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Etiology and Pathogenesis of Spotted Fever and Typhus Groups
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Rickettsiae are obligate, intracellular, Gram-negative bacteria. They are pleomorphic 0.3–1 μm coccobacilli composed of DNA and RNA and reproduce through binary fission. Rickettsiae are propagated by arthropod vectors that use mammals (and sometimes the arthropods themselves) as reservoirs of infection. Rickettsiae are separated into the spotted fever group and the typhus group on the basis of common genetics, immunologic patterns, and intracellular growth characteristics. The typhus group lives entirely within the cell cytoplasm, whereas the spotted fever group can reside within the cytoplasm or nucleus. Rickettsiae are differentiated by unique antigenic structures on cell surface proteins. Rickettsia rickettsii has two major surface proteins, outer membrane protein A (OmpA) and B (OmpB), which are the main targets for serological testing.
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Infection occurs through arthropod-induced breaks in the skin allowing access of the pathogen to the blood and lymph. Spotted fever rickettsiae are injected into the host through the saliva of the feeding tick, whereas typhus group rickettsiae enter through the feces of infected human body lice or fleas. Manipulation of the bite site, a long attachment of the arthropod, and exposure to arthropod hemolymph during tick removal aid in the transmission of pathogenic organisms. The rickettsial organisms then spread via the hematogenous and lymphatic systems, attach to endothelial cell membranes, and are phagocytosed. Spotted fever group rickettsiae stimulate host cells to produce reactive oxygen species and cause actin polymerization that aid in bacterial extrusion. In contrast, typhus group rickettsiae replicate intracellularly until the host cell bursts.3 The severe clinical manifestations of rickettsial infection (e.g., hypovolemia, purpura, pulmonary and cerebral edema) are caused by proliferation of bacteria within the vascular endothelium resulting in a multifocal, systemic vasculitis and microvascular leakage.4
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Rocky Mountain Spotted Fever
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Rocky Mountain Spotted Fever (RMSF) was first recognized in 1896 in the Snake River Valley of Idaho and was originally called black measles because of the characteristic appearance of the rash. Caused by the tick-borne R. rickettsii, it is the most frequently reported rickettsial infection in the United States. Fatal outcomes have been reported in 5% of treated cases, and as high as 20% of untreated cases.5
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The vector largely responsible for RMSF in the eastern two-thirds of the United States is the American dog tick, Dermacentor variabilis, whereas the Rocky Mountain wood tick, Dermacentor andersoni, is prevalent in the Western United States (Fig. 199-1). RMSF is most prevalent in the Southeastern and South Central states, during spring and early summer. Historically, children younger than 10 years of age had the highest incidence of RMSF; however, surveillance data in the United States during 2003 demonstrate a higher age-specific incidence in persons aged 40–64 years.6 The principal epidemiologic characteristics of RMSF are outlined in Table 199-1.
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Clinical and Laboratory Findings
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A high index of suspicion is important to the diagnosis of RMSF. One or two classic symptoms, outlined in Table 199-2, may be seen at presentation, but only about 60% of patients will have the complete clinical triad of fever [>39.5°C (102°F)], headache, and rash. Fever usually presents within the first 3 days of the illness, followed by a characteristic rash 2–4 days after the onset of fever. The rash usually starts on the wrists and ankles, spreading centripetally over the next 6–18 hours. Palms and soles are typically involved with relative sparing of the face.6 Cutaneous lesions are initially blanchable red macules that become papular and display evidence of petechiae or purpura (Fig. 199-2). Atypical “spotless” fever, seen in approximately 20% of cases does not imply milder disease, and is more common in the elderly and darker-skinned individuals.4 Periorbital edema, confusion, abdominal pain mimicking an acute abdomen, conjunctival injection, palatal petechiae, edema of dorsal hands, and calf pain are sometimes appreciated. Necrosis from overwhelming vasculitis is rare and preferentially occurs in peripheral locations such as the digits, penis, and scrotum (Fig. 199-3).7
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Thrombocytopenia, anemia, mild hyponatremia, and mild transaminitis may be present. The white blood cell count is typically normal, however an increase in bands may be observed.6 Severe and life-threatening cardiac, gastrointestinal, hepatic, neurologic, ophthalmologic, renal, and pulmonary manifestations can occur with delayed or inadequate treatment. In patients with severe RMSF who survive the acute illness, long-term sequelae are usually the result of neurologic deficits or acral necrosis. In a case series by Buckingham et al, of 92 children diagnosed with RMSF, the median delay between seeking medical attention and antibiotic therapy was 6 days, with only 49% reporting a tick bite.8 Table 199-2 outlines the cutaneous and systemic manifestations of RMSF, as well as common laboratory abnormalities.
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Histopathologic examination shows a septic vasculitis (Fig. 199-4). Early lesions demonstrate dermal edema with a predominantly perivascular lymphohistiocytic infiltrate and extravasated erythrocytes. Lymphohistiocytic vasculitis can progress to leukocytoclastic vasculitis. Basal cell vacuolization, lymphocytic exocytosis, fibrin thrombi, and capillary wall necrosis can also be appreciated. Immunohistology reveals positive staining for R. rickettsii in infected endothelial cells and tick hemolymph. (Fig. 199-5.) Most rickettsial diseases share a similar histology.
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Diagnosis and Differential Diagnosis
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Serologic examination using the indirect immunofluorescence assay (IFA) is the gold standard for diagnosis of RMSF. It detects convalescent antibodies (at a diagnostic titer of ≥64 IgG and ≥32 IgM) but is seldom diagnostic before the seventh day of disease, and often not until far into the second week. An effective treatment for RMSF should begin by the fifth day of illness. It is vital to begin empiric therapy while awaiting serologies. Because of inferior sensitivity and specificity, the Weil–Felix test (agglutination of certain Proteus sp.) and complement fixation tests have been largely supplanted by newer diagnostic methods. Immunohistochemical staining of skin or organ tissue biopsy and polymerase chain reaction (PCR) may also confirm the diagnosis.9
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When a patient presents without a rash, the differential diagnosis for RMSF is broad (Boxes 199-1 and 199-2). Macules and papules, petechiae, or purpuric lesions may sometimes develop in these diseases as well, further precluding the ability to distinguish them from RMSF on clinical grounds alone.
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Tetracyclines, specifically doxycycline, are the drugs of choice for all rickettsial diseases in patients of all ages, even during pregnancy. The use of tetracyclines in children with RMSF is no longer a subject of controversy. Although repeated exposure to tetracycline increases the risk of tooth staining, studies suggest that limited use of this antibiotic in children during the first 6–7 years of life has a negligible effect on the color of permanent incisors.10 Sulfa-based medications are not recommended, as they may result in a more complicated disease course.11
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Chloramphenicol may be used if tetracyclines are contraindicated because of allergies. Side effects include aplastic anemia, reversible bone marrow suppression, and gray baby syndrome in near-term gravidae,12 Aggressive supportive care is crucial, with particular attention to electrolyte and fluid balance. Treatment and management strategies for RMSF are listed in Table 199-1 and Box 199-3.
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Fulminant RMSF leading to more rapid decompensation has characteristically been reported in chronic alcoholics and black males with glucose-6-phosphate dehydrogenase deficiency. These patients have a higher risk of cutaneous necrosis.3 Prompt empiric administration of appropriate antibiotic therapy is recommended, as it is the most important factor affecting survival.
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Avoiding tick exposure, wearing protective clothing, performing tick checks regularly while in tick-infested areas, and proper tick extractions are important for lowering the risk of infection. Chemical repellants, such as diethyltoluamide (DEET) in concentrations up to 35%, are safe for use in adults and children. Prophylactic antibiotics after tick exposure are not recommended. Despite its life-threatening nature, vaccine development remains to be a low priority because of the availability of safe and effective antibiotics,13
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Mediterranean Spotted Fever and African Tick Bite Fever
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Several other tick-borne rickettsial species are pathogenic to humans. Mediterranean spotted fever (MSF), also known as Boutonneuse fever or Marseille fever, caused by Rickettsia conorii, was first documented as a cause of human rickettsial disease is 1932. MSF is the prototypical illness of the non-RMSF spotted fever group. African tick bite fever (ATBF), caused by Rickettsia africae, is a distinct clinical entity.
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R. conorii is transmitted by an infected Rhipicephalus sanguineus tick (see Fig. 199-1) and is endemic throughout Africa, the Middle East, and Southern Europe. Contact with dogs is reported in up to 90% of cases of MSF. Epidemiologic characteristics of MSF are summarized in Table 199-1. R. africae is transmitted by an infected Amblyomma tick endemic to sub-Saharan Africa.
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Clinical and Laboratory Findings
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The constitutional symptoms, systemic complications, and laboratory abnormalities of the tick-bite–associated spotted fevers are similar to those of RMSF. The classic cutaneous hallmark of this group is the tache noir, occurring in about 13%–68% of patients with R. conorii infection (Fig. 199-6A).14 The tache noir occurs at the site of inoculation as an erythematous, indurated papule with a central necrotic eschar that represents locally aggressive endothelial invasion by rickettsiae. Temporal and morphologic pattern of the rash in this group of spotted fevers is similar to RMSF; however, the eruption may be more diffuse and is less frequently petechial or purpuric (see Fig. 199-6B). The presence of multiple tick bites, multiple eschars (seen in 50% of patients with ATBF), and lymphadenitis, distinguish ATBF from MSF,1 although children with MSF may have cervical lymphadenopathy.14
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Diagnosis and Differential Diagnosis
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Like RMSF, diagnosis of MSF or ATBF is by IFA. Biopsy from an eschar for immunohistochemistry is particularly sensitive in MSF. PCR or western blot analysis can be used to differentiate between R. conorii and R. africae. Newer serologic assays and PCR have been useful in identifying the numerous emerging agents of spotted fever around the globe, including Rickettsia japonica (Japanese spotted fever) and Rickettsia slovaca.1 R. slovaca, along with Rickettsia raoultii have been associated with TIBOLA/DEBONEL (tick-borne lymphadenopathy/Dermacentor-borne necrosis erythema and lymphadenopathy), a recently recognized rickettsial disease associated with eschar formation at the tick-bite site and painful lymphadenopathy. TIBOLA/DEBONEL is usually seen in the pediatric population with tick-bites involving the scalp.15
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The rash of MSF generates a similar differential diagnosis as that of RMSF. If a tache noir is seen, one must also consider brown recluse spider bite, cutaneous anthrax, scrub typhus, rickettsialpox, aspergillosis, or mucormycosis.
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Guidelines for the treatment of MSF are outlined in Table 199-1. Overall, non-RMSF spotted fevers run a less aggressive course than RMSF. However, MSF has been reported to cause severe cardiac, renal and neurologic complications, as well as death in about 1% of cases.14 In general, all non-RMSF spotted fevers are treated similarly to MSF. Macrolide antibiotics may offer a better risk/benefit ratio than tetracyclines in the pediatric age group, however, doxycycline is still first-line therapy.16
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Rickettsialpox is an acute, self-limited, febrile disease so named because of its clinical resemblance to varicella (chickenpox). Its etiologic agent is Rickettsia akari. Mus musculus, the house mouse, is the reservoir, and the vector is the rodent mite, Liponyssoides sanguineus (formerly Allodermanyssus sanguineus).17 The colorless rodent mite inflicts a painless bite and is too small to be readily recognized by the victim.
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Most cases of rickettsialpox in the United States have occurred in large metropolitan areas of the Northeastern United States, with approximately one-half of the cases reported from New York City alone. Table 199-1 describes the salient epidemiologic features of rickettsialpox.
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Clinical and Laboratory Findings
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A primary lesion occurs at the site of the mite bite as early as 1–2 days after transmission. It consists of a painless, erythematous, indurated papule ranging in size from 0.5–3.0 cm. Vesicle formation is followed by desiccation which produces an eschar to form the characteristic tache noir (Fig. 199-7). Regional lymphadenopathy is common. Resolution of the primary lesion occurs within 1 month.
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Approximately 7 days after the primary lesion appears, fever, chills, diaphoresis, myalgia (often manifesting as backache), malaise, and headache begin. The fever persists with remissions for about 1 week before abating. Two to three days after the onset of systemic symptoms, a generalized papulovesicular eruption occurs (Fig. 199-7B). Small vesicles or pustules appear with subsequent central crust formation. Roughly 5–40 lesions may be found, typically resolving in 1 week. Less frequently, an enanthem, photophobia, generalized lymphadenopathy, and gastrointestinal symptoms may be noted. Thrombocytopenia is common during the acute febrile illness, and a mild leukopenia with a relative lymphocytosis may be seen.
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In contrast to RMSF, MSF, ATBF, and typhus group Rickettsioses, the perivascular macrophage, not the endothelial cell, appears to be the target of R. akari. Primary lesions are characterized by extensive necrosis and an acute inflammatory infiltrate. Secondary papulovesicular lesions display a subepidermal split with superficial edema, and a perivascular lymphohistiocytic infiltrate that can become vasculitic.
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Diagnosis and Differential Diagnosis
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Antibody titers peak after 3–4 weeks and could be delayed for up to 8 weeks with antibiotic use. Biopsy for direct immunofluorescence (DIF) with anti-R. rickettsii immunoglobulin is highly sensitive; however, due to cross-reactivity among the spotted fever group rickettsiae, confirmatory cross-adsorption testing may be considered with R. akari and R. rickettsii antigens. Tissue for DIF should be taken from a primary eschar, as lesions from the generalized eruption do not contain enough inoculum to become positive by DIF. If immunohistochemistry is inconclusive, PCR can be used to confirm infection.18
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The differential diagnosis includes varicella, smallpox, gonococcemia, infectious mononucleosis, echovirus (types 9 and 16), and coxsackievirus infection (A9, A16, and B5), in addition to those diseases discussed under the differential diagnosis of MSF. In varicella, one observes a “dewdrop on a rose petal,” referring to a primarily vesicular lesion surrounded by macular erythema. This is distinct from the erythematous papule surmounted by a vesicle seen with rickettsialpox.17 Fever occurs with the rash of varicella but precedes the eruption of rickettsialpox.
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Rickettsialpox is self-limited. Even without antibiotics, it will resolve within 2 weeks. In the rare severe case, tetracycline antibiotics continued for up to 5 days are the most effective therapy; defervescence is typical within 48 hours.17
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Endemic Typhus (Murine or Flea-Borne Typhus)
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Endemic typhus is caused mainly by Rickettsia typhi, and is classically transmitted to humans by the rat flea (Xenopsylla cheopis), with rats serving as the reservoir. Rickettsia felis has recently emerged as an important agent of endemic typhus with characteristics of both the typhus and spotted fever group rickettsiae. R. felis has been identified in peridomestic cats, dogs, opossums, and their fleas (e.g., cat flea, Ctenocephalides felis) in parts of southern Texas, southern California, and Mexico.19,20
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Murine typhus has been reported from all continents except Antarctica, although most cases today occur in Africa. It is most likely underdiagnosed and mistaken for a viral illness since flea bites are not usually recalled and most cases are self-limited.21 Epidemiologic characteristics are outlined in Table 199-1.
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Clinical and Laboratory Findings
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Most infected persons experience fever, headache, backache, and joint pain 6–14 days after contact with an infected flea. Nonspecific gastrointestinal symptoms may be present, especially in children.22 Extremely high fever, 41.1°C (106°F), may last up to 2 weeks. Commonly, a rash begins on the chest and spreads to the sides and back. The palms and soles are rarely involved. The rash may last only a few hours and consists of erythematous macules and/or papules. Petechiae are found infrequently. Rash is seen in less than 20% of patients at presentation. Fifty to sixty percent of patients will develop a rash over the course of the illness, with a median onset of 6 days after the onset of fever.19 More severe complications are uncommon but may include seizures, meningoencephalitis, retinitis, acute hepatitis, endocarditis, renal insufficiency, pneumonia, and respiratory failure. Thrombocytopenia, transaminitis, and hyponatremia are common, though usually mild.
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Diagnosis and Differential Diagnosis
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Diagnostic IFA titers are present in 50% of patients by day 7, virtually in 100% of patients by day 15; however, these may not distinguish between endemic and epidemic typhus. Western blot and cross-adsorption studies can differentiate the two diseases, however, they require expensive, specialized laboratories.21 The differential diagnosis of endemic typhus is broad as a result of the nonspecific nature of the cutaneous eruption (see Box 199-2).
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Treatment for endemic typhus is similar to that of RMSF (see Table 199-1). With institution of appropriate antibiotics, fever typically resolves in 2–3 days. Spontaneous recovery often occurs within 2 weeks in untreated patients. Prior infection with R. typhi provides lifelong immunity to subsequent infection.
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Epidemic (Louse-Borne) Typhus
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Epidemic typhus (also called prison fever, famine fever, or ship fever) is caused by R. prowazekii, and is transmitted to humans primarily via the body louse (Pediculus humanus var. corporis). Epidemic typhus may result in long-term latent asymptomatic infection. A re-ermergence of the illness known as Brill–Zinsser disease (BZD) can occur in survivors who may suffer recrudescent infection, even decades after the initial infection.
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Louse infestation occurs when cold weather, poor hygiene, crowding, and poverty are prevalent. These conditions are most commonly found today in refugee camps, and among the homeless and imprisoned. The most recent outbreak of epidemic typhus occurred in refugee camps in Burundi during the mid-1990s.23 Table 199-1 details the epidemiologic characteristics of epidemic typhus.
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The major reservoir for disease is humans, with lice acquiring the infection by feeding on persons with primary illness or BZD. The lice are spread through close personal contact or infested clothing. The infected louse will defecate while taking a blood meal, and the organisms in the feces are then scratched into the skin, enabling transmission. Lice die of infection within 3 weeks, however, their feces can be infectious for up to 100 days, therefore allowing human-to-human transmission through clothes or close contact. Contact with southern flying squirrels (Glaucomys volans) is associated with outbreaks of epidemic typhus in the Eastern United States, where the fleas or lice from these rodents can be important vectors.24
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Clinical and Laboratory Findings
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After an incubation period of 1–2 weeks, abrupt onset of intractable headache, fever [to 40°C (104°F)], chills, and myalgia occurs. If left untreated, prostration due to overwhelming hypotension and vascular collapse may ensue. Typically, a rash begins in the axillary folds and upper trunk on the fifth day of illness. Initial lesions consist of erythematous macules that become papular and petechial over several days. In contrast with most rickettsial diseases, the eruption spreads centrifugally but spares the face, palms, and soles. Complications include acral gangrene, cerebral thrombosis, and other neurologic sequelae, multiorgan system failure, and death. Laboratory abnormalities include thrombocytopenia, elevated transaminases, and elevated lactate dehydrogenase. Leukocytosis is seen in a minority of patients.
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BZD occurs as a recrudescence of previous infection with R. prowazekii. Provocation by immunologic stress induced by poor living conditions may play a role. The illness is usually milder than the primary disease. In the United States it was most commonly seen in those who were exposed to epidemic typhus in World War II.
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Diagnosis and Differential Diagnosis
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Techniques for diagnosis are identical to those used for other rickettsial diseases, with the IFA test the most widely used method. The differential diagnosis is similar to that of endemic typhus. The diagnosis of epidemic typhus should be considered when the appropriate clinical characteristics are seen in the setting of known or suspected louse infestation, or, in the United States, when a history of an exposure to flying squirrels is elicited. The centrifugal spread, lack of eschar, and predilection for colder months helps differentiate epidemic typhus from other rickettsial infections. Endemic typhus is typically less severe than epidemic typhus. When lice and rats are both prevalent (poor hygienic conditions, prison, etc.), a risk exists for both diseases. In such situations, it is critical to discriminate between R. typhi and R. prowazekii infections, as the latter has markedly greater epidemic potential.
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Fatal illness is rare if proper therapy is initiated early (see Table 199-1). Although a single dose of doxycycline may be curative, optimal therapy should be continued for 2–3 days after defervescence. BZD is treated identically to primary epidemic typhus. Therapy failures have been documented with azithromycin for BZD.25
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Prevention begins with regular bathing and clothes washing. Delousing with appropriate agents, such as permethrin, malathion, lindane or DDT, is effective. A vaccine is available, but recommended only for high-risk groups.
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Scrub typhus (Tsutsugamushi fever or chigger fever), is a mite-transmitted zoonosis caused by Orientia tsutsugamushi. The vector is the larval stage (chigger) of the trombiculid mite (Leptotrombidium deliense and other Leptotrombidium sp.). The mites and the rodents that carry them serve as the major reservoirs.
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Named for the type of vegetation that harbors the mite vector, scrub typhus is endemic to a region spanning the Indian subcontinent to Eastern Asia and the Western Pacific Rim (Japan, Korea, India, Pakistan, Taiwan, Southeast Asia, and Australia). Scrub vegetation is a transitional terrain between tall forests and cleared land, composed of plantations, fields, groves, and tall grass. Accordingly, the illness is more common in rural settings and is a common occupational disease. Because of the long incubation period, scrub typhus can present in travelers returning to nonepidemic areas.
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Clinical and Laboratory Findings
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An erythematous papule appears within 2 days of the chigger bite and undergoes ulceration and eschar formation in one-half to two-thirds of patients. The eschar may be absent in intertriginous areas. Regional lymphadenopathy is followed by generalized lymphadenopathy. One to 2 weeks after the bite, there is a sudden onset of high fever [40°–40.6°C, (104°–105°F)]. Chills, headache, cough, myalgia, anorexia, nausea, diarrhea, dyspnea, ocular pain, and conjunctival injection are variably present. A centrifugal macular and then papular eruption occurs in approximately 35% of cases about 4–5 days after the fever begins. The eruption starts on the trunk, spreads to the extremities, and fades within a few days. Hepatosplenomegaly and a relative bradycardia may be appreciated. Severe complications include adult respiratory distress syndrome, myocarditis, pericarditis, disseminated intravascular coagulation, hemophagocytic syndrome, retinal vein occlusion, renal failure, and hepatitis. Nuchal rigidity, meningoencephalitis, tremors, slurred speech, deafness, and tinnitus are seen rarely. Examination of the cerebrospinal fluid in these cases reveals only a slight monocytosis.
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Diagnosis and Differential Diagnosis
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The differential diagnosis is similar to that for endemic typhus. Enzyme-linked immunosorbent assay, dot blot urine immunoassay, rapid immunochromatographic flow assay, and PCR have the greatest sensitivity and specificity but are limited by their availability in endemic areas. Diagnostically, IFA remains the gold standard. Conclusive diagnosis is based on a fourfold increase in titer of paired samples drawn at least 2 weeks apart. A single acute titer of more than 1:50 can be used as a preliminary diagnostic cutoff in travelers returning from endemic areas.26 In 2009, an association was reported between high O. tsutsugamushi DNA loads determined by PCR and disease severity.27
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Although single dose or short courses (3 days) of doxycycline may prove to be efficacious, treatment is recommended for 14 days. Naturally occurring doxycycline- and chloramphenicol-resistant strains of O. tsutsugamushi have been found in Northern Thailand, Azithromycin, rifampin, and ciprofloxacin are alternatives in this setting.28 With the institution of proper antibiotics, defervescence occurs abruptly, usually within 24 hours. In untreated patients, fever lasts for about 2 weeks. Vaccine development has yielded disappointing results; however, is crucial in this era of antibiotic resistance.29
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DEET applied to the skin or impregnated into clothing is effective at preventing transmission. Chemoprophylaxis with weekly doxycycline may be efficacious when traveling to endemic areas. Rodent control may paradoxically increase the risk of human disease as chiggers lose their natural host and target humans.