bite the patient.

CLINICAL MANIFESTATIONS

Typhus begins abruptly with fever, headaches, and myalgias, which may have led to the crouched posture termed sutama in the largest recent outbreak in Burundi. Cough and neurologic signs (stupor, confusion, or coma) are common. A rash is observed in 20 to 80% of patients, depending on the population studied; it is probably commonly underobserved on dark skin. It generally starts in the axilla and then spreads. The rash is usually macular but can be papular or purpuric in severe cases. In some cases, diarrhea and jaundice are reported. Splenomegaly is infrequently found. In severe cases, shock occurs and the fatality rate is 20 to 30%. Leukopenia, thrombocytopenia, and anemia as well as an increase in serum hepatic enzymes may be noted. Sylvatic typhus in the United States is caused by an R. prowazekii variant and is a milder disease. The most prominent clinical features are neurologic. Few cases have been described, and nearly all occurred in areas where the eastern flying squirrel is found, east of the Mississippi.

1960

CHAPTER 335  RICKETTSIAL INFECTIONS  

Brill-Zinsser disease is difficult to diagnose because rash is rare and recent exposure to lice can be lacking. Interviewing the patient may reveal prior exposure to lice, associated or not with a diagnosis of typhus in previous years. The disease is mild and the prognosis is good.

DIAGNOSIS

The diagnosis of typhus should be considered when grouped cases of high fever with confusion are observed in patients exposed to lice. The most common diagnostic error is to attribute the findings to typhoid, which can have fatal consequences because the antimicrobials typically prescribed for that condition (β-lactams, cotrimoxazole, and quinolones) are ineffective treatment of typhus. In tropical countries, typhus is frequently confused with malaria, hemorrhagic fever, and dengue. In people with lice, it can be confused with trench fever and relapsing fever, but treatment for both can be prescribed. The diagnosis of typhus should be clinical because the fatality rate is high and the treatment safe and efficient. Any outbreak of unexplained fever in unhygienic environments may suggest typhus, including outbreaks during civil wars (such as in Algeria, Rwanda, and Burundi), during social collapses (such as in Russia and Ukraine), in jails (such as in Rwanda and Burundi), and in chronically poor and cold countries. The diagnosis is based mainly on serology, in which there is cross-reaction with R. typhi (see earlier). When the investigation is performed under difficult field conditions, a drop of blood applied on filter paper and sent to a reference laboratory is valuable for serologic testing. Culture and PCR are helpful and can be performed with a skin biopsy sample or blood. Lice are good diagnostic tools because they can be tested even when dry and can be sent in closed containers without specific temperature conditions.

TREATMENT  Treatment of typhus is extremely simple, cheap, and effective; 200 mg of doxycycline orally in two divided doses is life-saving. Comatose patients should be treated parenterally. In allergic patients, chloramphenicol is the only known alternative, prescribed at a dose of 2 g/day for 10 days. There is no current vaccination, and the fight against lice is the major prevention strategy. Because lice are fragile, changing and boiling clothes are efficient. When this is not possible, insecticide (primarily permethrin) or ivermectin orally should be used.

SCRUB TYPHUS (ORIENTIA TSUTSUGAMUSHI) EPIDEMIOLOGY

Scrub typhus is transmitted by the bite of trombiculid mite (Chapter 367) larvae infected by O. tsutsugamushi. These mites, also named chiggers, are vertically infected through their mother. Scrub typhus distribution is limited to a triangle extending between northern Japan, eastern Australia, and eastern Russia and includes the Far East, China, and the Indian subcontinent. All together, 1 billion people may be exposed. Seasonality is determined by the emergence of larvae. It is one of the three most common causes of prolonged fever in rural Asia; in temperate zones, it occurs mainly in autumn and to a lesser extent in spring. O. tsutsugamushi species have a wide heterogenicity that may allow the definition of several species, but a single species is currently recognized with many serotypes. The more frequent are Kato, Karp, Gilliam, and Kawasaki.

CLINICAL MANIFESTATIONS

The disease occurs in patients exposed to rural or urban foci of scrub typhus after a delay of 10 or more days. The onset is usually sudden and includes fever, headache, and myalgias. Attentive examination may reveal an inoculation eschar at the site of the mite bite and tender draining lymph nodes. Generalized lymphadenopathy and rash may be observed. The symptoms vary according to organ involvement. Neuromeningeal symptoms are relatively common. Severe forms can be manifested as septic shock. Abortion commonly occurs in pregnant women. Leukopenia, thrombocytopenia, and increased levels of hepatic enzymes can occur. Evolution depends on the hosts and strains, and the fatality rate ranges from 0 to 30%. Scrub typhus is not more severe in HIV-infected patients, and surprisingly, HIV suppressive factors appear to be produced during infection. Relapses may occur in this disease.

DIAGNOSIS

Diagnosis may be difficult. Because the clinical features are frequently not specific, epidemiologic factors are critical. A diagnosis of infectious mononucleosis has erroneously been made in patients with scrub typhus. The bacterium can be detected by culture (in cells or mice) or by PCR in blood and biopsy specimens. The serologic technique first used was agglutination of Proteus mirabilis serotype OXK in the Weil-Felix reaction. This test lacks sensitivity and specificity and should be replaced by IFA or enzyme-linked immunosorbent assay tests using the three or four major serotypes.

TREATMENT  Chloramphenicol was the mainstay of treatment for many years, but now doxycycline is recommended. Single-day treatment with doxycycline is followed by relapses, and even repeated treatment for 2 days at a 7-day interval does not prevent all relapses. Hence, the currently recommended regimen is doxycycline, 100 mg orally twice a day, for 7 days. Cases resistant to doxycycline have been reported, and rifampin (600 mg orally daily) is a reasonable alternative. Quinolones should be avoided. Prophylaxis is based on the use of repellents.

RICKETTSIALPOX (RICKETTSIA AKARI) EPIDEMIOLOGY Rickettsialpox was first described in New York City, where it is still prevalent, by a general practitioner in 1946. R. akari, the causal agent, is transmitted by the bite of the mouse mite (Liponyssoides sanguineus). Its prevalence is probably underestimated; an active search revealed 13 cases in a New York hospital in the 1980s. Cases have been reported in Arizona, Utah, and Ohio. After the terrorist attacks of 9/11/01, cases of black skin eschars were investigated as possible anthrax in New York but were in fact rickettsialpox. High seroprevalence was reported among intravenous drug users in Baltimore. Cases have also been reported from Russia, Ukraine, Slovenia, and Korea.

CLINICAL MANIFESTATIONS

Ten days after the mite bite, the beginning of the illness is marked by fever, headache, and myalgia. Careful examination reveals an inoculation eschar and a draining lymphadenopathy that could be mistaken for cutaneous anthrax. Two to 6 days later, a rash appears and comprises 5 to 40 macular, then papular and vesicular spots. This aspect led to the name of the disease. It is frequently mistaken for chickenpox. The disease is usually mild.

DIAGNOSIS

The diagnosis can be made by serologic testing with IFA. Specific antigens react with high titer, but antibodies to other Rickettsia may be detected. The diagnosis may also be made on skin specimens by culture, immunodetection, or PCR.

TREATMENT  Doxycycline is highly efficient in these patients. Prevention is based on the control of mice.

EHRLICHIOSES AND ANAPLASMOSES DEFINITION The index case of modern ehrlichiosis was reported in the United States in 1987. The patient died of fever, presumably acquired after a tick bite in Arkansas, despite receiving chloramphenicol. The patient had several initially confusing diagnostic features; on blood smears, morulae in polymorphonuclear (PMN) cells were seen, and antibodies to Ehrlichia canis, a pathogen of dogs but not humans, were detected. He was then thought to have Ehrlichia chaffeensis, but this bacterium infects monocytes, not PMN cells. A diagnosis of Anaplasma phagocytophilum infection (or human granulocytic ehrlichiosis [HGE]) was considered, but the tick vector of this disease is absent in Arkansas. The most likely diagnosis is currently believed to be

CHAPTER 335  RICKETTSIAL INFECTIONS  

infection with Ehrlichia ewingii, an agent transmitted by Amblyomma americanum that is prevalent in Arkansas, infects PMN cells, and cross-reacts with E. canis, although it typically affects immunocompromised hosts. This case illustrates the progress in knowledge on ehrlichioses and how difficult it is to conclude the etiology of an atypical infection definitively on the basis of serology alone. All Ehrlichia pathogenic for humans except E. ewingii can be cultured. The ehrlichiae have been reclassified into four genera, mainly on the basis of 16S ribosomal RNA–derived phylogenetic analysis. Two are the tick-associated genera Ehrlichia and Anaplasma (A. phagocytophilum, or the HGE agent that was formerly named Ehrlichia phagocytophila). One is a helminth-associated genus, Neorickettsia, including Neorickettsia sennetsu (formerly Rickettsia sennetsu, then Ehrlichia sennetsu). The fourth is Wolbachia pipientis, a bacterium associated with arthropods (insects, crustaceans, and acarids) and helminth worms (mainly filaria). These organisms elicit cross-reactive antibodies. Ehrlichiae multiply exclusively in vacuoles of their eukaryotic cell host, where they form clusters known as morulae. The vacuoles are derived from phagosomes and help the organism escape bactericidal lysosomal fusion. In humans, ehrlichiae are associated with monocytes (E. chaffeensis, E. canis, N. sennetsu) or PMN cells (A. phagocytophilum, E. ewingii). Ehrlichioses can be acquired through tick bites, by ingestion of nematodes through contaminated water or animals (fish, snails), or as a consequence of filariasis.

American Human Monocytic Ehrlichiosis (Ehrlichia chaffeensis) EPIDEMIOLOGY Human monocytic ehrlichiosis (HME) is caused by E. chaffeensis. This organism has been isolated or identified by PCR mainly in the United States, in the southeastern, south central, and mid-Atlantic states and California (Table 335-3). In the United States, A. americanum (Lone Star tick) is the vector (Chapter 367) and the white-tailed deer is the main mammalian reservoir. Immature ticks are infected by blood while feeding on persistently bacteremic reservoirs. E. chaffeensis is transmitted transstadially in the tick and infects its next host (deer or human) during its next blood meal. The disease epidemiology reflects the tick habitat and activity, with most cases being contracted in the southern United States, in rural areas, and from April to September. In highly endemic areas, the incidence can reach 100 cases per 100,000 inhabitants. The severity is age dependent, which may explain the lower incidence reported in children. Males are more often affected than females, with a sex ratio of 4:1.

CLINICAL MANIFESTATIONS

The incubation lasts for 7 to 10 days after an identified tick exposure in 80% of cases. Patients have fever, headache, malaise, nausea, and anorexia.

TABLE 335-3 EHRLICHIOSES AND ANAPLASMOSES GEOGRAPHIC REPARTITION South central, southeastern, mid-Atlantic coastal states

DISEASE American monocytic ehrlichiosis

AGENT Ehrlichia chaffeensis

VECTOR Amblyomma americanum

Human granulocytic ehrlichiosis

Anaplasma phagocytophilum

Ixodes ricinus

Europe, China

Ixodes scapularis

Northeast, upper Midwest, northern California

E. ewingii

Ehrlichia ewingii

Amblyomma americanum

South central, southeastern, mid-Atlantic coastal states

Japanese monocytic ehrlichiosis

Neorickettsia sennetsu

Helminth of the gray mullet?

Japan

E. canis

Ehrlichia canis

Rhipicephalus sanguineus

Venezuela

1961

Untreated patients worsen and may require intensive care. Digestive tract involvement consisting of nausea, vomiting, diarrhea, and abdominal pain is common. Central nervous system infection is manifested in many forms from confusion to coma. A rash is observed in a third of cases and lymphadenopathy in a fourth. In severe forms, sepsis syndrome and MODS may occur. The white blood cell count typically shows leukopenia, caused by both lymphopenia and neutropenia. Thrombocytopenia is also frequently noticed; anemia may appear later. Coagulopathy may be observed in severe forms. Increases in serum enzymes, including AST, ALT, and LDH, may reflect organ involvement, as does creatininemia. CSF examination in patients with neurologic symptoms reveals pleocytosis and increased protein levels. Cells may be monocytic or PMN. The prognosis depends on early antimicrobial treatment, but the fatality rate is still high at 2.5%. In persons coinfected with HIV, it may be most severe; in one series, 6 of 13 patients died.

DIAGNOSIS

The diagnosis of HME should be considered in patients with a history of tick exposure and unexplained fever. HME resembles RMSF, but rash is less frequent. Later in the disease, it can be misdiagnosed as anything that causes severe sepsis. Leukopenia associated with thrombocytopenia and an increase in liver enzyme levels may establish the etiology. Careful examination of blood and CSF smears may help identify typical morulae. Treatment should be started in any suspected case. The diagnosis can be confirmed by culture in specialized laboratories using a canine cell line, DH82. However, PCR is more practical; confirmatory PCR using a second target gene is useful. Most cases are currently diagnosed serologically by a fourfold or greater increase in antibody titer or by seroconversion. The reference technique is IFA. A single titer of 25 is indicative of the diagnosis. There are cross-reactive antibodies among Ehrlichia species and with A. phagocytophilum. Western blotting may be valuable to distinguish among these bacteria.

TREATMENT  Doxycycline (100 mg twice daily for adults) is the drug of choice for patients with ehrlichiosis. The optimal duration of therapy has not been established, but current regimens recommend continuation of treatment for at least 3 days after the fever subsides and until evidence of clinical improvement, for a minimum total course of 5 to 7 days. Severe or complicated disease may require longer treatment courses. Because tetracyclines are contraindicated in pregnancy, rifampin has been used successfully in a limited number of pregnant women with documented HME.

Human Granulocytic Ehrlichiosis (Anaplasma phagocytophilum) EPIDEMIOLOGY

The first human case of A. phagocytophilum infection was recognized in 1990. The disease is found in America, Asia, and Europe (Fig. 335-4). It is transmitted by Ixodes scapularis (eastern North America), Ixodes pacificus (western North America), Ixodes ricinus (Europe), and Ixodes persulcatus (Asia), the vectors of Lyme disease (Chapter 329), and its epidemiology is similar. Coinfection with the two diseases may occur. The temporal distribution of the disease parallels that of nymph tick activity, with two peaks in spring and autumn. Ticks are born free of Ehrlichia and are infected while feeding on bacteremic small mammals. Deer play a major role as hosts of adult ticks and reservoirs. In highly endemic areas, the incidence can reach 50 per 100,000 inhabitants per year. The mean age of diagnosed patients is high, and males are more frequently infected than females, with a sex ratio of 3:1.

CLINICAL MANIFESTATIONS

The incubation time is usually between 7 and 10 days, and 80% of patients report a history of tick exposure. Many infections may be asymptomatic or too mild to require a diagnostic procedure. The disease frequently begins abruptly, with fever, headache, malaise, and myalgias that may be particularly severe. Rash is found in less than 10% of cases. Visceral involvement may be observed and includes digestive symptoms such as nausea, vomiting, and diarrhea. Neurologic symptoms may include confusion, meningitis, and meningoencephalitis.

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The evolution of the disease is favorable in most cases, even without specific therapy, but the disease may evolve to septic shock in some patients. Patients with underlying diseases are more at risk of dying. Most deaths are the consequence of Ehrlichia-induced immunosuppression, and patients may experience invasive aspergillosis, candidiasis, cryptococcosis, and herpes esophagitis.

DIAGNOSIS

Laboratory findings consist of the association of thrombocytopenia and leukopenia (lymphopenia or neutropenia). An increase in serum transaminases is also frequent. The diagnosis can be made by careful examination of blood smears for morulae within PMN cells. Culture from blood is possible in appropriate cells (HL-60), and PCR is useful as for HME. Most cases are diagnosed by serologic testing with IFA, which is comparable to that in HME (see earlier).

TREATMENT  Treatment is also similar to that of HME except that A. phagocytophilum is susceptible to fluoroquinolones in vitro, but these drugs have not been tested in patients.

Ehrlichia ewingii

Canine granulocytic ehrlichiosis, reported in the United States in 1972, is caused by E. ewingii. This bacterium was characterized by amplification and sequencing of the 16S ribosomal RNA gene. The vector of E. ewingii is A. americanum (Chapter 367), which also transmits E. chaffeensis. Among 60 cases of ehrlichiosis in Missouri in 1999, 4 were caused by E. ewingii; 4 other cases have been reported since by the CDC. The disease was prevalent in immunocompromised hosts (seven of eight) coinfected with HIV or receiving immunosuppressive drugs. Patients who report tick exposure are noted to have fever, thrombocytopenia, leukopenia, and various symptoms, including meningitis. Morulae may be seen on blood smears in PMN cells. The evolution in reported cases was good; patients responded dramatically to doxycycline. Patients have antibodies to E. chaffeensis, and PCR has been shown to be useful when it is applied to blood samples. This diagnosis should be considered when ehrlichiosis is suspected in immunocompromised patients exposed to A. americanum ticks.

Ehrlichia canis

Canine monocytic ehrlichiosis was reported first in Algeria in the 1930s. It is caused by E. canis and transmitted by the dog tick R. sanguineus (Chapter 367). This tick is found worldwide and is prevalent in temperate and hot areas. In 1996, a single case of infection was reported in an asymptomatic man from Venezuela who owned an infected dog. Recently, cases have been reported in patients in South America.

Wolbachia Species

Wolbachia bacteria are endosymbionts of arthropods and nematodes. They were known to be present in filarial worms, but it was later shown that they may play a role in human disease. These bacteria manipulate the fertility of their host. Eradication of Wolbachia in filariae may lead to infertility and stop the microfilariae from spreading. This effect was demonstrated by field treatment with doxycycline in patients with onchocerciasis. The patients improved when treated with this drug, which is effective on Wolbachia and subsequently on the worm’s fertility but not on the worm itself. In 2001, it was shown that the adverse reactions observed after treatment of lymphatic filariasis may be caused by the release of Wolbachia from destroyed worms. Some authors suggested that eradicating Wolbachia before the anthelmintic prescription would avoid these reactions. For some reason, Loa loa (Chapter 366) do not harbor Wolbachia, and the genome of Wolbachia integrated in the Brugia malayi genome makes it inaccessible to therapy.

Q FEVER DEFINITION

Q fever is a worldwide zoonosis caused by Coxiella burnetii. The name Q fever is derived from “query” to emphasize the surprising aspect of the disease first described in Queensland, Australia, in 1935 by Derrick. The infection in humans is variable in its severity, clinical expression, and natural course (i.e., acute or chronic). It is considered by the CDC to be a potential agent of bioterrorism. Ungulates and pets are the major sources of human infection.

The Pathogen

C. burnetii is a gram-negative bacterium that naturally infects its host’s monocytes. It multiplies in an acidic vacuole. Strains are heterogeneous genetically and antigenically and are associated with acute infections of variable severity. C. burnetii in vitro generates a deleted, avirulent mutant also named phase II.

Anaplasma phagocytophilum (HGE)

E. chaffeensis (HME) E. ewingii

E. canis

FIGURE 335-4.  Geographic distribution of ehrlichioses. HGE = human granulocytic ehrlichiosis; HME = human monocytic ehrlichiosis.

Neorickettsia sennetsu

CHAPTER 335  RICKETTSIAL INFECTIONS  

This mutant exhibits diagnostic antigens that are useful because they are more reactive during acute infection. C. burnetii is incompletely eliminated after acute infection. In immunocompromised hosts and patients with cardiac valve lesions, C. burnetii continues to multiply despite high levels of antibodies and causes chronic infection. Control of the disease in acute Q fever is associated with the formation of a granuloma.

EPIDEMIOLOGY

C. burnetii infects a wide range of animals, including mammals, birds, and ticks. Ungulates and pets (cats and dogs) are the most common source of the disease. Mammals are infected through aerosols and may shed Coxiella in feces, urine, milk, and birth products. Humans are usually infected by aerosols or less frequently by exposure to milk products. Interhuman infections through sexual intercourse, during delivery, or by blood transfusion have been reported. Coxiella survives in the environment and can be spread far by the wind. In the past few years, major outbreaks were related to sheep and goats. The disease is partly seasonal and related to lambing time. The current geographic repartition is largely unknown. Males have more severe disease but are not more often exposed to Q fever, and middle-aged people are more frequently affected and hospitalized. The number of reported cases recently increased dramatically in Europe and Asia. Many American soldiers were infected in Iraq.

CLINICAL MANIFESTATIONS

After contamination by C. burnetii, 60% of patients seroconvert without apparent disease, 38% experience a self-limited disease, and only 2% require diagnostic evaluation. Months to years after the primary infection, a chronic infection associated with an immunocompromised situation, a cardiac valve lesion, or a vascular prosthesis or aneurysm develops in 0.2 to 0.5% of patients. Patients with diagnosed acute infection may have a variety of symptoms (Table 335-4). Isolated prolonged fever was observed in 14% of more than 1000 patients. Pneumonia was found in 37% and was the only symptom in 17%. This percentage may vary according to the place of study and reach 90% of diagnosed cases. Some cases may be associated with respiratory distress. Hepatitis is found in 60% of patients and is the sole manifestation in 40%. The association of fever and a moderate increase in transaminases is an

TABLE 335-4 SITUATIONS THAT SHOULD PROMPT SEROLOGIC TESTING FOR Q FEVER ACUTE Q FEVER (PHASE II ANTIGEN AND IgG ≥ 200 AND IgM ≥ 50) Fever in a patient in contact with ungulates Unexplained prolonged fever (>7 days) Granulomatous hepatitis Fever and thrombocytopenia Meningoencephalitis Myocarditis Erythema nodosum Fever during pregnancy Fever in a patient in contact with a parturient pet Unexplained atypical pneumonia Fever and an increase in transaminases (2-5 times the normal level) Aseptic meningitis Guillain-Barré syndrome Pericarditis Spontaneous abortion CHRONIC Q FEVER (PHASE I ANTIGEN AND IgG ≥ 800 AND IgA ≥ 100) Blood culture–negative endocarditis Patient with a valvulopathy and unexplained Fever Weight loss Fatigue Increased erythrocyte sedimentation rate Increased transaminases Thrombocytopenia Patient with unusually rapid degradation of a prosthetic valve Fever in a patient with a vascular aneurysm or prosthesis Aseptic osteomyelitis Chronic pericarditis Multiple spontaneous abortions

1963

important clue. Some hepatitides, specifically in middle-aged men, are associated with an inflammatory syndrome and autoantibodies and may be resistant to antimicrobial treatment. Liver biopsy, when it is performed, exhibits granulomas that may be typified by a lipid vacuole and surrounded by a fibrinoid ring in the form of a doughnut. Less frequently, in 1.5% of cases, patients exhibit a rash. Patients can have specific neurologic manifestations such as meningitis, encephalitis, meningoencephalitis, or peripheral neuropathy. In 1 to 2% of cases, patients have cardiovascular manifestations, such as pericarditis or more rarely myocarditis. Evolution is usually favorable even without treatment, except in special hosts. In pregnant women, symptomatic or not, Q fever compromises the pregnancy. When infected during the first trimester, the patient usually aborts spontaneously. When the patient is infected later, the disease can result in fetal death or prematurity, or the outcome may be normal. Chronic uterine infection may develop in half the patients infected during pregnancy, and they may later experience multiple spontaneous abortions. Thirty percent to 50% of patients with heart valve or vascular lesions may experience chronic endocarditis within 2 years. This evolution is not prevented by regular treatment. Patients with Q fever endocarditis have a chronic infection with low-grade fever, progressive degradation of valve function, and progressive heart failure. Fever is intermittent, and vegetations are frequently absent on cardiac echocardiography. Endocarditis is therefore not frequently considered in the initial differential diagnosis. If it is not diagnosed, the disease progressively worsens, and emboli (mainly cerebral) as well as renal insufficiency, splenomegaly, and hepatomegaly may be observed. Digital clubbing may also be seen. The main clue to the diagnosis in a patient with a valvulopathy is unexplained sickness (unexplained fatigue, weight loss, fever), a biologic abnormality (leukopenia, increased erythrocyte sedimentation rate, thrombocytopenia, increase in hepatic enzymes), or rapid degradation of a prosthetic valve. Chronic osteomyelitis, hepatitis, and infection of an aneurysm and vascular prosthesis have been reported. Leukopenia may be observed; thrombocytopenia is frequent, as are increases in hepatic enzymes. Circulating anticoagulant associated with antiphospholipid antibodies may be observed (Chapter 177), as may anti– smooth muscle antibodies. During endocarditis, antinuclear antibodies, microhematuria, and rheumatoid factor are frequently found.

DIAGNOSIS

The diagnosis is based mainly on serology (see Table 335-4). Direct detection by culture and PCR or immunochemistry in valve, liver, or blood samples is also useful, but serologic evaluation by IFA is the best method. Two antigens (phase I and phase II) can be tested. Acute Q fever is diagnosed when seroconversion or a fourfold increase is obtained with phase II antigen. A single serum test exhibiting IgG antibodies of 200 or greater and IgM of 50 or greater against phase II is also diagnostic. During chronic Q fever, antibodies are at higher titer and directed against both phase I and phase II. IgG against phase I at a titer of 800 or 1600 is diagnostic of chronic infection, as is IgA at 100 or greater. Serology is useful for follow-up of patients with acute Q fever and underlying disease and those with treated chronic Q fever.

TREATMENT  Treatment is easy during acute Q fever. Doxycycline is the most efficient antimicrobial, and it should be prescribed for 2 weeks. Some patients with hepatitis do not respond well because of an excessive immune response. They rapidly improve with a short course of glucocorticoids. In pregnant women, cotrimoxazole during the entire pregnancy may decrease the chance of an unfavorable outcome. As for endocarditis, bactericidal treatment is necessary. In vitro, antimicrobial efficacy is impaired by the low pH of the vacuole in which C. burnetii resides. Hydroxychloroquine increases the pH of this vacuole and restores the bactericidal effect of doxycycline. In patients with endocarditis, the recommended treatment is a combination of doxycycline (200 mg daily) and hydroxychloroquine (600 mg/day, then adjusted to reach a 1-mg/ mL plasma concentration). This regimen is prescribed for 18 to 36 months according to serologic results. We recently observed that a more rapid favorable outcome was obtained with doxycycline serum levels higher than 5 µg/ mL. Some strains may be resistant to doxycycline, and new macrolides may be an alternative. The major problem with this treatment is photosensitivity; sun exposure should be avoided. An alternative treatment is a combination of doxycycline and ofloxacin for 3 years or more.

PREVENTION

Prevention is based on veterinary control in animals. A vaccine is currently available in Australia. SUGGESTED READING Openshaw JJ, Swerdlow DL, Krebs JW, et al. Rocky mountain spotted fever in the United Satates, 20002007: interpreting contemporary increases in incidence. Am J Trop Med Hyg. 2010;83:174-182. Review noting a 0.3% case-fatality rate.