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192 Rickettsial Diseases

■ ■FURTHER READING Arvikar SL, Steere AC: Diagnosis and treatment of Lyme arthritis.

Infect Dis Clin North Am 36:563, 2022. Aucott JN: Posttreatment Lyme disease syndrome. Infect Dis Clin North Am 29:309, 2015. Branda JA, Steere AC: Laboratory diagnosis of Lyme borreliosis. Clin Micro Rev 34:e00018, 2021. Branda JA et al: Two-tiered antibody testing for Lyme disease with use of 2 enzyme immunoassays, a whole-cell sonicate enzyme immu­ noassay followed by a VlsE C6 peptide enzyme immunoassay. Clin Infect Dis 53:541, 2011. Klempner MS et al: Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 345:85, 2001. Lantos PM et al: Clinical practice guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology, and the American College of Rheumatology (ACR): 2020 guidelines for the prevention, diagnosis, and treatment of Lyme disease. Clin Infect Dis 72:1, 2021. Lemieux JE et al: Whole genome sequencing of human Borrelia burg­ dorferi isolates reveals linked blocks of accessory genome elements located on plasmids and associated with human dissemination. PLoS Pathog 17:e1011243, 2023. Li X et al: Burden and viability of Borrelia burgdorferi in skin or joints of patients with erythema migrans or Lyme arthritis. Arthritis Rheum 63:2238, 2011. Lochhead RB et al: Lyme arthritis, linking infection, inflammation, and autoimmunity. Nat Rev Rheumatol 17:449, 2021. Oschmann P et al: Stages and syndromes of neuroborreliosis. J Neurol PART 5 Infectious Diseases 245:262, 1998. Steere AC: Lyme disease. N Engl J Med 345:115, 2001. Steere AC: Posttreatment Lyme disease syndromes: Distinct pathogenesis caused by maladaptive host responses. J Clin Invest 130:2148, 2020. Steere AC et al: Prospective study of serologic tests for Lyme disease. Clin Infect Dis 47:188, 2008. Steere AC et al: Lyme borreliosis. Nat Rev Dis Primers 2:16090, 2016. Ursinus J et al: Prevalence of persistent symptoms after treatment for Lyme borreliosis: A prospective observational cohort study. Lancet Reg Health Eur 6:100142, 2021. Erratum in: Lancet Reg Health Eur 27:100622, 2023. Section 10 Diseases Caused by Rickettsiae, Mycoplasmas, and Chlamydiae David H. Walker, J. Stephen Dumler,

Lucas S. Blanton, Chantal P. Rovers

Rickettsial Diseases Rickettsiae are a heterogeneous group of small, obligately intracel­ lular, gram-negative coccobacilli and short bacilli, most of which are transmitted by a tick, mite, flea, or louse vector. Except in the case of louse-borne typhus, humans are incidental hosts. Among rickettsiae, Coxiella burnetii, Rickettsia prowazekii, and Rickettsia typhi have the well-documented ability to survive for an extended period outside the reservoir or vector and to be extremely infectious: inhalation of a single Coxiella microorganism can cause pneumonia. High-level infectivity and severe illness after inhalation make R. prowazekii, R. rickettsii, R. typhi, R. conorii, and C. burnetii bioterrorism threats (Chap. S4). Clinical infections with rickettsiae can be classified according to (1) the taxonomy and diverse microbial characteristics of the agents, which

belong to seven genera (Rickettsia, Orientia, Ehrlichia, Anaplasma, Neor­ ickettsia, “Candidatus Neoehrlichia,” and Coxiella); (2) epidemiology; or (3) clinical manifestations. The clinical manifestations of all the acute presentations are similar during the first 5 days: fever, headache, and myalgias with or without nausea, vomiting, and cough. As the course progresses, clinical manifestations—including a macular, maculopapu­ lar, or vesicular rash; eschar; pneumonitis; and meningoencephalitis— vary from one disease to another. Given the many etiologic agents with varied mechanisms of transmission, geographic distributions, and asso­ ciated disease manifestations, the consideration of rickettsial diseases as a single entity poses complex challenges (Table 192-1). Establishing the etiologic diagnosis of rickettsioses is very diffi­ cult during the acute stage of illness, and definitive diagnosis usually requires the examination of serum samples during the acute and con­ valescent phases of illness. Heightened clinical suspicion is based on epidemiologic data, history of exposure to vectors or reservoir animals, travel to endemic locations, clinical manifestations (sometimes includ­ ing rash or eschar), and characteristic laboratory findings (including thrombocytopenia, normal or low white blood cell [WBC] counts, elevated hepatic enzyme levels, and hyponatremia). Such suspicion should prompt empirical treatment. Doxycycline is the empirical drug of choice for most of these infections. Only one agent, C. burnetii, has been documented to cause chronic illness. One other species, R. prowazekii, causes recrudescent illness (Brill-Zinsser disease) when latent infection is reactivated years after resolution of the acute illness. Rickettsial infections dominated by fever may resolve without fur­ ther clinical evolution. However, after nonspecific early manifestations, the illnesses can also evolve along one or more of several principal clinical lines: (1) development of a macular or maculopapular rash; (2) development of an eschar at the site of tick or mite feeding, which can occur during the incubation period; (3) development of a vesicular rash (often in rickettsialpox, R. parkeri infection, and African tick-bite fever); (4) development of pneumonitis with chest radiographic opaci­ ties and/or rales (Q fever and severe cases of Rocky Mountain spotted fever [RMSF], Mediterranean spotted fever [MSF], louse-borne typhus, human monocytotropic ehrlichiosis [HME], human granulocytotropic anaplasmosis [HGA], scrub typhus, and murine typhus); (5) develop­ ment of meningoencephalitis (louse-borne typhus and severe cases of RMSF, scrub typhus, HME, murine typhus, MSF, and [rarely] Q fever); and (6) progressive hypotension and multiorgan failure as seen with sepsis or toxic shock syndromes (RMSF, MSF, louse-borne typhus, murine typhus, scrub typhus, HME, HGA, and neoehrlichiosis). Epidemiologic clues to the transmission of a particular pathogen include (1) environmental exposure to ticks, fleas, or mites during the season of activity of the vector species for the disease in the appropri­ ate geographic region (spotted fever and typhus rickettsioses, scrub typhus, ehrlichiosis, anaplasmosis); (2) travel to or residence in an endemic geographic region during the incubation period (Table 192-1); (3) exposure to parturient ruminants, cats, and dogs (Q fever); (4) exposure to flying squirrels (R. prowazekii infection); and (5) history of previous louse-borne typhus (recrudescent typhus). Clinical laboratory findings such as thrombocytopenia (particularly in spotted fever and typhus rickettsioses, ehrlichiosis, anaplasmosis, and scrub typhus), normal or low WBC counts, mild to moderate serum elevations of hepatic aminotransferases, and hyponatremia sug­ gest some common pathophysiologic mechanisms. Application of these clinical, epidemiologic, and laboratory prin­ ciples requires consideration of a rickettsial diagnosis and knowledge of the individual diseases. TICK-, MITE-, LOUSE-, AND FLEA-BORNE RICKETTSIOSES These diseases, caused by organisms of the genera Rickettsia and Ori­ entia in the family Rickettsiaceae, result from endothelial cell infection and increased vascular permeability. Pathogenic rickettsial species are very closely related, have small genomes (as a result of reductive evolu­ tion, which eliminated many genes for biosynthesis of intracellularly available molecules), and are traditionally separated into typhus and spotted fever groups on the basis of lipopolysaccharide antigens. Some

TABLE 192-1  Features of Selected Rickettsial Infections DISEASE ORGANISM TRANSMISSION Rocky Mountain spotted fever (RMSF) Rickettsia rickettsii Tick bite: Dermacentor andersoni, D. variabilis,

D. similis Amblyomma cajennense,

A sculptum, A. patinoi,

A. mixtum, A. aureolatum Rhipicephalus sanguineus Mexico, South America, United States Mediterranean spotted fever (MSF) R. conorii Tick bite: R. sanguineus,

R. pumilio African tick-bite fever R. africae Tick bite: A. hebraeum,

A. variegatum Maculatum disease R. parkeri Tick bite: A. maculatum,

A. triste, A. tigrinum, A. ovale Pacific Coast tick fever Rickettsia ssp californica Tick bite: D. occidentalis United States 3–9 5–14

+++ Rickettsialpox R. akari Mite bite: Liponyssoides sanguineus Tick-borne lymphadenopathy R. slovaca,

R. raoultii Tick bite: D. marginatus,

D. reticularis Flea-borne spotted fever R. felis Flea (mechanism undetermined): Ctenocephalides felis Epidemic typhus R. prowazekii Louse feces: Pediculus humanus humanus, fleas and lice of flying squirrels, or recrudescence Murine typhus R. typhi Flea feces: Xenopsylla cheopis, C. felis, others Human monocytotropic ehrlichiosis (HME) Ehrlichia chaffeensis Tick bite: A. americanum, D. variabilis Ewingii ehrlichiosis E. ewingii Tick bite: A. americanum United States 1–21 4–21

None   Unnamed ehrlichiosis E. muris ssp. eauclairensis Tick bite: Ixodes scapularis United States Unknown 3–14

None   Human granulocytotropic anaplasmosis (HGA) Anaplasma phagocytophilum Tick bite: I. scapularis, I. ricinus, I. pacificus, I. persulcatus, Haemaphysalis concinna Unnamed disease A. capra I. persulcatus Northeastern China, France Neoehrlichiosis “Candidatus Neoehrlichia mikurensis” Tick bite: I. ricinus, I. persulcatus, Haemaphysalis concinna Scrub typhus Orientia tsutsugamushi Mite bite: Leptotrombidium deliense, others O. chuto Mite bite Africa and Western Asia Candidatus O. chiloensis Mite bite Chile Q fever Coxiella burnetii Inhalation of aerosols of infected parturition material (goats, sheep, cattle, cats, others), ingestion of infected milk or milk products a++++, severe; +++, marked; ++, moderate; +, present in a small proportion of cases; —, not a noted feature.

GEOGRAPHIC RANGE INCUBATION PERIOD, DAYS DURATION, DAYS RASH, % ESCHAR, % LYMPHADENOPATHYa United States 2–14 10–20

<1 + Central/

South America Southern Europe, Africa, Middle East, central Asia 5–7 7–14

Sub-Saharan Africa, West Indies 4–10 4–19

+++ United States, South America 2–10 6–16

++ United States, Ukraine, Turkey, Mexico, Croatia 10–17 3–11

+++ Europe 7–9 17–180

++++ CHAPTER 192 Worldwide 8–16 8–16

— Worldwide 7–14 10–18

None — Rickettsial Diseases Worldwide 8–16 9–18

None — United States 1–21 3–21

None ++ United States, Europe, Asia 4–8 3–14 Rare None — Unknown 11–21

Europe, China ≥8 11–75

None   Asia, Australia, Pacific and Indian Ocean islands 9–18 6–21

+++ Worldwide except New Zealand, Antarctica 3–30 5–57 4–18% None —

diseases and their agents (e.g., R. africae, R. parkeri, and R. sibirica) are too similar to require separate descriptions. Indeed, the similarities among MSF (R. conorii [all strains] and R. massiliae), North Asian tick typhus (R. sibirica), Japanese spotted fever (R. japonica), and Flinders Island spotted fever (R. honei) far outweigh their minor variations. The Rickettsiaceae that cause life-threatening infections are, in order of decreasing case–fatality rate, R. rickettsii (RMSF); R. prowazekii (louse-borne typhus); Orientia tsutsugamushi (scrub typhus); R. cono­ rii (MSF); R. typhi (murine typhus); and, in rare cases, other spotted fever–group (SFG) organisms. Some agents (e.g., R. parkeri, R. africae, Rickettsia 364D, R. akari, R. slovaca, R. honei, R. felis, R. massiliae,

R. helvetica, R. heilongjiangensis, R. aeschlimannii, and R. monacensis) have never been documented to cause a fatal illness. The most preva­ lent SFG rickettsia in the United States, R. amblyommatis, has been circumstantially associated with asymptomatic seroconversion in most persons and with self-limited illness in others.

■ ■ROCKY MOUNTAIN SPOTTED FEVER Epidemiology  RMSF occurs in 47 states (with the highest preva­ lence in the south-central and southeastern states) as well as in Canada, Mexico, and Central and South America. The infection is transmit­ ted by Dermacentor variabilis, the American dog tick, in the eastern two-thirds of the United States; by D. andersoni, the Rocky Mountain wood tick, in the western United States; by D. similis in California; by Rhipicephalus sanguineus, the brown dog tick, in Mexico, Arizona, and probably Colombia; and by Amblyomma sculptum, A. mixtum, A. patinoi, A. cajennense, A. tonelliae, and A. aureolatum in Central and/ or South America. Maintained partially by transovarian transmission from one generation of ticks to the next, R. rickettsii can be acquired by uninfected ticks through the ingestion of a blood meal from rick­ ettsemic small mammals or by co-feeding adjacent to an infected tick. PART 5 Infectious Diseases Humans become infected during tick season (in the Northern Hemisphere, from April to September), although some cases occur in winter. The mortality rate was 20–25% in the preantibiotic era and has been reported at ~3–5% in the postantibiotic era, principally because of delayed diagnosis and treatment. Recent reporting of a relatively low mortality rate (0.4%) for spotted fever rickettsiosis is likely an artifact related to the abundance of less pathogenic SFG rickettsial species likely causing subclinical or undiagnosed infection with cross-reactive anti-SFG antibodies and to a relatively low proportion of diagnostically confirmed cases. Indeed, the reported case–fatality rates in confirmed cases in the United States and in parts of Arizona, where R. rickettsii is the sole infecting SFG species, are 9% and 10%, respectively. The case– fatality rate is highest among children (<10 years of age) and in the later decades of life (>70 years). For unknown reasons, the case–fatality rate of RMSF in Mexico and Brazil approaches 50%. Pathogenesis  R. rickettsii organisms are inoculated into the dermis along with secretions of the tick’s salivary glands after ≥6 h of feeding. The rickettsiae spread lymphohematogenously throughout the body and infect numerous foci of contiguous endothelial cells. The dosedependent incubation period is ~1 week (range, 2–14 days). Occlusive thrombosis and ischemic necrosis are not the fundamental pathologic bases for tissue and organ injury. Instead, increased vascular perme­ ability, with resulting edema, hypovolemia, and ischemia, is responsible. Consumption of platelets results in thrombocytopenia in 32–52% of patients, but disseminated intravascular coagulation (DIC) with hypofi­ brinogenemia is rare. Activation of platelets, generation of thrombin, and activation of the fibrinolytic system all appear to be homeostatic physi­ ologic responses to endothelial injury by nonocclusive hemostatic plugs. Clinical Manifestations  Early in the illness, when medical atten­ tion usually is first sought, RMSF is difficult to distinguish from many self-limiting viral illnesses. Fever, headache, malaise, myalgia, nausea, vomiting, and anorexia are the most common symptoms during the first 3 days. The patient becomes progressively more ill as vascular infec­ tion and injury advance. In one large series, only one-third of patients were diagnosed with presumptive RMSF early in the clinical course and treated appropriately as outpatients. In the tertiary-care setting, RMSF is

all too often recognized only when late severe manifestations, develop­ ing at the end of the first week or during the second week of illness in patients without appropriate treatment, prompt return to a physician or hospital and admission to an intensive care unit. The progressive nature of the infection is clearly manifested in the skin. Rash is evident in only 14% of patients on the first day of illness and in only 49% during the first 3 days. Erythematous macules (1–5 mm) appear first on the wrists and ankles and then on the remainder of the extremities and the trunk. Later, more severe vascular damage results in frank hemor­ rhage at the center of the maculopapule, producing a petechia that does not disappear upon compression (Fig. 192-1). This sequence of events is sometimes delayed or aborted by effective treatment. However, the rash is a variable manifestation, appearing on day 6 or later in 20% of cases and not appearing at all in ~10% of cases. Petechiae occur in 41–59% of cases, appearing on or after day 6 in 74% of cases that manifest a rash. Involve­ ment of the palms and soles, often considered diagnostically important, usually develops relatively late in the course (after day 5 in 43% of cases) and does not develop at all in 18–64% of cases. Hypovolemia leads to prerenal azotemia and (in 17% of cases) hypo­ tension. Infection of the pulmonary microcirculation leads to noncar­ diogenic pulmonary edema; 12% of patients have acute respiratory distress syndrome, and 8% require mechanical ventilation. Cardiac involvement manifests as dysrhythmia in 7–16% of cases. Besides respiratory failure, central nervous system (CNS) involve­ ment is the other important determinant of the outcome of RMSF. Encephalitis, presenting as confusion or lethargy, is apparent in 26–28% of cases. Progressively severe encephalitis manifests as stupor or delirium in 21–26% of cases, ataxia in 18%, coma in 10%, and sei­ zures in 8%. Numerous focal neurologic deficits have been reported. A B FIGURE 192-1  A. Petechial lesions of Rocky Mountain spotted fever on the lower legs and soles of a young, previously healthy patient. B. Close-up of lesions from the same patient. (Photos courtesy of Dr. Lindsey Baden; with permission.)

Meningoencephalitis results in cerebrospinal fluid (CSF) pleocytosis in 34–38% of cases; usually there are 10–100 cells/μL and a mono­ nuclear predominance, but occasionally there are >100 cells/μL and a polymorphonuclear predominance. The CSF protein concentration is increased in 30–35% of cases, but the CSF glucose concentration is usually normal. Acute kidney injury, often reversible with rehydration, is caused by acute tubular necrosis in severe cases with shock. Hepatic injury with increased serum aminotransferase concentrations (38% of cases) is due to multifocal death of individual hepatocytes without hepatic failure. Jaundice is recognized in 9% of cases and an elevated serum bilirubin concentration in 18–30%. Life-threatening bleeding is rare. Anemia develops in 30% of cases and is severe enough to require transfusions in 11%. Blood is detected in the stool or vomitus of 10% of patients, and death has followed mas­ sive upper-gastrointestinal hemorrhage. Other characteristic clinical laboratory findings include increased plasma levels of proteins of the acute-phase response (C-reactive pro­ tein, procalcitonin, fibrinogen, ferritin, and others), hypoalbuminemia, and hyponatremia (in 56% of cases) due to the appropriate secretion of antidiuretic hormone in response to the hypovolemic state. Myositis occurs occasionally, with marked elevations in serum creatine kinase levels and multifocal rhabdomyonecrosis. Ocular involvement includes conjunctivitis in 30% of cases and retinal vein engorgement, flame hemorrhages, arterial occlusion, and papilledema with normal CSF pressure in some instances. Severe RMSF can present as sepsis or septic shock. In untreated fatal cases, death occurs 8–15 days after onset. A rare presentation, fulmi­ nant RMSF, is fatal within 5 days after onset. This fulminant presenta­ tion is seen most often in male black patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and may be related to an undefined effect of hemolysis on the rickettsial infection. Although survivors of RMSF usually return to their previous state of health, permanent sequelae, including neurologic deficits and gangrene necessitating amputation of extremities, may follow severe illness. Diagnosis  The diagnosis of RMSF during the acute stage is more difficult than is generally appreciated. The most important epidemio­ logic factor is a history of exposure to a potentially tick-infested envi­ ronment within the 14 days preceding disease onset during a season of possible tick activity. However, only 60% of patients actually recall being bitten by a tick during the incubation period. The differential diagnosis for early clinical manifestations of RMSF (fever, headache, and myalgia without a rash) includes influenza, enteroviral infection, infectious mononucleosis, viral hepatitis, lep­ tospirosis, typhoid fever, gram-negative or gram-positive bacterial sepsis, HME, HGA, murine typhus, sylvatic flying-squirrel typhus, and rickettsialpox. Enterocolitis may be suggested by nausea, vomit­ ing, and abdominal pain; prominence of abdominal tenderness has resulted in exploratory laparotomy. CNS involvement can masquerade as bacterial or viral meningoencephalitis. Cough, pulmonary signs, and chest radiographic opacities can lead to a diagnostic consideration of bronchitis or pneumonia. At presentation during the first 3 days of illness, only 3% of patients exhibit the classic triad of fever, rash, and history of tick exposure. When a rash appears, a diagnosis of RMSF should be considered. However, many illnesses considered in the differential diagnosis also can be associ­ ated with a rash, including rubeola, rubella, meningococcemia, dissemi­ nated gonococcal infection, secondary syphilis, toxic shock syndrome, drug hypersensitivity, immune thrombocytopenic purpura, thrombotic thrombocytopenic purpura, Kawasaki syndrome, and immune complex vasculitis. Conversely, any person in an endemic area with a provisional diagnosis of one of the above illnesses could have RMSF. Thus, if a viral infection is suspected during RMSF season in an endemic area, it should always be kept in mind that RMSF can mimic viral infection early in the course; if the illness worsens over the next couple of days after initial presentation, the patient should return for reevaluation. The most common serologic test for confirmation of the diagnosis is the indirect immunofluorescence assay. Not until 7–10 days after onset

is a reactive titer of ≥64 first detectable. The sensitivity and specific­ ity of the indirect immunofluorescence IgG assay are 89–100% and 99–100%, respectively. Detection of IgM is no more sensitive in early illness and is subject to nonspecific cross-reactivity. It is important to understand that serologic tests for RMSF are usually negative at the time of presentation for medical care and that treatment should not be delayed while a positive serologic result is awaited. Because of significant seropositivity in the expanding geographic distribution of Amblyomma americanum ticks, a positive serologic titer in the first 5–6 days of illness represents preexisting antibody unrelated to the current illness.

The only diagnostic test that has proven useful during the acute ill­ ness is immunohistologic examination of a cutaneous biopsy sample from a rash lesion for R. rickettsii. Examination of a 3-mm punch biopsy from such a lesion is 70% sensitive and 100% specific, and poly­ merase chain reaction (PCR) on a rash biopsy would likely yield even higher sensitivity. PCR amplification for detection of R. rickettsii DNA in peripheral blood is not adequately sensitive. Although rickettsiae are present in large quantities in heavily infected foci of endothelial cells, there are relatively low quantities in the circulation. Cultiva­ tion of rickettsiae in cell culture is feasible but is seldom undertaken because of technical difficulty and biohazard concerns. The recent dramatic increase in the reported incidence of RMSF correlates with the use of single-titer SFG cross-reactive enzyme immunoassay serol­ ogy. Few cases are specifically determined to be caused by R. rickettsii. Currently, many febrile persons who do not have RMSF present with cross-reactive antibodies, possibly because of previous exposure to the highly prevalent SFG rickettsia R. amblyommatis. CHAPTER 192 TREATMENT Rocky Mountain Spotted Fever The drug of choice for the treatment of both children and adults with RMSF is doxycycline. Because of the severity of RMSF, imme­ diate empirical administration of doxycycline should be strongly considered for any patient with a consistent clinical presentation in the appropriate epidemiologic setting. Doxycycline is adminis­ tered orally (or, with coma or vomiting, intravenously) at 100 mg twice daily. For children with suspected RMSF, up to five courses of doxycycline may be administered with minimal risk of den­ tal staining. In patients with allergy to doxycycline, desensitiza­ tion should be considered. Once considered an alternative during pregnancy, chloramphenicol is not readily available in the United States. Although available in much of the world, it is less effective than doxycycline. Fortunately, there is little evidence to support the occurrence of tetracycline-associated adverse events in moth­ ers (hepatotoxicity) and fetuses (staining of deciduous teeth and teratogenicity) who receive doxycycline. The antirickettsial drug should be administered until the patient is afebrile and improving clinically—usually 3–5 days after defervescence. β-Lactam antibiot­ ics, erythromycin, and aminoglycosides have no role in the treat­ ment of RMSF, and sulfa-containing drugs are associated with more adverse outcomes than no treatment at all. There is little clinical experience with fluoroquinolones, clarithromycin, and azithromy­ cin, which are not recommended. The most seriously ill patients are managed in intensive care units, with careful administration of fluids to achieve optimal tissue perfusion without precipitating noncardiogenic pulmonary edema. In some severely ill patients, hypoxemia requires intubation and mechanical ventilation; oliguric or anuric acute renal failure requires renal replacement therapy; seizures necessitate the use of antiseizure medication; anemia or severe hemorrhage necessitates transfusions of packed red blood cells; or bleeding with severe thrombocytopenia requires platelet transfusions. Rickettsial Diseases Prevention  Avoidance of tick bites is the only available preventive approach. Use of protective clothing and tick repellents, inspection of the body once or twice a day, and removal of ticks before they inoculate

rickettsiae reduce the risk of infection. Prophylactic doxycycline treat­ ment of tick bites has no proven role in preventing RMSF.

■ ■MEDITERRANEAN SPOTTED FEVER (BOUTONNEUSE FEVER), AFRICAN TICK-BITE FEVER, AND OTHER TICK-BORNE SPOTTED FEVERS Epidemiology and Clinical Manifestations  R. conorii is preva­ lent in southern Europe, Africa, and southwestern and south-central Asia. The disease is characterized by high fever, rash, and—in most geographic locales—an inoculation eschar (tâche noire) that appears before the onset of fever at the site of the tick bite. A severe form of the disease (mortality rate, 50%) occurs in patients with diabetes, alcohol­ ism, or heart failure. African tick-bite fever, caused by R. africae, occurs in rural areas of sub-Saharan Africa and in the Caribbean islands and is transmitted by Amblyomma hebraeum and A. variegatum ticks. The average incuba­ tion period is 4–10 days. The mild illness consists of headache, fever, eschar, and regional lymphadenopathy. Amblyomma ticks, a high por­ tion of which are infected with R. africae, often feed in groups, with the consequent development of multiple eschars. Rash may be vesicular, sparse, or absent altogether. Because of tourism in sub-Saharan Africa, African tick-bite fever is the rickettsiosis most frequently imported into Europe and North America. Maculatum disease, a similar disease caused by the closely related species R. parkeri, is transmitted by A. maculatum and found in a low percentage of A. americanum ticks in the United States. It is also transmitted by A. triste in South America and Arizona as well as A. tigrinum and A. ovale in South America. R. japonica causes Japanese spotted fever, which also occurs in Korea, Thailand, Laos, and China. Similar diseases in northern Asia are caused by R. sibirica and R. heilongjiangensis. Queensland tick typhus due to R. australis is transmitted by Ixodes holocyclus ticks. Flinders Island spotted fever, found on the island for which it is named as well as in Tasmania, mainland Australia, and Asia, is caused by R. honei. In Europe, patients infected with R. slovaca by a wintertime Dermacentor tick bite usually manifest an afebrile illness with an eschar (usually on the scalp) and painful regional lymphadenopathy; R. raoultii causes a similar syndrome in Europe and Asia. PART 5 Infectious Diseases 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 iden­ tification of the etiologic species. In an endemic area, a possible diag­ nosis 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) continued 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), ciprofloxacin (750 mg bid orally for 7 days), and 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

FIGURE 192-2  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.) locations in the United States and in Ukraine, Croatia, Mexico, and Turkey. Investigation of eschars suspected of representing bioterror­ ism-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. 192-2). 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. 192-3); in some cases, the rash remains macular or maculopapular. Some patients develop nausea, vomiting, abdominal pain, cough, con­ junctivitis, or photophobia. Without treatment, fever lasts 6–10 days. Diagnosis and Treatment  Clinical, epidemiologic, and conva­ lescent serologic data establish the diagnosis of a 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 world­ wide. Maintained transovarially in the geographically widespread cat flea, Ctenocephalides felis, the infection has been described as moder­ ately severe, with fever, rash, and headache as well as CNS, gastroin­ testinal, and pulmonary symptoms on the basis of PCR, which often detects organisms in healthy persons. Patient isolates are lacking. ■ ■EPIDEMIC (LOUSE-BORNE) TYPHUS Epidemiology  The human body louse (Pediculus humanus humanus) lives in clothing under poor hygienic conditions and usually in impov­ erished cold areas. Lice acquire R. prowazekii when they ingest blood from a rickettsemic patient. The rickettsiae multiply in the louse’s mid­ gut 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. A small focus was documented in Russia in 1998, sporadic cases were reported from Algeria, and frequent outbreaks occurred in Peru, Rwanda and Burundi. Eastern flying squirrels (Glaucomys volans) and their lice and fleas maintain R. prowazekii in a zoonotic cycle and transmit infection to humans.

A B FIGURE 192-3  A. Papulovesicular lesions on the trunk of the patient with rickettsialpox shown in Fig. 192-2. 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.) 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 spo­ radic 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. S4). Infec­ tions 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 promi­ nent, 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 maculo­ papular, petechial, and confluent. The rash often goes undetected on black skin; 60% of African patients have spotless epidemic typhus. Pho­ tophobia, with considerable conjunctival injection, is common. The tongue may be dry, brown, and furred. Confusion and coma associated with meningoencephalitis 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 infec­ tions 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 misdiag­ nosed as typhoid fever in tropical countries (Chap. 171). This means even serologic studies are often unavailable in settings of louse-borne typhus. Epidemics can be recognized by the serologic or immunohisto­ chemical 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 rickettsialaden flea feces contaminate pruritic bite lesions; less frequently, the flea bite transmits the organisms. Transmission can also occur via inha­ lation of aerosolized rickettsiae from flea feces. Infected rats appear healthy, although they are rickettsemic for ~2 weeks. CHAPTER 192 In the United States, murine typhus occurs mainly in Texas, where the disease is expanding northward, and in southern California, where it appears to affect people experiencing homelessness disproportion­ ally. The incidence is steadily increasing in both of these states, 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. Rickettsial Diseases 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. Sub­ sequently, 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 intersti­ tial 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 dis­ ease, and treatment with a sulfonamide; the case–fatality rate is 0.4%.

Diagnosis and Treatment  Serologic studies of acute- and con­ valescent-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). Where available, chloramphenicol is an alternative. Ciprofloxacin and azithromycin are active in vitro, but clinically, they are less effective than doxycycline. ■ ■SCRUB TYPHUS Epidemiology  O. tsutsugamushi differs substantially from Rickett­ sia 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, serologic evidence of infection in other parts of South and Central America and Africa, and the discovery of Orientia chuto infection in southwestern Asia challenge the classic epidemiology of scrub typhus. PART 5 Infectious Diseases 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 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 returning travelers 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, enzyme immunoassays, and rapid diagnostic assays using lateral flow chromatographic tests) 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). In severe scrub typhus, the combination of doxycycline and azithromycin is beneficial compared to monotherapy of either agent. Some cases of scrub typhus in Thailand are poorly responsive to doxy­ cycline or chloramphenicol but respond to azithromycin and rifampin. EHRLICHIOSES AND ANAPLASMOSES Ehrlichioses are acute febrile infections caused by members of the family Anaplasmataceae, which is made up of obligately intracellular organ­ isms of more than five genera, including those with established human pathogens: 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. 192-4). Four Ehrlichia species, two Anaplasma species, and one Neoehrlichia species are transmitted by ticks to humans and cause infec­ tion that can be severe and prevalent. E. chaffeensis, the agent of HME,

FIGURE 192-4  Peripheral-blood smear from a patient with human granulocytotropic anaplasmosis. A neutrophil contains two morulae (vacuoles filled with Anaplasma phagocytophilum). (Photo courtesy of Dr. J. Stephen Dumler.) and E. muris subsp. eauclairensis infect predominantly mononuclear phagocytes; E. ewingii and A. phagocytophilum infect neutrophils. Infec­ tions with “Candidatus Neoehrlichia mikurensis,” A. capra, and A. bovis are less well characterized but have been reported to grow in endothe­ lium, erythrocytes, and monocytes, respectively. Ehrlichia, “Candidatus Neoehrlichia,” and Anaplasma are main­ tained 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 pathogenic­ ity; 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 pathogen of human neorickettsiosis has been described: N. sennetsu causes sen­ netsu fever, an infectious mononucleosis–like illness first identified in 1953 in association with the ingestion of raw fish containing N. sen­ netsu–infected flukes. ■ ■HUMAN MONOCYTOTROPIC EHRLICHIOSIS Epidemiology  More than 25,480 cases of E. chaffeensis infec­ tion had been reported to the U.S. Centers for Disease Control and Prevention (CDC) as of November 2023. 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 Eng­ land, and midwestern states. All stages of the Lone Star tick (A. ameri­ canum), 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. Transfusion-related infections are documented, as are infections in patients with organ transplants. The incidence of HME is highest in patients 60–84 years of age; however, 9% of infections occur in children ≤19 years of age, and these include severe and fatal infec­ tions. 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 hematog­ enously from the dermal blood pool created by the feeding tick. After a median incubation period of 8 days, illness develops. Clinical manifes­ tations 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, hemophagocytic lymphohistiocytosis 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 differen­ tial diagnosis of HME; 66% of patients have leukopenia (initially lym­ phopenia, 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 not necessary in patients receiving prompt empirical treatment. In addition, hospital stay and illness duration are length­ ened 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 amino­ transferase activities. Morulae are demonstrated in <10% of peripheralblood 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 eauclai­ rensis 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. ■ ■“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 amplifica­ tion and sequence analysis, this organism was identified as the cause of severe and sometimes prolonged febrile illnesses in European immu­ nocompromised 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 presenta­ tion is similar to those of HME and HGA except for an often prolonged course and a predilection for venous thrombosis. 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. chaffeen­ sis 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 defer­ vescence. 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 avoid­ ance 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 November 2023, 64,225 cases of HGA had been reported to the CDC, most in the upper Midwest and north­ eastern 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 small mammals, such as whitefooted mice and squirrels, and large animals such as 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 the inci­ dence of infection in persons older than 60 years is 7 times higher than in those younger than 15 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, vom­ iting, or diarrhea (22–40%); cough (27%); or confusion (17%). A rash in HGA (5%) most often reflects co-infection with Borrelia, resulting in erythema migrans. Most patients develop thrombocytopenia (80%) and/or leukopenia (63%) with increased serum hepatic aminotransfer­ ase levels (80%). CHAPTER 192 Rickettsial Diseases Life-threatening complications occur most often in the elderly and include renal failure, acute respiratory distress syndrome, a toxic shock–like syndrome, pneumonia, a DIC- or sepsis-like syndrome and hemophagocytic lymphohistiocytosis. Meningoencephalitis is rare in documented cases of HGA. Other documented neurologic sequelae include brachial plexopathy, cranial nerve involvement, and demyelinat­ ing polyneuropathy. Infection of patients with a preexisting immuno­ compromising 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 condi­ tion. 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 transmit­ ted 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 diag­ nosis. 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 anti­ body 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 and A. bovis 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 Haemaphysalis longicornis ticks, and at least seven additional species can carry it over a distribution across Asia and eastern Europe. All patients responded to doxycycline treatment and survived.

Anaplasma bovis was recently identified in four human patients in a surveillance study of suspected Lyme borreliosis, HGA, HME, and babesiosis in the United States and in two patients with fever, myalgias, and rash in China. All six patients were between the ages of 35 and 71 years; four were male, and two were female. The apparent tick vec­ tors are Dermacentor variabilis in the United States and Haemaphysalis longicornis in China. Both Chinese patients recovered after antimicro­ bial treatment. 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. PART 5 Infectious Diseases 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 sheep, goats, and cattle. 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 for weeks to months after parturition, but also in 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 in veterinary populations, but the majority of human Q fever cases are associated with aerosol transmission from infected livestock. Infections in animals are usu­ ally 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. S4), with a high infectivity rate and pneumonia as the major manifestation. Persons most at risk for Q fever include abattoir workers, veterinar­ ians, farmers, and other individuals who have contact with infected animals (particularly newborn animals), but outbreaks often affect people without any livestock contact. 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 veteri­ narians were seropositive, compared to ~3% of the population overall. Seroprevalence data confirm that Q fever is underreported in many countries. 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 childbirth in an infected woman, surgery, autopsy, blood transfusion, or organ transplantation of an infected individual. Multiple outbreaks involving laboratory staff have been reported in the past. Some evi­ dence 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 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 epi­ demiology: 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 variability in human susceptibility to C. burnetii can influ­ ence 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 hyper­ endemic: 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 dif­ fer 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 infec­ tion (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, spon­ taneous rupture of the spleen, transient hypoplastic anemia, hemolytic anemia, hemophagocytic lymphohistiocytosis, meningitis, encephalitis, 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, nau­ sea, 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. Case– fatality rate of acute Q fever is ~1–2%. Acute Q fever occasionally complicates pregnancy. In one series, it resulted in premature birth in 35% of cases and in abortion or neo­ natal 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.

Rickettsial Diseases

CHAPTER 192 TABLE 192-2  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 (18FDG-PET, 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 aIn absence of acute infection. Abbreviations: AUS, abdominal ultrasound; CRP, C-reactive protein; CT, computed tomography; 18FDG-PET, fluorodeoxyglucose positron emission tomography; ESR, erythrocyte sedimentation rate; IFA, indirect fluorescent antibody assay; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography. Q FEVER FATIGUE SYNDROME  Prolonged fatigue follows acute Q fever in up to 20% of cases and can be accompanied by a constellation of symptoms, including headaches, sweats, arthralgia, and myalgias. Sev­ eral hypotheses regarding the etiology exist, including host and genetic factors, cytokine dysregulation, and a partly biopsychological etiology with C. burnetii acting as a trigger for fatigue development. A random­ ized controlled trial including 155 patients with strictly diagnosed Q fever fatigue syndrome showed that long-term treatment with doxy­ cycline did not reduce fatigue severity compared to placebo, so antibi­ otics 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  Following symptomatic or asymptomatic primary infection, 1−5% of all patients develop chronic Q fever. Chronic Q fever endocarditis, infected aneurysms, or infected vascular prosthe­ ses are most frequently observed. The primary infection often has not been recognized or was asymptomatic, and the median duration between primary infection and manifestation of chronic infection is 13 months, with the largest observed interval between acute infection and diagnosis of chronic Q fever being >9 years. Risk factors for the development of chronic Q fever include male sex, older age, valvu­ lopathy or prior valve surgery, aneurysms, vascular prostheses, renal insufficiency, and immunocompromised state. Diagnosing chronic Q fever is difficult, as patients are sometimes asymptomatic until com­ plications occur and 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 diag­ nosis. 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, elevated inflammatory markers, 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 313 patients with proven chronic Q fever in the Netherlands, 65% 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 posi­ tivity 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 proven chronic Q fever after the Dutch outbreak. Chronic Q fever–related mortality was high­ est 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 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 immuno­ sorbent 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, labora­ tory, and imaging criteria. There has been debate on the optimal set of criteria, but the Dutch literature-based consensus guideline (Table 192-2) 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 computed tomography (FDG-PET/CT) can detect not only prosthetic valvular infection but also intravascular infection elsewhere, osteo­ myelitis, 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