These diseases, caused by organisms of the genera Rickettsia and Orientia in the family Rickettsiaceae, result from endothelial infection and increased vascular permeability. Pathogenic rickettsial species are very closely related, have small genomes (as a result of reductive evolution, 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 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 the 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. conorii (MSF); R. typhi (murine typhus); and, in rare cases, other spotted fever–group organisms. Some agents (e.g., R. parkeri, R. africae, 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.
Rocky Mountain Spotted Fever
RMSF occurs in 47 states (with the highest prevalence in the south-central and southeastern states) as well as in Canada, Mexico, and Central and South America. The infection is transmitted by Dermacentor variabilis, the American dog tick, in the eastern two-thirds of the United States and California; by D. andersoni, the Rocky Mountain wood tick, in the western United States; by Rhipicephalus sanguineus in Mexico, Arizona, and probably Brazil; and by Amblyomma cajennense in Central and South America. Maintained principally 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 rickettsemic small mammals.
Humans become infected during tick season (in the Northern Hemisphere, from May to September), although some cases occur in winter. The mortality rate was 20–25% in the preantibiotic era and remains at ∼3–5% principally because of delayed diagnosis and treatment. The case-fatality ratio increases with each decade of life above age 20.
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 dose-dependent incubation period is ∼1 week (range, 2–14 days). Occlusive thrombosis and ischemic necrosis are not the fundamental pathologic basis for tissue and organ injury. Instead, increased vascular permeability, with resulting edema, hypovolemia, and ischemia, is responsible. Consumption of platelets results in thrombocytopenia in 32–52% of patients, but disseminated intravascular coagulation with hypofibrinogenemia is rare. Activation of platelets, generation of thrombin, and activation of the fibrinolytic system all appear to be homeostatic physiologic responses to endothelial injury.
Early in the illness, when medical attention 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 infection 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, developing 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. 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 hemorrhage at the center of the maculopapule, producing a petechia that does not disappear upon compression (Fig. 174-1). 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 9–16% of cases. Petechiae occur in 41–59% of cases, appearing on or after day 6 in 74% of cases that manifest a rash. Involvement 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.
Top: Petechial lesions of Rocky Mountain spotted fever on the lower legs and soles of a young, previously healthy patient. Bottom: Close-up of lesions from the same patient. (Photos courtesy of Dr. Lindsey Baden;with permission.)
Hypovolemia leads to prerenal azotemia and (in 17% of cases) hypotension. Infection of the pulmonary microcirculation leads to noncardiogenic pulmonary edema; 12% of patients have severe respiratory disease, and 8% require mechanical ventilation. Cardiac involvement manifests as dysrhythmia in 7–16% of cases.
Besides respiratory failure, central nervous system (CNS) involvement 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 seizures in 8%. Numerous focal neurologic deficits have been reported. Meningoencephalitis results in cerebrospinal fluid (CSF) pleocytosis in 34–38% of cases; usually there are 10–100 cells/μL and a mononuclear 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.
Renal failure, 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 focal 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 stools or vomitus of 10% of patients, and death has followed massive upper gastrointestinal hemorrhage.
Other characteristic clinical laboratory findings include increased plasma levels of proteins of the acute-phase response (C-reactive protein, 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.
In untreated cases, the patient usually dies 8–15 days after onset. A rare presentation, fulminant RMSF, is fatal within 5 days after onset. This fulminant presentation 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.
The diagnosis of RMSF during the acute stage is more difficult than is generally appreciated. The most important epidemiologic factor is a history of exposure to a potentially tick-infested environment within the 12 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, leptospirosis, 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, vomiting, and abdominal pain; prominence of abdominal tenderness has resulted in exploratory laparotomy. CNS involvement may masquerade as bacterial or viral meningoencephalitis. Cough, pulmonary signs, and chest radiographic opacities may 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 certainly be considered. However, many illnesses considered in the differential diagnosis may also be associated with a rash, including rubeola, rubella, meningococcemia, disseminated gonococcal infection, secondary syphilis, toxic shock syndrome, drug hypersensitivity, idiopathic 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 may 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 diagnostic titer of ≥1:64 usually detectable. The sensitivity and specificity of the indirect immunofluorescence assay are 94–100% and 100%, respectively. 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.
The only diagnostic test that is useful during the acute illness is immunohistologic examination of a cutaneousbiopsy 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. The sensitivity of polymerase chain reaction (PCR) amplification and detection of R. rickettsii DNA in peripheral blood is improving. However, although rickettsiae are present in large quantities in heavily infected foci of endothelial cells, there are relatively low quantities in the circulation. Cultivation of rickettsiae in cell culture is feasible but is seldom undertaken because of biohazard concerns. The recent dramatic increase in the reported incidence of RMSF correlates with the use of single-titer spotted fever–group cross-reactive enzyme immunoassay serology, with which few cases are specifically determined to be caused by R. rickettsii.
Treatment: Rocky Mountain Spotted Fever
The drug of choice for the treatment of both children and adults with RMSF is doxycycline, except when the patient is pregnant or allergic to this drug (see below). Because of the severity of RMSF, immediate empirical administration of doxycycline should be strongly considered for any patient with a consistent clinical presentation in the appropriate epidemiologic setting. Doxycycline is administered orally (or, in the presence of coma or vomiting, intravenously) at 200 mg/d in two divided doses. For children with suspected RMSF, up to five courses of doxycycline may be administered with minimal risk of dental staining. Other regimens include oral tetracycline (25–50 mg/kg per day) in four divided doses. Treatment with chloramphenicol, a less effective drug, is advised only for patients who are pregnant or allergic to doxycycline. The antirickettsial drug should be administered until the patient has been afebrile and improving clinically for 2–3 days. β-Lactam antibiotics, erythromycin, and aminoglycosides have no role in the treatment of RMSF, and sulfa-containing drugs are likely to exacerbate this infection. There is little clinical experience with fluoroquinolones, clarithromycin, and azithromycin, 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 hemodialysis; 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. Heparin is not a useful component of treatment, and there is no evidence that glucocorticoids affect outcome.
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.
Mediterranean Spotted Fever (Boutonneuse Fever), African Tick-Bite Fever, and Other Tick-Borne Spotted Fevers
R. conorii is prevalent in southern Europe, Africa, and southwestern and south-central Asia. Regional names for the disease caused by this organism include Mediterranean spotted fever, Kenya tick typhus, Indian tick typhus, Israeli spotted fever, and Astrakhan spotted fever. The disease is characterized by high fever, rash, and—in most geographic locales—an inoculation eschar (tâche noire) at the site of the tick bite. A severe form of the disease (mortality rate, 50%) occurs in patients with diabetes, alcoholism, 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 incubation period is 4–10 days. The mild illness consists of headache, fever, eschar, and regional lymphadenopathy. Amblyomma ticks 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 most frequently imported rickettsiosis in Europe and North America. A similar disease caused by the very closely related R. parkeri is transmitted by A. maculatum in the United States and A. triste in South America.
R. japonica causes Japanese spotted fever, which also occurs in Korea. 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. Flinders Island spotted fever, found on the island for which it is named as well as in Tasmania, mainland Australia, and southeastern Asia, is caused by R. honei. In Europe, patients infected with R. slovaca after a wintertime Dermacentor tick bite manifest an afebrile illness with an eschar (usually on the scalp) and painful regional lymphadenopathy.
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 or blood samples. The serologic identification of the etiologic species requires knowledge of all the potential agents as well as expensive, laborious cross-adsorption of the patient—s serum. In an endemic area, a possible diagnosis of one of these rickettsial spotted fevers should be considered when patients present with fever, rash, and/or a skin lesion consisting of a black necrotic area or a crust surrounded by erythema.
Treatment: Tick-Borne Spotted Fevers
Successful therapeutic agents include doxycycline (100 mg bid orally for 1–5 days), ciprofloxacin (750 mg bid orally for 5 days), and chloramphenicol (500 mg qid orally for 7–10 days). Pregnant patients may be treated with josamycin (3 g/d orally for 5 days). 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.
R. akari infects mice and their mites (Liponyssoides sanguineus), which maintain the organisms by transovarian transmission.
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 cutaneousanthrax revealed that rickettsialpox occurs more frequently than previously realized.
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. 174-2). 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, onset is marked by malaise, chills, fever, headache, and myalgia. A macular rash appears 2–6 days after onset and evolves sequentially into papules, vesicles, and crusts that heal without scarring (Fig. 174-3). The rash may remain macular or maculopapular. Some patients develop nausea, vomiting, abdominal pain, cough, conjunctivitis, or photophobia. If untreated, fever lasts 6–10 days.
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.)
Top: Papulovesicular lesions on the trunk of the patient with rickettsialpox shown in Fig. 174-2. Bottom: 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.)
Clinical, epidemiologic, and convalescent serologic data establish the diagnosis of a spotted fever–group rickettsiosis that is seldom pursued further. Doxycycline is the drug of choice for treatment.
An emerging rickettsiosis caused by R. felis occurs worldwide. Maintained transovarially in the geographically widespread cat flea Ctenocephalides felis, the infection has been described as moderately severe, with fever, rash, headache, and CNS, gastrointestinal, and pulmonary symptoms.
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 contaminates pruritic bite lesions; less frequently, the flea bite transmits the organisms. Transmission also may 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 southern Texas and southern California, where the classic rat/flea cycle is absent and an opossum/cat flea (C. felis) cycle is prominent. 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 June in southern 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.
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. Nearly all patients experience nausea and vomiting early in the illness.
The duration of untreated illness averages 12 days (range, 9–18 days). Rash 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 and never appearing in the others. The initial macular rash is often 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, mildly increased serum hepatic aminotransferases, and prerenal azotemia. Complications may 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%. In a study of children with murine typhus, 50% suffered only nocturnal fevers, feeling well enough for active daytime play.
Cultivation, PCR, or cross-adsorption serologic studies of acute- and convalescent-phase sera can provide a specific diagnosis, and an immunohistochemical method for identification of typhus group-specific antigens has been developed. Nevertheless, most patients are treated empirically with doxycycline (100 mg bid orally for 7–15 days) on the basis of clinical suspicion. Ciprofloxacin provides an alternative if doxycycline is contraindicated. Serologic methods are usually used when laboratory confirmation of the diagnosis is sought.
Epidemic (Louse-Borne) Typhus
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 midgut epithelial cells of the louse and are shed in the louse—s 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 occurred in Russia in 1998; sporadic cases have been reported from Algeria, and frequent outbreaks have occurred in Peru. Eastern flying squirrels (Glaucomys volans) and their lice and fleas maintain R. prowazekii in a zoonotic cycle. The fleas transmit the infection sporadically 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.
Rickettsiae are potential agents of bioterrorism (Chap. 221). Infections with R. prowazekii and R. rickettsii have high case-fatality ratios. These organisms cause difficult-to-diagnose diseases, are highly infectious when inhaled as aerosols, and have been selected for resistance to tetracycline or chloramphenicol in the laboratory.
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, occurring in 70% of patients. Myalgias are usually severe. In the outbreak in Burundi, the disease was referred to as sutama ("crouching"), a designation reflecting the posture of patients attempting to alleviate the pain. 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 is not detected in black skin; 60% of African patients have spotless epidemic typhus. Photophobia, with considerable conjunctival injection and eye pain, 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.
Epidemic typhus is sometimes misdiagnosed as typhoid fever in tropical countries (Chap. 153). The means even for serologic studies are often unavailable in settings of louse-borne typhus. Epidemics may 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. Cross-adsorption indirect fluorescent antibody (IFA) studies can distinguish R. prowazekii and R. typhi infections. Doxycycline (200 mg/d, given in two divided doses) is administered orally or—if the patient is comatose or vomiting—intravenously. Although under epidemic conditions a single 200-mg dose has proved effective, treatment is generally continued until 2–3 days after defervescence. Pregnant patients should be evaluated individually and treated with either chloramphenicol early in pregnancy or, if necessary, doxycycline late in pregnancy.
Prevention of epidemic typhus involves control of body lice. Clothes should be changed regularly, and insecticides should be used every 6 weeks to control the louse population.