1435CHAPTER 187 Rickettsial Diseases

FIGURE 187-2 Eschar at the site of the mite bite in a patient with rickettsialpox.

(Reprinted from A Krusell et al: Emerg Infect Dis 8:727, 2002. Photo obtained by

Dr. Kenneth Kaye.)

FIGURE 187-3 A. Papulovesicular lesions on the trunk of the patient with

rickettsialpox shown in Fig. 187-2. B. Close-up of lesions from the same patient.

(Reprinted from A Krusell et al: Emerg Infect Dis 8:727, 2002. Photos obtained by

Dr. Kenneth Kaye.)

A

B

Diagnosis Diagnosis of these tick-borne spotted fevers is based

on clinical and epidemiologic findings and is confirmed by serology,

immunohistochemical demonstration of rickettsiae in skin biopsy

specimens, cell-culture isolation of rickettsiae, or PCR of skin biopsy,

eschar biopsy or swab, or blood samples. Serologic diagnosis detects

antibodies to antigens shared among SFG rickettsiae, hindering identification of the etiologic species. In an endemic area, a possible diagnosis of rickettsial spotted fevers should be considered when patients

present with fever, rash, and/or a skin lesion consisting of a black

necrotic lesion or a crust surrounded by erythema.

TREATMENT

Tick-Borne Spotted Fevers

As with RMSF, severe cases should be treated with doxycycline

(100 mg bid orally) for 3–5 days after defervescence. Alternative

agents for milder disease include doxycycline (100 mg bid orally for

1–5 days), chloramphenicol (500 mg qid orally for 7–10 days), and

ciprofloxacin (750 mg bid orally for 7 days). Pregnant patients may

be treated with josamycin (3 g/d orally for 5 days) where available.

Data on the efficacy of treatment of mildly ill children with clarithromycin or azithromycin should not be extrapolated to adults or to

patients with moderate or severe illness.

■ RICKETTSIALPOX

R. akari infects mice and their mites (Liponyssoides sanguineus), which

maintain the organisms by transovarial transmission.

Epidemiology Rickettsialpox is recognized principally in New York

City, but cases have also been reported in other urban and rural locations

in the United States and in Ukraine, Croatia, Mexico, and Turkey. Investigation of eschars suspected of representing bioterrorism-associated

cutaneous anthrax revealed that rickettsialpox occurs more frequently

than previously realized.

Clinical Manifestations A papule forms at the site of the mite’s

feeding, develops a central vesicle, and becomes a 1- to 2.5-cm painless

black crusted eschar surrounded by an erythematous halo (Fig. 187-2).

Enlargement of the regional lymph nodes draining the eschar suggests

initial lymphogenous spread. After an incubation period of 10–17 days,

during which the eschar and regional lymphadenopathy frequently go

unnoticed, disease onset is marked by malaise, chills, fever, headache,

and myalgia. A macular rash appears 2–6 days after onset and usually

evolves sequentially into papules, vesicles, and crusts that heal without

scarring (Fig. 187-3); in some cases, the rash remains macular or maculopapular. Some patients develop nausea, vomiting, abdominal pain,

cough, conjunctivitis, or photophobia. Without treatment, fever lasts

6–10 days.

Diagnosis and Treatment Clinical, epidemiologic, and convalescent serologic data establish the diagnosis of an SFG rickettsiosis

that is seldom pursued further. Doxycycline is the drug of choice for

treatment.

■ FLEA-BORNE SPOTTED FEVER

Rickettsia felis is suspected to cause an emerging rickettsiosis worldwide. Maintained transovarially in the geographically widespread cat

flea, Ctenocephalides felis, the infection has been described as moderately severe, with fever, rash, and headache as well as CNS, gastrointestinal, and pulmonary symptoms on the basis of PCR, which often

detects organisms in healthy persons. Patient isolates and serologic

support are lacking.

■ EPIDEMIC (LOUSE-BORNE) TYPHUS

Epidemiology The human body louse (Pediculus humanus corporis) lives in clothing under poor hygienic conditions and usually in

impoverished cold areas. Lice acquire R. prowazekii when they ingest

blood from a rickettsemic patient. The rickettsiae multiply in the

louse’s midgut epithelial cells and are shed in its feces. The infected

louse leaves a febrile person and deposits infected feces on its subsequent host during its blood meal; the patient autoinoculates the organisms by scratching. The louse is killed by the rickettsiae and does not

pass R. prowazekii to its offspring.

Epidemic typhus haunts regions afflicted by wars and disasters. An

outbreak involved 100,000 people in refugee camps in Burundi in 1997.

1436 PART 5 Infectious Diseases

A small focus was documented in Russia in 1998, sporadic cases were

reported from Algeria, and frequent outbreaks occurred in Peru and

Rwanda. Eastern flying squirrels (Glaucomys volans) and their lice and

fleas maintain R. prowazekii in a zoonotic cycle and transmit infection

to humans.

Brill-Zinsser disease is a recrudescent illness occurring years after

acute epidemic typhus, probably as a result of waning immunity.

R. prowazekii remains latent for years; its reactivation results in sporadic cases of disease in louse-free populations or in epidemics in

louse-infested populations. Recrudescence has been documented after

flying squirrel–associated typhus.

Rickettsiae are potential agents of bioterrorism (Chap. S3). Infections with R. prowazekii and R. rickettsii have high case–fatality ratios.

These organisms cause difficult-to-diagnose diseases and are highly

infectious when inhaled as aerosols. Organisms resistant to tetracycline

or chloramphenicol have been developed in the laboratory.

Clinical Manifestations After an incubation period of ~1–2 weeks,

the onset of illness is abrupt, with prostration, severe headache, and

fever rising rapidly to 38.8°–40.0°C (102°–104°F). Cough is prominent,

developing in 70% of patients. Myalgias are usually severe. A rash

begins on the upper trunk, usually on the fifth day, and then becomes

generalized, involving the entire body except the face, palms, and soles.

Initially, this rash is macular; without treatment, it becomes maculopapular, petechial, and confluent. The rash often goes undetected

on black skin; 60% of African patients have spotless epidemic typhus.

Photophobia, with considerable conjunctival injection, is common.

The tongue may be dry, brown, and furred. Confusion and coma are

common. Skin necrosis and gangrene of the digits as well as interstitial

pneumonia may occur in severe cases. Untreated disease is fatal in

7–40% of cases, with outcome depending primarily on the condition of

the host. Patients with untreated infections develop renal insufficiency

and multiorgan involvement in which neurologic manifestations are

frequently prominent. Overall, 12% of patients with epidemic typhus

have neurologic involvement. Infection associated with North American

flying squirrels is a milder illness; whether this milder disease is due

to host factors (e.g., better health status) or attenuated virulence is

unknown.

Diagnosis and Treatment Epidemic typhus is sometimes misdiagnosed as typhoid fever in tropical countries (Chap. 165). The

means even for serologic studies are often unavailable in settings of

louse-borne typhus. Epidemics can be recognized by the serologic or

immunohistochemical diagnosis of a single case or by detection of

R. prowazekii in a louse found on a patient. Doxycycline (100 mg bid)

is administered orally or—if the patient is comatose or vomiting—

intravenously and continued until 3–5 days after defervescence. Under

epidemic conditions, a single 200-mg oral dose can be tried but fails

in some cases. Pregnant patients should be evaluated individually and

treated with chloramphenicol early in pregnancy or with doxycycline

late in pregnancy.

Prevention Prevention of epidemic typhus involves control of

body lice. Clothes should regularly be changed and laundered in hot

water, and insecticides can be used every 6 weeks to control the louse

population.

■ ENDEMIC MURINE TYPHUS

Epidemiology R. typhi is maintained in mammalian host–flea

cycles, with rats (Rattus rattus and R. norvegicus) and the Oriental rat

flea (Xenopsylla cheopis) as the classic zoonotic niche. Fleas acquire

R. typhi from rickettsemic rats and carry the organism throughout

their life span. Nonimmune rats and humans are infected when

rickettsia-laden flea feces contaminate pruritic bite lesions; less frequently, the flea bite transmits the organisms. Transmission can also

occur via inhalation of aerosolized rickettsiae from flea feces. Infected

rats appear healthy, although they are rickettsemic for ~2 weeks.

Murine typhus occurs mainly in Texas and southern California,

where the classic rat–flea cycle is absent and an opossum–cat flea

(C. felis) cycle is highly suspected. Globally, endemic typhus occurs

mainly in warm (often coastal) areas throughout the tropics and subtropics, where it is highly prevalent though often unrecognized. The

incidence peaks from April through July in Texas and during the warm

months of summer and early fall in other geographic locations. Patients

seldom recall exposure to fleas, although exposure to animals such as

cats, opossums, and rats is reported in nearly 40% of cases.

Clinical Manifestations The incubation period of experimental

murine typhus averages 11 days (range, 8–16 days). Headache, myalgia,

arthralgia, nausea, and malaise develop 1–3 days before onset of chills

and fever. Patients often experience nausea and vomiting.

The duration of untreated illness averages 12 days (range, 9–18 days).

Rash occurs in approximately half of all patients. It is present in only

13% of patients at presentation for medical care (usually ~4 days after

onset of fever), appearing an average of 2 days later in half of the

remaining patients. The initial macular rash is often faint and detected

by careful inspection of the axilla or the inner surface of the arm. Subsequently, the rash becomes maculopapular, involving the trunk more

often than the extremities; it is seldom petechial and rarely involves

the face, palms, or soles. A rash is detected in only 20% of patients with

darkly pigmented skin.

Pulmonary involvement is frequently prominent; 35% of patients

have a hacking, nonproductive cough, and 23% of patients who

undergo chest radiography have pulmonary densities due to interstitial

pneumonia, pulmonary edema, and pleural effusions. Bibasilar rales

are the most common pulmonary sign. Less common clinical manifestations include abdominal pain, confusion, stupor, seizures, ataxia,

coma, and jaundice. Clinical laboratory studies frequently reveal anemia and leukopenia early in the course, leukocytosis late in the course,

thrombocytopenia, hyponatremia, hypoalbuminemia, increased serum

levels of hepatic aminotransferases, and prerenal azotemia. Complications can include respiratory failure, hematemesis, cerebral hemorrhage, and hemolysis. Severe illness necessitates the admission of 10%

of hospitalized patients to an intensive care unit. Greater severity is

generally associated with old age, underlying disease, and treatment

with a sulfonamide; the case–fatality rate is 1%.

Diagnosis and Treatment Serologic studies of acute- and

convalescent-phase serum samples can provide a diagnosis, and an

immunohistochemical method for identification of typhus groupspecific antigens in biopsy samples has been developed. Cultivation

is used infrequently and is not widely available. PCR of the blood is

not adequately sensitive. When endemic typhus is suspected, patients

should be treated empirically with doxycycline (100 mg twice daily by

mouth for 7 days). Chloramphenicol, ciprofloxacin, and azithromycin

are less effective alternatives.

■ SCRUB TYPHUS

Epidemiology O. tsutsugamushi differs substantially from Rickettsia species both genetically and in cell-wall composition (i.e., it lacks

lipopolysaccharide). O. tsutsugamushi is maintained by transovarial

transmission in trombiculid mites. After hatching, infected larval mites

(chiggers, the only stage that feeds on a host) inoculate organisms into

the skin. Infected chiggers are particularly likely to be found in areas

of heavy scrub vegetation during the wet season, when mites lay eggs.

Scrub typhus is endemic and reemerging in eastern and southern

Asia, northern Australia, and islands of the western Pacific and Indian

Oceans. Infections are prevalent in these regions; in some areas, >3%

of the population is infected or reinfected each month. Immunity to

the homologous strain wanes over 1–3 years, and the organisms exhibit

remarkable antigenic diversity with loss of cross-protective immunity

in as short a period as 1 month. Emerging cases in Chile and Africa

challenge the classic epidemiology of scrub typhus.

Clinical Manifestations Illness varies from mild and self-limiting

to fatal. After an incubation period of 6–21 days, onset is characterized

by fever, headache, myalgia, cough, and gastrointestinal symptoms.

Some patients recover spontaneously after a few days. The classic case

1437CHAPTER 187 Rickettsial Diseases

description includes an eschar where the chigger has fed, regional

lymphadenopathy, and a maculopapular rash—signs that are seldom

seen in indigenous patients. In fact, <50% of Westerners develop an

eschar, and <40% develop a rash (on day 4–6 of illness). Severe cases

typically manifest with encephalitis and interstitial pneumonia due to

vascular injury. The case–fatality rate for untreated classic cases is 6%

but would probably be lower if all mild cases were diagnosed.

Diagnosis and Treatment Serologic assays (indirect fluorescent

antibody, indirect immunoperoxidase, and enzyme immunoassays) are

the mainstays of laboratory diagnosis. PCR amplification of Orientia

genes from eschars is effective, but less so for blood. Patients are treated

with oral doxycycline (100 mg twice daily for 7–15 days), azithromycin

(500 mg for 3 days), or chloramphenicol (500 mg four times daily for

7–15 days).

Some cases of scrub typhus in Thailand are poorly responsive to

doxycycline or chloramphenicol but respond to azithromycin and

rifampin.

EHRLICHIOSES AND ANAPLASMOSIS

Ehrlichioses are acute febrile infections caused by members of the

family Anaplasmataceae, which is made up of obligately intracellular organisms of five genera: Ehrlichia, Anaplasma, Wolbachia,

“Candidatus Neoehrlichia,” and Neorickettsia. The bacteria reside in

vertebrate reservoirs and target vacuoles of hematopoietic—and, for

some species, endothelial—cells (Fig. 187-4). Four Ehrlichia species,

two Anaplasma species, and one Neoehrlichia species are transmitted

by ticks to humans and cause infection that can be severe and prevalent. E. chaffeensis, the agent of HME, and E. muris subsp. eauclairensis infect predominantly mononuclear phagocytes; E. ewingii and

A. phagocytophilum infect neutrophils. Infections with “Candidatus

Neoehrlichia mikurensis” and A. capra are less well characterized but

have been reported to grow in endothelium and human erythrocytes,

respectively.

Ehrlichia, “Candidatus Neoehrlichia,” and Anaplasma are maintained by horizontal tick–mammal–tick transmission, and humans

are only inadvertently infected. Wolbachiae are associated with human

filariasis, since they are important for filarial viability and pathogenicity; antibiotic treatment targeting wolbachiae is a strategy for

filariasis control. Neorickettsiae parasitize flukes (trematodes) that in

turn parasitize aquatic snails, fish, and insects. Only a single human

neorickettsiosis has been described: sennetsu fever, an infectious

mononucleosis–like illness first identified in 1953 in association with

the ingestion of raw fish containing N. sennetsu–infected flukes.

■ HUMAN MONOCYTOTROPIC EHRLICHIOSIS

Epidemiology More than 20,732 cases of E. chaffeensis infection

had been reported to the U.S. Centers for Disease Control and Prevention (CDC) as of January 2020. However, active prospective surveillance

documented an incidence as high as 414 cases per 100,000 population

in some U.S. regions. Most E. chaffeensis infections are identified in

the south-central, southeastern, and mid-Atlantic states, but cases have

also been recognized in California, New York, New England, and midwestern states. All stages of the Lone Star tick (A. americanum), which

is expanding its geographic range, feed on white-tailed deer—a major

reservoir. Dogs and coyotes also serve as reservoirs and often lack clinical signs. Tick bites and exposures are frequently reported by patients

in rural areas, and 64% of infections occur in May through July. The

median age of HME patients is 55 years; however, 11% of infections

occur in children ≤19 years of age, and these include severe and fatal

infections. Of patients with HME, 59% are male.

E. chaffeensis has been detected in South and Central America,

Africa, and Asia.

Clinical Manifestations E. chaffeensis disseminates hematogenously from the dermal blood pool created by the feeding tick. After a

median incubation period of 8 days, illness develops. Clinical manifestations are undifferentiated and include fever (97% of cases), headache

(70%), myalgia (68%), and malaise (77%). Less frequently observed

are nausea, vomiting, and diarrhea (28–57%); cough (30%); rash (29%

overall, 6% at presentation); and confusion (20%). HME can be severe:

77% of patients with confirmed cases are hospitalized, and 2% die. Lifethreatening complications include renal failure, meningoencephalitis,

acute respiratory distress syndrome, a DIC-like syndrome, pneumonia,

septic shock, cardiac failure, hepatitis, hemorrhage, and—in immunocompromised patients—overwhelming ehrlichial infection; patients

with diabetes, cancer, organ transplantation, asplenia, hepatitis C, or

HIV infection have a 2.3 relative risk for death. Laboratory findings

are valuable in the differential diagnosis of HME; 66% of patients

have leukopenia (initially lymphopenia, later neutropenia), 86% have

thrombocytopenia, and 89% have elevated serum levels of hepatic

aminotransferases. Despite low blood cell counts, the bone marrow is

hypercellular, and noncaseating granulomas can be present. Vasculitis

is not a component of HME.

Diagnosis HME can be fatal. If not given empirical doxycycline

treatment, 39% and 40% of patients with HME require admission

to an intensive care unit and mechanical ventilation, respectively;

these measures are necessary in no patients receiving prompt empirical treatment. In addition, hospital stay and illness duration are

lengthened in untreated patients by 8 and 12 days, respectively. The

diagnosis is suggested by fever, known tick exposure in the preceding

3 weeks, thrombocytopenia and/or leukopenia, and increased serum

aminotransferase activities. Morulae are demonstrated in <10% of

peripheral-blood smears. HME can be confirmed during active infection by PCR amplification of E. chaffeensis nucleic acids in blood

obtained before the start of doxycycline therapy. Retrospective serodiagnosis requires a consistent clinical picture and a fourfold increase in

E. chaffeensis antibody titer to ≥128 in paired serum samples obtained

~3 weeks apart. Separate specific diagnostic tests are necessary for

HME and HGA (see below).

■ EWINGII EHRLICHIOSIS AND

EHRLICHIA MURIS EAUCLAIRENSIS INFECTIONS

Ehrlichia ewingii resembles E. chaffeensis in its tick vector (A. americanum) and vertebrate reservoirs (white-tailed deer and dogs). E. muris

eauclairensis causes human infections after Ixodes scapularis tick

exposure in Wisconsin and Minnesota. E. ewingii and E. muris illnesses are similar to but less severe than HME. Many cases occur in

immunocompromised patients. Human infections with E. canis have

been documented as subclinical ehrlichemia. No specific serologic

diagnostic tests for these other ehrlichiae are readily available, and

E. chaffeensis serologic tests can be positive when the infecting agent is

actually a different species of Ehrlichia.

FIGURE 187-4 Peripheral-blood smear from a patient with human granulocytotropic

anaplasmosis. A neutrophil contains two morulae (vacuoles filled with

A. phagocytophilum). (Photo courtesy of Dr. J. Stephen Dumler.)

1438 PART 5 Infectious Diseases

■ “CANDIDATUS NEOEHRLICHIA MIKURENSIS”

INFECTION

“Candidatus Neoehrlichia mikurensis,” a bacterium in a phylogenetic

clade between Ehrlichia and Anaplasma, was originally identified in

Ixodes ricinus ticks from the Netherlands and in mice and Ixodes ovatus

ticks from Japan. By means of broad-range 16S rRNA gene amplification and sequence analysis, this organism was identified as the cause of

severe and sometimes prolonged febrile illnesses in European immunocompromised patients with tick bites or exposures and in Chinese

patients developing a mild febrile illness after being bitten by Ixodes

persulcatus and Haemaphysalis concinna ticks. The clinical presentation is similar to those of HME and HGA. Specific diagnostic methods

have been developed but are not widely available.

TREATMENT

Ehrlichioses

Doxycycline is effective for HME as well as other ehrlichioses; the

use of this drug in “Candidatus N. mikurensis” infection is associated with disease resolution. Therapy with doxycycline (100 mg

given PO or IV twice daily) or tetracycline (250–500 mg given PO

every 6 h) lowers hospitalization rates and shortens fever duration.

E. chaffeensis is not susceptible to chloramphenicol in vitro, and

the use of this drug is controversial. While a few reports document

E. chaffeensis persistence in humans, this finding is rare; most infections are cured by short courses of doxycycline continuing for 3–5 days

after defervescence. Although poorly studied for this indication,

rifampin may be suitable when doxycycline is contraindicated.

Prevention HME, E. ewingii ehrlichiosis, E. muris ehrlichiosis, and

“Candidatus N. mikurensis” infection can be prevented by the avoidance of ticks in endemic areas. The use of protective clothing and tick

repellents, careful postexposure tick searches, and prompt removal of

attached ticks probably diminish infection risk.

■ HUMAN GRANULOCYTOTROPIC ANAPLASMOSIS

Epidemiology As of January 2021, 45,186 cases of HGA had been

reported to the CDC, most in the upper-midwestern and northeastern

United States. The global geographic distribution is similar to that

of Lyme disease because of the shared Ixodes tick vectors. Natural

reservoirs for A. phagocytophilum are white-footed mice, squirrels,

and white-tailed deer in the United States and red deer in Europe.

HGA incidence peaks in May through July, but the disease can occur

throughout the year with exposure to Ixodes ticks. HGA often affects

males (59%) and older persons (median age, 51 years).

Clinical Manifestations Seroprevalence rates are high in endemic

regions; thus, it seems likely that most individuals develop subclinical

infections. The incubation period for HGA is 4–8 days, after which the

disease manifests as fever (75–100% of cases), myalgia (73%), headache (82%), and malaise (97%). A minority of patients develop nausea,

vomiting, or diarrhea (20–40%); cough (27%); or confusion (17%). A

rash in HGA (5%) almost invariably reflects co-infection with Borrelia,

resulting in erythema migrans. Most patients develop thrombocytopenia (80%) and/or leukopenia (63%) with increased serum hepatic

aminotransferase levels (80%).

Life-threatening complications occur most often in the elderly

and include renal failure, adult respiratory distress syndrome, a toxic

shock–like syndrome, pneumonia, and a DIC- or sepsis-like syndrome.

Meningoencephalitis is rare in documented cases of HGA. Other documented neurologic sequelae include brachial plexopathy, cranial nerve

involvement, and demyelinating polyneuropathy. Infection of patients

with a preexisting immunocompromising condition (diabetes, immunosuppressive medications, asplenia, arthritis) is associated with a 3.0

relative risk for life-threatening complications. Of patients with HGA,

31% are hospitalized, and 7% require intensive care. The case–fatality

rate is 0.3%, but the relative risk for death is 16 if infection occurs with

an immunosuppressive condition. Neither vasculitis nor granulomas

are components of HGA. While patients can be co-infected with Borrelia burgdorferi and Babesia microti (transmitted by the same tick vector[s]), there is little evidence that these infections increase the severity

or persistence of HGA. HGA transmitted by transfusion (including the

transfusion of leukoreduced blood or platelets) has now been reported

in at least nine cases, including a fatality.

Diagnosis HGA should be included in the differential diagnosis of

influenza-like illnesses during seasons with Ixodes tick activity (May

through December), especially in the context of a known tick bite

or exposure. Concurrent thrombocytopenia, leukopenia, or elevated

serum levels of alanine or aspartate aminotransferase further increase

the likelihood of HGA. Many HGA patients develop Lyme disease

antibodies in the absence of clinical findings consistent with that diagnosis. Thus, HGA should be considered in the differential diagnosis

of atypical severe Lyme disease presentations. Peripheral-blood film

examination for neutrophil morulae can yield a diagnosis in 20–75%

of infections. PCR testing of blood from patients with active disease

before doxycycline therapy is sensitive and specific. Serodiagnosis is

retrospective, requiring a fourfold increase in A. phagocytophilum antibody titer (to ≥128) in paired serum samples obtained 1 month apart.

Since seroprevalence is high in some regions, a single acute-phase titer

should not be used for diagnosis.

Anaplasma capra Infection Human infection by A. capra, first

isolated from goat blood, was identified in 28 patients from northeastern China. Patients presented with fever, headache, malaise, dizziness,

myalgias, and chills, but these manifestations were less severe than

in HGA. Hospitalization was recorded for 18% of patients, and 14%

had underlying disorders, including hyperglycemia, hypertension,

coronary heart disease, diabetes, and cancer. Five patients had severe

manifestations, including one with encephalitic signs and A. capra

DNA present in CSF. A. capra is found most often in I. persulcatus

ticks in this region. All patients responded to doxycycline treatment

and survived.

TREATMENT

Human Granulocytotropic Anaplasmosis

No prospective studies of therapy for HGA have been conducted.

However, doxycycline (100 mg PO twice daily) is effective. Rifampin

therapy is associated with improvement of HGA in pregnant women

and children. Most treated patients defervesce within 24–48 h.

Prevention HGA prevention requires tick avoidance. Transmission

can be documented as few as 4 h after a tick bite.

Q FEVER

The agent of Q fever is C. burnetii, a small pleomorphic coccobacillus

with a gram-negative cell wall, that was first isolated in 1935 and called

a rickettsia due to its presence in ticks, intracellular replication, small

size, and staining characteristics, but it is now known to be genetically

quite distinct from Rickettsiaceae and to have a number of unique

features. It survives in harsh environments, escapes intracellular killing

in macrophages by inhibiting the final step in phagosome maturation,

and has adapted to the acidic phagolysosome.

Epidemiology Q fever is a zoonosis: transmission of C. burnetii

to humans typically occurs by inhalation after it has been shed by

animals. The primary sources of human infection are infected cattle,

sheep, and goats. At parturition, when large amounts of C. burnetii are

present in the fetus, placenta, membranes, and fluids, the bacterium

readily contaminates the environment. Smaller amounts can be shed

in milk, urine, and feces. Once shed, C. burnetii can remain viable in

manure, hay, soil, etc., for many years after which it can be aerosolized

and inhaled, even after traveling miles from the source by wind. A

variety of other vertebrate animals can be hosts of C. burnetii, including

birds, cats, dogs, rabbits, skunks, raccoons, deer, bears, sloths, kangaroos, and marine animals. C. burnetii has also been found in several

tick species, which could be important for maintenance of the agent

1439CHAPTER 187 Rickettsial Diseases

in veterinary populations, but the majority of human Q fever cases are

associated with aerosol transmission from infected livestock. Infections in animals are usually asymptomatic, but abortions and stillbirth

have been observed in pregnant goats and sheep. Because it is easily

dispersed as an aerosol and because of the extremely low infectious

dose required for human infection (probably between 1 and 10 viable

bacteria), C. burnetii is a potential agent of bioterrorism (Chap. S3),

with a high infectivity rate and pneumonia as the major manifestation.

Persons at risk for Q fever include abattoir workers, veterinarians,

farmers, and other individuals who have contact with infected animals

(particularly newborn animals). In Canada and the Netherlands, 65%

and 72%, respectively, of persons living and/or working on dairy cattle

farms were seropositive, and in the United States, 22% of veterinarians

were seropositive, compared to ~3% of the population overall. The

organism is shed in milk for weeks to months after parturition. An

outbreak of Q fever associated with ingestion of raw milk confirmed

the oral route of transmission, although this route is uncommon. In

rare instances, person-to-person transmission follows labor and childbirth in an infected woman, autopsy of an infected individual, or blood

transfusion. Multiple outbreaks involving laboratory staff have been

reported in the past. Some evidence suggests that C. burnetii can be sexually transmitted among humans. Some unusual modes of C. burnetii

transmission to humans include treatment with live fetal sheep cells,

which was responsible for cases in six persons in Germany, and percutaneous infection after crushing an infected tick between the fingers.

Infections due to C. burnetii occur in most geographic locations

except New Zealand and Antarctica. Several factors influence the epidemiology: environmental conditions such as high concentrations of

animals, high animal pregnancy rates, dry weather, and the strength

and direction of winds. In addition to differences between strains of

C. burnetii, the inherent variability in human susceptibility to C. burnetii

can influence transmission and development of disease. Some people

become sick after exposure, whereas others have only mild symptoms

that are not sufficient to lead them to seek medical assistance, and ~60%

have asymptomatic seroconversion. Q fever continues to be endemic

in Australia and France. In Cayenne, French Guiana, Q fever is hyperendemic: 40% of all community-acquired pneumonias are caused by

C. burnetii. The largest known outbreak occurred between 2007 and

2010 in the Netherlands. Over 4000 cases were reported, and over

40,000 people were infected. The outbreak was due to a combination

of high-density goat farming in areas with large urban populations and

environmental factors. Farms where spread did not occur had high

vegetation density and lower groundwater concentrations.

Young age seems to be protective against disease caused by

C. burnetii. In a large outbreak in Switzerland, symptomatic infection

occurred five times more often among persons >15 years of age than

among younger individuals. In many outbreaks, men are affected more

commonly than women.

Clinical Manifestations •  ACUTE Q FEVER The incubation

period is 3–30 days. The primary manifestations of acute Q fever differ

geographically. During the Dutch outbreak, but also in Canada and

Croatia, pneumonia is the more common presentation. In some countries where Q fever is endemic, such as France and Israel, hepatitis is

more common. These differences could reflect the route of infection

(i.e., ingestion of contaminated milk for hepatitis and inhalation of

contaminated aerosols for pneumonia) or strain differences. In the

Dutch outbreak, sequelae of infection in pregnant women were rare;

this was not the case among pregnant women elsewhere. Pericarditis, myocarditis, acalculous cholecystitis, pancreatitis, lymphadenitis,

spontaneous rupture of the spleen, transient hypoplastic anemia,

hemolytic anemia, hemophagocytic lymphohistiocytosis, optic neuritis, and erythema nodosum are less common manifestations.

The symptoms of acute Q fever are nonspecific; common among

them are fever, extreme fatigue, photophobia, and severe headache that

is frequently retro-orbital. Other symptoms include chills, sweats, nausea, vomiting, and diarrhea. Cough develops in about half of patients

with Q fever pneumonia. A nonspecific rash may be evident in 4–18%

of patients. The WBC count is usually normal. Thrombocytopenia

occurs in ~25% of patients, and reactive thrombocytosis frequently

develops during recovery. Biochemical markers of autoimmunity, such

as anticytoplasmic antibodies (ANCA), antinuclear antibodies (ANA),

anti–smooth muscle antibodies, or antiphospholipid antibodies, are

often present in acute Q fever. Chest radiography can show opacities

similar to those seen in pneumonia caused by other pathogens.

Acute Q fever occasionally complicates pregnancy. In one series, it

resulted in premature birth in 35% of cases and in abortion or neonatal death in 43%. Neonatal death and lower infant birth weight are

reported up to three times more often among women seropositive for

C. burnetii in some areas but not others.

Q FEVER FATIGUE SYNDROME Prolonged fatigue follows Q fever in up

to 20% of cases and can be accompanied by a constellation of symptoms, including headaches, sweats, arthralgia, and myalgias. Several

hypotheses regarding the etiology exist, including biopsychological

etiology with C. burnetii acting as trigger for fatigue development,

host and genetic factors, and cytokine dysregulation. A randomized

controlled trial including 155 patients with strictly diagnosed Q fever

fatigue syndrome showed that long-term treatment with doxycycline

did not reduce fatigue severity compared to placebo, so antibiotics

should not be prescribed for these patients. Cognitive behavioral

therapy aimed at fatigue-related cognitions and behaviors thought to

perpetuate symptoms was effective in reducing fatigue severity in the

short term. The beneficial effect of this treatment, however, was not

maintained after 1 year.

CHRONIC Q FEVER Although it has recently been proposed that this

entity be renamed persistent Q fever, we prefer the term chronic Q fever.

Following primary infection, 1−5% of all patients develop chronic Q

fever. Chronic Q fever endocarditis, infected aneurysms, or infected

vascular prostheses are most frequently observed. The primary infection often has not been recognized or was asymptomatic, and the duration between primary infection and manifestation of chronic infection

may be several years. The largest observed interval between acute

infection and diagnosis of chronic Q fever was >9 years. Risk factors for

the development of chronic Q fever include valvulopathy or prior valve

surgery, aneurysms, vascular prostheses, renal insufficiency, older age,

immunocompromised state, and malignancy. Diagnosing chronic Q

fever is difficult, as patients often present with nonspecific symptoms,

such as fever, night sweats, weight loss, fatigue, and malaise. Fever can

be absent and is frequently low grade. C-reactive protein is often low

or even normal. Chronic Q fever endocarditis differs from endocarditis

caused by other bacteria, manifesting as endothelium-covered nodules

on the valves, aortic root abscess, or new or rapidly increasing valve

insufficiency. A high index of suspicion is necessary for timely diagnosis. Patients with chronic Q fever are often ill for >1 year before the

diagnosis is made. The disease should be suspected in all patients with

culture-negative endocarditis. In addition, all patients with valvular

heart disease, an aneurysm or vascular prosthesis and unexplained

weight loss, fever, stroke, unexpected aneurysm growth, and/or progressive heart failure should be tested for C. burnetii infection. Other

manifestations of chronic Q fever include lymphadenitis and bone

infection including vertebral osteomyelitis and prosthetic joint infection. Of 249 patients with proven chronic Q fever in the Netherlands,

61% developed complications. The most frequently observed complications were acute aneurysms, heart failure, and noncardiac abscesses.

One in six patients with vascular chronic Q fever develops arterial

fistula, including aortoenteric fistula, aortocaval fistula, aortobronchial

fistula, and arteriocutaneous fistula. PCR positivity at any time during

the disease, presence of prosthetic material, and older age were associated with complications. Q fever–related mortality was 25% in patients

diagnosed with chronic Q fever after the Dutch outbreak. Chronic Q

fever–related mortality was highest in patients with both endocarditis

and vascular infection (33%), followed by patients with vascular infection only (25%), and was lowest in endocarditis patients (12%).

Diagnosis Culture of C. burnetii from buffy-coat blood samples or

tissue specimens is possible but requires a biosafety level 3 laboratory

and is not used in clinical practice. PCR detects C. burnetii DNA in

1440 PART 5 Infectious Diseases

blood and tissue specimens, including paraffin-embedded samples.

The detection of antibodies to C. burnetii is the most commonly used

method for the diagnosis of Q fever. Available serologic assays are

indirect fluorescent antibody (IFA) assay, enzyme-linked immunosorbent assay (ELISA), and complement fixation test (CFT), with IFA

being the gold standard. IFA tests are useful for the detection of and

discrimination between acute and chronic infection and have excellent

sensitivity and specificity. The diagnosis of acute Q fever is dependent

on seroconversion, defined as a fourfold increase in IgG titer for phase

II antigens between acute- and convalescent-phase samples. In the first

1−2 weeks of illness, PCR on blood or serum can also be positive. A

high phase I IgG titer (e.g., >512) is suggestive of chronic Q fever, but

alone, it is not enough for a definite diagnosis. A positive PCR for C.

burnetii in blood or tissue in the absence of an acute infection confirms

the diagnosis, but PCR on blood is negative in the majority of patients

and tissue samples are often very difficult to obtain. The diagnosis of

chronic Q fever should be based on a combination of clinical, laboratory, and imaging criteria. There has been debate on the optimal

set of criteria, but the Dutch literature-based consensus guideline

(Table 187-2) appears to be the most sensitive and is easy to use.

Valvular vegetations are detected in only 12% of patients with Q

fever endocarditis by transthoracic echocardiography, but the rate of

detection is higher (21–50%) with transesophageal echocardiography.

Fluorodeoxyglucose positron emission tomography combined with CT

(FDG-PET/CT) can detect not only prosthetic valvular infection but

also intravascular infection elsewhere, osteomyelitis, and lymphadenitis.

In native valve endocarditis, specificity is very high but sensitivity is low,

so a normal FDG-PET/CT scan cannot exclude native valve endocarditis. A study including 273 FDG-PET/CT scans performed at diagnosis

in patients suspected of chronic Q fever showed that, even after serology, PCR, and often ultrasound or CT had been performed, FDG-PET/

CT led to a change in diagnosis or treatment in 20% of patients. Adding

FDG uptake in a heart valve as a major criterion to the Duke criteria led

to a 1.9-fold increase of definite endocarditis diagnoses. Of 218 scans

performed during follow-up, 57% resulted in treatment adjustment. In

case of suspected chronic Q fever, FDG-PET/CT should be considered.

TREATMENT

Q Fever

ANTIBIOTICS

In vitro, C. burnetii is susceptible to doxycycline, quinolones,

trimethoprim-sulfamethoxazole (TMP-SMX), macrolides, and

rifampin. Although antimicrobial susceptibility testing is not routinely performed and resistance to doxycycline does not appear to

be a common problem in clinical practice, doxycycline-resistant

isolates do exist.

Treatment of acute Q fever with doxycycline (100 mg twice daily

for 14 days) is usually successful. Quinolones also are effective.

When Q fever is diagnosed during pregnancy, treatment with TMPSMX is recommended for the duration of the pregnancy.

Treatment with doxycycline and hydroxychloroquine for

6−12 months following acute infection should be considered in

patients with valve abnormalities, a prosthetic heart valve, an aneurysm, or vascular prosthesis. This appeared to be effective in preventing progression to chronic Q fever in patients with valvulopathy.

The exact indications and duration of prophylaxis should be based

on a careful consideration of possible benefits and side effects.

Decisions on treatment of chronic Q fever are challenging, so

consultation with an infectious diseases expert is recommended.

There is no indication for antibiotic therapy in those with possible

chronic Q fever (only elevated phase I IgG without symptoms or

an infectious focus). Addition of hydroxychloroquine (to alkalinize the phagolysosome) renders doxycycline bactericidal against

C. burnetii, and the combination of doxycycline 100 mg twice daily

with 200 mg hydroxychloroquine three times daily is currently the

favored regimen. It is advised to determine serum levels of doxycycline aiming for concentrations between 5 and 10 mg/L. Patients

treated with this regimen must be advised about photosensitivity

and retinal toxicity risks; however, side effects should not lead to

cessation of therapy too easily since it appears to be the most effective approach for this serious infection that has a high mortality

despite treatment. Patients treated with hydroxychloroquine are at

risk for developing retinopathy, so they should be evaluated by an

ophthalmologist before starting treatment and every 6−12 months

during the course of therapy. If doxycycline-hydroxychloroquine

cannot be used, the regimen chosen should include at least two

antibiotics active against C. burnetii. In a study including 322

patients with chronic Q fever, treatment with doxycycline combined with a quinolone appeared to be a safe alternative.

Minimum treatment duration is 18 months for native valve

endocarditis and other manifestations without prosthetic material

and 24 months for patients with prosthetic valve endocarditis or

infected vascular prostheses. Many patients with vascular infection

need prolonged treatment before the infection resolves, and surgical intervention is often necessary to remove an infected graft if

the patient does not respond to antibiotic therapy. Abscesses need

drainage for antibiotic therapy to be successful. A fourfold decrease

in phase I IgG and the disappearance of phase II IgM was found to

be a favorable prognostic indicator for patients with Q fever endocarditis, but defining cure of chronic Q fever after the minimum

treatment duration should be based on a combination of imaging (if

abnormal at diagnosis), decline of serologic titers, negativity of PCR

on blood or serum, and improvement of symptoms.

FOLLOW-UP

After acute Q fever, patients without risk factors for developing

chronic Q fever should be evaluated clinically and serologically

after 6 months. When IgG phase I is <1024 and clinical symptoms

TABLE 187-2 Diagnostic Criteria for Chronic Q Fever as Defined by the

Dutch Q Fever Consensus Group

PROVEN CHRONIC

Q FEVER

PROBABLE CHRONIC

Q FEVER

POSSIBLE CHRONIC

Q FEVER

1. Positive Coxiella

burnetii PCR in blood

or tissuea

OR

2. IFA ≥1:800 or 1:1024 for

C. burnetii phase I IgG

AND

Definite endocarditis

according to the modified

Duke criteria

OR

Proven large vessel or

prosthetic infection by

imaging studies (18FDGPET, CT, MRI, or AUS)

IFA ≥1:800 or 1:1024 for

C. burnetii phase I IgG

AND AT LEAST ONE OF

THE FOLLOWING:

Valvulopathy not meeting

the major criteria of the

modified Duke criteria

Known aneurysm and/or

vascular or cardiac valve

prosthesis without signs

of infection by means of

TEE/TTE, 18FDG-PET, CT,

MRI, or AUS

Suspected osteomyelitis

or hepatitis as

manifestation of chronic

Q fever

Pregnancy

Symptoms and signs

of chronic infection,

such as fever, weight

loss, night sweats,

hepatosplenomegaly, and

persistently raised ESR

and CRP

Granulomatous tissue

inflammation, proven by

histologic examination

Immunocompromised

state

IFA ≥1:800 or 1:1024 for

C. burnetii phase I IgG

without manifestations

meeting the criteria

for proven or probable

chronic Q fever

a

In absence of acute infection.

Abbreviations: AUS, abdominal ultrasound; CRP, C-reactive protein; 18FDG-PET,

fluorodeoxyglucose positron emission tomography; ESR, erythrocyte sedimentation

rate; IFA, indirect fluorescent antibody assay; PCR, polymerase chain reaction; TEE,

transesophageal echocardiography; TTE, transthoracic echocardiography.

1441CHAPTER 188 Infections Due to Mycoplasmas

do not suggest chronic infection, follow-up can be stopped. For

patients with a very high risk of developing chronic Q fever who

have received antibiotics for 6−12 months or patients with immunosuppression or other risk factors not treated with antibiotics

for a prolonged period of time, follow-up with serology and PCR

every 3−6 months for 2 years is recommended. During treatment

of chronic Q fever, patients should be followed every 3 months to

evaluate symptoms, side effects, serology, and PCR. When new

complications are suspected, imaging should be repeated. After the

end of treatment, relapse has been described up to 5 years later. It is

therefore recommended to continue monitoring with serology and

PCR until a minimum of 5 years after end of treatment.

Prevention A whole-cell vaccine (Q-Vax) licensed in Australia

effectively prevents Q fever in abattoir workers. Vaccine is given only

to people without a history of Q fever and negative results in both

serologic and skin testing that is performed with intradermal diluted

C. burnetii vaccine. Cases among abattoir workers in Australia declined

dramatically as a result of a vaccination program.

Good animal-husbandry practices are important in preventing

widespread contamination of the environment by C. burnetii. These

practices include isolating aborting animals for up to 14 days, raising

feed bunks to prevent contamination of feed by excreta, destroying

aborted materials (by burning and burying fetal membranes and stillborn animals), and wearing masks and gloves when handling aborted

materials. Vaccination of sheep and goats and a culling program were

effective in the Netherlands outbreak.

During an outbreak of Q fever and for 4 weeks after it ceases, blood

donations should not be accepted from individuals who live in the

affected area.

Acknowledgment

The authors thank Thomas Marrie, MD, for his significant contributions

to this chapter in the previous editions.

■ FURTHER READING

Biggs HM et al: Diagnosis and management of tickborne rickettsial

diseases: Rocky Mountain spotted fever and other spotted fever group

rickettsioses, ehrlichioses, and anaplasmosis—United States. MMWR

65:1, 2016.

Eldin C et al: From Q fever to Coxiella burnetii infection: A paradigm

change. Clin Microbiol Rev 30:115, 2017.

Ismail N, Mcbride JW: Tick-borne emerging infections: Ehrlichiosis

and anaplasmosis. Clin Lab Med 37:317, 2017.

Straily A et al: Antibody titers reactive with Rickettsia rickettsii in

blood donors and implications for surveillance of spotted fever rickettsiosis in the United States. J Infect Dis 221:1371, 2020.

Weitzel T et al: Scrub typhus in continental Chile, 2016-2018. Emerg

Infect Dis 25:1214, 2019.

Mycoplasmas are prokaryotes of the class Mollicutes. Their size

(150–350 nm) is closer to that of viruses than to that of typical bacteria. Unlike viruses, however, mycoplasmas grow in cell-free culture

media; in fact, they are the smallest organisms capable of independent

replication.

The entire genomes of many Mycoplasma species have been

sequenced and have been found to be among the smallest of all

prokaryotic genomes. Sequencing information for these genomes

188 Infections Due to

Mycoplasmas

R. Doug Hardy

has helped define the minimal set of genes necessary for cellular life.

The absence of genes related to the synthesis of amino acids, fatty acid

metabolism, and cholesterol dictates the mycoplasmas’ parasitic or

saprophytic dependence on a host for exogenous nutrients and necessitates the use of complex fastidious media to culture these organisms.

Mycoplasmas lack a cell wall and are bound only by a cell membrane.

The absence of a cell wall explains the inactivity of β-lactam antibiotics

(penicillins and cephalosporins) against infections caused by these

organisms.

At least 13 Mycoplasma species, 2 Acholeplasma species, and 2 Ureaplasma species have been isolated from humans. Most of these species

are thought to be normal inhabitants of oral and urogenital mucous

membranes. M. pneumoniae, M. hominis, M. genitalium, U. urealyticum, and U. parvum have been shown conclusively to be pathogenic

in immunocompetent humans. M. pneumoniae primarily infects the

respiratory tract, while M. hominis, M. genitalium, U. urealyticum, and

U. parvum are associated with a variety of genitourinary tract disorders

and neonatal infections. Other mycoplasmas may cause disease in

immunocompromised persons.

MYCOPLASMA PNEUMONIAE

■ PATHOGENESIS

M. pneumoniae is generally thought to act as an extracellular pathogen.

Although the organism has been shown to exist and replicate within

human cells, it is not known whether these intracellular events contribute to the pathogenesis of disease. M. pneumoniae attaches to ciliated

respiratory epithelial cells by means of a complex terminal organelle

at the tip of one end of the organism. Cytoadherence is mediated by

interactive adhesins and accessory proteins clustered on this organelle.

After extracellular attachment, M. pneumoniae causes injury to host

respiratory tissue. The mechanism of injury is thought to be mediated

by the production of hydrogen peroxide and of an ADP-ribosylating

and vacuolating cytotoxin of M. pneumoniae that has many similarities

to pertussis toxin. Because mycoplasmas lack a cell wall, they also lack

cell wall–derived stimulators of the innate immune system, such as

lipopolysaccharide, lipoteichoic acid, and murein (peptidoglycan) fragments. However, lipoproteins from the mycoplasmal cell membrane

appear to have inflammatory properties, probably acting through

Toll-like receptors (primarily TLR2) on macrophages and other cells.

Lung biopsy specimens from patients with M. pneumoniae respiratory

tract infection reveal an inflammatory process involving the trachea,

bronchioles, and peribronchial tissue, with a monocytic infiltrate that

coincides with a luminal exudate of polymorphonuclear leukocytes.

Experimental evidence indicates that innate immunity provides

most of the host’s defense against mycoplasmal infection in the lungs,

whereas cellular immunity may actually play an immunopathogenic

role, exacerbating mycoplasmal lung disease. Humoral immunity

appears to provide protection against dissemination of M. pneumoniae

infection; patients with humoral immunodeficiencies do not have

more severe lung disease than do immunocompetent patients in the

early stages of infection but more often develop disseminated infection

resulting in syndromes such as arthritis, meningitis, and osteomyelitis.

The immunity that follows severe M. pneumoniae infections is more

protective and longer-lasting than that following mild infections. Genuine second attacks of M. pneumoniae pneumonia have been reported

infrequently.

■ EPIDEMIOLOGY

M. pneumoniae infection occurs worldwide. It is likely that the incidence

of upper respiratory illness due to M. pneumoniae is up to 20 times

that of pneumonia caused by this organism. Infection is spread from

one person to another by respiratory droplets expectorated during

coughing and results in clinically apparent disease in an estimated

80% of cases. The incubation period for M. pneumoniae is 2–4 weeks;

therefore, the time-course of infection in a specific population may be

several weeks long. Intrafamilial attack rates are as high as 84% among

children and 41% among adults. Outbreaks of M. pneumoniae illness

often occur in institutional settings such as military bases, boarding