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InternalMed_Harrison. The differential diagnosis of leptospirosis is broad, reflecting the diverse clinical presentations of the disease. Although leptospirosis transmission is more common in tropical and subtropical regions, the absence of a travel history does not exclude the diagnosis. When fever, headache, and myalgia predominate, influenza and other common and less common (e.g., dengue and chikungunya) viral infections should be considered. Malaria, typhoid fever, ehrlichiosis, viral hepatitis, and acute HIV infection may mimic the early stages of leptospirosis and are important to recognize. Rickettsial diseases, hantavirus infections (hemorrhagic fever with renal syndrome or hantavirus cardiopulmonary syndrome), and dengue share epidemiologic and clinical features with leptospirosis. Dual infections have been reported. In this light, it is advisable to conduct serologic testing for hantavirus, rickettsiae, and dengue virus when leptospirosis is suspected. When bleeding is detected, dengue


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InternalMed_Harrison. have been reported. In this light, it is advisable to conduct serologic testing for hantavirus, rickettsiae, and dengue virus when leptospirosis is suspected. When bleeding is detected, dengue hemorrhagic fever and other viral hemorrhagic fevers, including hantavirus infection, yellow fever, Rift Valley fever, filovirus infections, and Lassa fever, should be considered.


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InternalMed_Harrison. Severe leptospirosis should be treated with IV penicillin (Table 208-1) as soon as the diagnosis is considered. Leptospires are highly susceptible to a broad range of antibiotics, and early intervention may prevent the development of major organ system failure or lessen its severity. Although studies supporting antibiotic therapy have produced conflicting results, clinical trials are difficult to perform in settings where patients frequently present for medical care with late stages of disease. Antibiotics are less likely to benefit patients in whom organ damage has already occurred. Two open-label randomized studies comparing penicillin with parenteral cefotaxime, parenteral ceftriaxone, and doxycycline showed no significant differences among the antibiotics with regard to complications and mortality risk. Thus ceftriaxone, cefotaxime, or doxycycline is a satisfactory alternative to penicillin for the treatment of severe leptospirosis.


InternalMed_Harrison

InternalMed_Harrison. In mild cases, oral treatment with doxycycline, azithromycin, ampicillin, or amoxicillin is recommended. In regions where rickettsial diseases are coendemic, doxycycline or azithromycin is the drug of choice. In rare instances, a Jarisch-Herxheimer reaction develops within hours after the initiation of antimicrobial therapy. Moderate/severe leptospirosis Penicillin (1.5 million units IV or IM q6h) or Ceftriaxone (2 g/d IV) or Cefotaxime (1 g IV q6h) or Doxycycline (loading dose of 200 mg IV, aAll regimens are given for 7 days. bDoxycycline should not be given to pregnant women or children. c The efficacy of doxycycline prophylaxis in endemic or epidemic settings remains unclear. Experiments in animal models and a cost-effectiveness model indicate that azithromycin has a number of characteristics that may make it efficacious in treatment and prophylaxis.


InternalMed_Harrison

InternalMed_Harrison. Aggressive supportive care for leptospirosis is essential and can be life-saving. Patients with nonoliguric renal dysfunction require aggressive fluid and electrolyte resuscitation to prevent dehydration and precipitation of oliguric renal failure. Peritoneal dialysis or hemodialysis should be provided to patients with oliguric renal failure. Rapid initiation of hemodialysis has been shown to reduce mortality risk and typically is necessary only for short periods. Patients with pulmonary hemorrhage may have reduced pulmonary compliance (as seen in ARDS) and may benefit from mechanical ventilation with low tidal volumes to avoid high ventilation pressures. Evidence is contradictory for the use of glucocorticoids and desmopressin as adjunct therapy for pulmonary involvement associated with severe leptospirosis.


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InternalMed_Harrison. Most patients with leptospirosis recover. However, post-leptospirosis symptoms, mainly of a depression-like nature, may occur and persist for years after the acute disease. Mortality rates are highest among patients who are elderly and those who have severe disease (pulmonary hemorrhage, Weil’s syndrome). Leptospirosis during pregnancy is associated with high fetal mortality rates. Long-term follow-up of patients with renal failure and hepatic dysfunction has documented good recovery of renal and hepatic function. Individuals who may be exposed to Leptospira through their occupations or their involvement in recreational freshwater activities should be informed about the risks. Measures for controlling leptospirosis include avoidance of exposure to urine and tissues from infected animals through proper eyewear, footwear, and other protective equipment. Targeted rodent control strategies could be considered.


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InternalMed_Harrison. Vaccines for agricultural and companion animals are gener ally available, and their use should be encouraged. The veteri nary vaccine used in a given area should contain the serovars known to be present in that area. Unfortunately, some vaccinated animals still excrete leptospires in their urine. Vaccination of humans against a specific serovar prevalent in an area has been undertaken in some European and Asian countries and has proved effective. Although a large-scale trial of vaccine in humans has been reported from Cuba, no conclusions can be drawn about efficacy and adverse reactions because of insufficient details on study design. The efficacy of chemoprophylaxis with doxycycline (200 mg once a week) or azithromycin (in pregnant women and children) is being disputed, but focused pre-and postexposure administration is indicated in instances of well-defined short-term exposure (Table 208-1).


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InternalMed_Harrison. 1146 Relapsing Fever Alan G. Barbour Relapsing fever is caused by infection with any of several species of Borrelia spirochetes. Physicians in ancient Greece distinguished relapsing fever from other febrile disorders by its characteristic clinical presentation: two or more fever episodes separated by varying peri-209 ods of well-being. In the nineteenth century, relapsing fever was one of the first diseases to be associated with a specific microbe by virtue of its characteristic laboratory finding: the presence of large numbers of spirochetes of the genus Borrelia in the blood.


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InternalMed_Harrison. The host responds with systemic inflammation that results in an illness ranging from a flulike syndrome to sepsis. Other manifestations are the consequences of central nervous system (CNS) involvement and coagulopathy. Antigenic variation of the spirochetes’ surface proteins accounts for the infection’s relapsing course. Acquired immunity follows the serial development of antibodies to each of the several variants appearing during an infection. Treatment with antibiotics results in rapid cure but at the risk of a moderate to severe Jarisch-Herxheimer reaction. the twentieth century and currently occurs in northeastern


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InternalMed_Harrison. the twentieth century and currently occurs in northeastern Africa. At present, however, most cases of relapsing fever are tick-borne in origin. Sporadic cases and small outbreaks are focally distributed on most continents, with Africa most affected. In North America, the majority of reports of relapsing fever have been from the western United States and Canada. Nevertheless, the recent discovery that another species in the relapsing fever group causes human disease in the same geographic distribution as Lyme disease (Chap. 210) confounds epidemiologic distinctions between the two major types of Borrelia infection.


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InternalMed_Harrison. Coiled, thin microscopic filaments that swim in one direction and then coil up before heading in another were first observed in the blood of patients with relapsing fever in the 1880s (www.youtube .com/watch?v=VxDPV2lBd9U). These microbes were categorized as spirochetes and grouped as several species in the genus Borrelia. It was not until the 1960s that the organisms were isolated in pure culture. The breakthrough cultivation medium and its derivatives are rich in their ingredients, ranging from simple (e.g., amino acids and N-acetylglucosamine) to more complex (e.g., serum and protein hydrolysates). The limited biosynthetic capacity of Borrelia cells is accounted for by a genome content one-quarter that of Escherichia coli.


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InternalMed_Harrison. Like other spirochetes, the helix-shaped Borrelia cells have two membranes, the outer of which is more loosely secured than in other double-membrane bacteria, such as E. coli. As a consequence, fixed organisms with damaged membranes can assume a variety of morphologies in smears and histologic preparations. The flagella of spirochetes run between the two membranes and are not on the cell surface. Although technically gram-negative in their staining properties, the 10to 20-μm-long Borrelia cells, with a diameter of 0.1–0.2 μm, are too narrow to be seen by bright-field microscopy of Gram-stained specimens.


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InternalMed_Harrison. The several species of Borrelia that cause relapsing fever have restricted geographic distributions (Table 209-1). The excep tion is Borrelia recurrentis, which is also the only species transmitted by the louse. Louse-borne relapsing fever (LBRF) is usually acquired from a body louse (Pediculus humanus corporis), with humans serving as the reservoir. Acquisition occurs not from the bite itself but from either rubbing the insect’s feces into the bite site with the fingers in response to irritation or inoculation of feces into the conjunctivae or an open wound. Although LBRF transmission is currently limited to Ethiopia and adjacent countries, the disease has had a global distribution in the past, and that potential remains. Epidemics with thousands of cases of LBRF can occur under circumstances of famine, natural disaster, refugee migration, and war.


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InternalMed_Harrison. All other known species of relapsing fever agents are tick-borne—in most cases, by soft ticks of the genus Ornithodoros (Fig. 209-1). Tick-borne relapsing fever (TBRF) is found on most continents but is absent or rare in tropical, low-desert, arctic, or alpine environments. For most species, the reservoirs of infection are small to medium-sized mammals, usually rodents but sometimes pigs and other domestic animals living in or around human habitats. However, one species, Borrelia duttonii in sub-Saharan Africa, is largely maintained by tick transmission between human hosts. In North America, TBRF occurs as single cases or small case clusters through transient exposure of persons to infested buildings or caves in less populated areas where the rodent reservoirs have nests. The two main Borrelia species involved in North America are Borrelia hermsii (in the mountainous west) and Borrelia turicatae (in the southwestern and south-central regions). The soft tick vectors typically feed for


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InternalMed_Harrison. species involved in North America are Borrelia hermsii (in the mountainous west) and Borrelia turicatae (in the southwestern and south-central regions). The soft tick vectors typically feed for no more than 30 min, usually without being noticed, while the victim is sleeping. Transovarial transmission from one generation of ticks to the next means that infection risk may persist in an area long after incriminated mammalian reservoirs have been eradicated.


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InternalMed_Harrison. A newly recognized pathogen, Borrelia miyamotoi, belongs to the clade of relapsing fever species but is transmitted to humans from other mammals by hard ticks (e.g., Ixodes scapularis in the eastern United States) that also transmit Lyme disease, babesiosis, anaplasmosis, ehrlichiosis, and arboviral encephalitis. B. miyamotoi is acquired through outdoor activities and through contact with ticks in forested and shrubby areas during recreation, work, or activities around the home. In residents of areas where B. miyamotoi and Borrelia burgdorferi coexist, the prevalence of antibodies to the former is about one-third of that to the latter. Unlike LBRF spirochetes, TBRF spirochetes enter the body in the tick’s saliva with the onset of feeding. From an inoculum of a few cells, the spirochetes proliferate in the blood, doubling every 6 h to numbers of 106–107/mL or more. Borrelia species are extracellular pathogens; their


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InternalMed_Harrison. TABLE 209-1 RELAPsIng FEvER BORRELIA sPECIEs, By gEOgRAPHIC REgIOn, vECTOR, And PRIMARy REsERvOIR aAlthough transmission is currently limited to Ethiopia and adjacent countries, B. recurrentis infection has had a global distribution in the past, and that potential remains. FIGuRE 209-1 Ornithodoros turicata soft ticks of different ages.


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InternalMed_Harrison. FIGuRE 209-1 Ornithodoros turicata soft ticks of different ages. presence inside cells likely represents a dead end for the bacteria after phagocytosis. Binding of the spirochetes to erythrocytes leads to aggregation of red blood cells, their sequestration in the spleen and liver, and hepatosplenomegaly and anemia. A bleeding disorder is probably the consequence of thrombocytopenia, impaired hepatic production of clotting factors, and/or blockage of small vessels by aggregates of spirochetes, erythrocytes, and platelets. Some species are neurotropic and frequently enter the brain, where they are comparatively sheltered from host immunity. Relapsing fever spirochetes can cross the maternal-fetal barrier and cause placental damage and inflammation, leading to intrauterine growth retardation and congenital infection.


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InternalMed_Harrison. Although Borrelia species do not have potent exotoxins or a lipopolysaccharide endotoxin, they have abundant membrane-associated lipoproteins whose recognition and binding by Toll-like receptors on host cells can lead to a proinflammatory process similar to that in endotoxemia, with elevations of tumor necrosis factor α, interleukin 6, and interleukin 8 concentrations.


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InternalMed_Harrison. IgM antibodies specific for the serotype-defining surface lipoprotein appear after a few days of infection and soon reach a concentration that causes lysis of bacteria in the blood through either direct bactericidal action or opsonization. The release of large amounts of lipoproteins and other bacterial products from dying bacteria provokes a “crisis,” during which there can be an increase in temperature, hypotension, and other signs of shock. A similar phenomenon occurring in some patients soon after the initiation of antibiotic treatment is characterized by the abrupt worsening of the condition, which is called a Jarisch-Herxheimer reaction (JHR).


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InternalMed_Harrison. Relapsing fever presents with the sudden onset of fever. Febrile periods are punctuated by intervening afebrile periods of a few days; this pattern occurs at least twice. The patient’s temperature is ≥39°C and may be as high as 43°C. The first fever episode often ends in a crisis lasting ~15–30 min and consisting of rigors, a further elevation in temperature, and increases in pulse and blood pressure. The crisis phase is followed by profuse diaphoresis, falling temperature, and hypotension, which usually persist for several hours. In LBRF, the first episode of fever is unremitting for 3–6 days; it is usually followed by a single milder episode. In TBRF, multiple febrile periods last 1–3 days each. In both forms, the interval between fevers ranges from 4 to 14 days, sometimes with symptoms of malaise and fatigue.


InternalMed_Harrison

InternalMed_Harrison. The symptoms that accompany the fevers are usually nonspecific. Headache, neck stiffness, arthralgia, myalgia, and nausea may accompany the first and subsequent febrile episodes. An enlarging spleen and liver cause abdominal pain. A nonproductive cough is common during LBRF and—in combination with fever and myalgias—may suggest influenza. Acute respiratory distress syndrome may occur during TBRF. On physical examination, the patient may be delirious or apathetic. There may be body lice in the patient’s clothes or signs of insect bites. In regions with B. miyamotoi infection, a hard tick may be embedded in the skin. Epistaxis, petechiae, and ecchymoses are common during LBRF but not in TBRF. Splenomegaly or spleen tenderness is common in both forms of relapsing fever. The majority of patients with LBRF and ~10% of patients with TBRF have discernible hepatomegaly.


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InternalMed_Harrison. Localizing neurologic findings are more common in TBRF than in LBRF. In North America, B. turicatae infection has neurologic manifestations more often than B. hermsii infection. Meningoencephalitis can result in residual hemiplegia or aphasia. Myelitis and radiculopathy may develop. Unilateral or bilateral Bell’s palsy and deafness from sev-1147 enth or eighth cranial nerve involvement are the most common forms of cranial neuritis and typically present in the second or third febrile episode, not the first. Visual impairment from unilateral or bilateral iridocyclitis or panophthalmitis may be permanent. In LBRF, neurologic manifestations such as altered mental state or stiff neck are thought to be secondary to spirochetemia and systemic inflammation rather than to direct invasion of the nervous system.


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InternalMed_Harrison. Myocarditis appears to be common in both forms of relapsing fever and accounts for some deaths. Most commonly, myocarditis is evidenced by gallops on cardiac auscultation, a prolonged QTc interval, and cardiomegaly and pulmonary edema on chest radiography. General laboratory studies are not specific. Mild to moderate normocytic anemia is common, but frank hemolysis and hemoglobinuria do not develop. Leukocyte counts are usually in the normal range or only slightly elevated, and leukopenia can occur during the crisis. Platelet counts can fall below 50,000/µL. Laboratory evidence of hepatitis can be found, with elevated serum concentrations of unconjugated bilirubin and aminotransferases; the prothrombin and partial thromboplastin times may be moderately prolonged.


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InternalMed_Harrison. Analysis of the cerebrospinal fluid (CSF) is indicated in cases of suspected relapsing fever with signs of meningitis or meningoencephalitis. The presence of mononuclear pleocytosis and mildly to moderately elevated protein levels justifies intravenous antibiotic therapy in TBRF. The manifestations and course of B. miyamotoi infection remain incompletely characterized, but reports to date indicate that the sign most often reported by patients at presentation is fever without respi ratory symptoms starting 1–2 weeks after a tick bite and recurring once or twice in some cases. Meningoencephalitis with spirochetes in the CSF was documented in one immunodeficient adult. Relapsing fever should be considered in a patient with the characteristic fever pattern and a history of recent exposure—i.e., within 1–2 weeks before illness onset—to body lice or soft-bodied ticks in geographic areas with documented current or past transmission.


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InternalMed_Harrison. Because of the longevity of the ticks and the transovarial transmission of the pathogen in the ticks, a case of relapsing fever may be diagnosed many years after the last case reported in that locale.


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InternalMed_Harrison. The bedrock for laboratory diagnosis remains the same as it has been for a century: direct detection of the spirochetes by microscopy of the blood. Manual differential counts of white blood cells by Wright or Giemsa stain usually reveal spirochetes in thin blood smears if their concentration is ≥105/mL and several oil-immersion fields are examined (Fig. 209-2). The preferred time to obtain a blood specimen is between the fever’s onset and its peak. Lower concentrations of spirochetes may be revealed by a thick blood smear that is either directly stained with acridine orange and then examined by fluorescence microscopy or treated with 0.5% acetic acid before Giemsa or Wright staining. An alternative to a fixed blood smear is a wet mount of anti-coagulated blood mixed with saline and examined by phase-contrast or dark-field microscopy for motile spirochetes.


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InternalMed_Harrison. Polymerase chain reaction (PCR) and similar DNA amplification procedures are increasingly used for examination of an extract of blood. PCR may reveal spirochetes between febrile episodes, since there are already escape variants in the population when the first wave of bacteria is neutralized. Culture of blood or CSF in Barbour-Stoenner-Kelly broth medium is an option for isolation of Borrelia species except for B. miyamotoi, which is noncultivable or poorly cultivable. However, few laboratories offer this service. An alternative for tick-borne Borrelia species, including B. miyamotoi, is inoculation of blood or CSF into immunodeficient mice and examination of the animal’s blood after a few days.


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InternalMed_Harrison. Options for serologic confirmation of infection are limited. Most assays that are available commercially or in reference laboratories are based on whole cells of a single Borrelia species. These assays may not detect the major variant antigens to which the patient is mainly responding or may yield false-positive results due to antibodies to cross-reactive antigens of related bacteria, including B. burgdorferi. The most FIGuRE 209-2 Photomicrograph of tick-borne relapsing fever spirochete (Borrelia turicatae) in a Wright-Giemsa-stained thin blood smear. Included in the figure are a polymorphonuclear leukocyte and two platelets. promising new assays under development are based on recombinant antigens such as GlpQ, a protein antigen of all relapsing fever Borrelia species (including B. miyamotoi) but not of any Lyme disease species.


InternalMed_Harrison

InternalMed_Harrison. Depending on the patient’s history of residential, occupational, travel, and recreational exposures, the differential diagnosis of relapsing fever includes one or more of the following infections that feature either periodicity in the fever pattern or an extended single febrile period with nonspecific constitutional symptoms: Colorado tick fever (which, along with dengue, can have a “saddleback” fever course), Rocky Mountain spotted fever and other rickettsioses, ehrlichiosis, anaplasmosis, tick-borne arbovirus infection, and babesiosis in North America, Europe, Russia, and northeastern Asia. Elsewhere in the Americas and Asia and in most of Africa, malaria, typhoid fever, typhus and other rickettsioses, dengue, brucellosis, and leptospirosis may also be considered. Depending on the geographic area and types of exposure, malaria, louse-borne typhus, typhoid fever, or Lyme disease may complicate relapsing fever.


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InternalMed_Harrison. Penicillins and tetracyclines have been the antibiotics of choice for relapsing fever for several decades. Erythromycin has been a longstanding second choice. There is no evidence of acquired resistance to these antibiotics. Borrelia species are also susceptible to most cephalosporins and chloramphenicol, but there is less clinical experience with these drugs. Borreliae are relatively resistant to rifampin, sulfonamides, fluoroquinolones, and aminoglycosides. Spirochetes are no longer detectable in the blood within a few hours after the first dose of an effective antibiotic.


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InternalMed_Harrison. A single dose of antibiotic is usually sufficient for the treatment of LBRF (Fig. 209-3). The recurrence rate after antibiotic treatment is ≤5%. For adults, a single dose of oral tetracycline (500 mg), oral doxycycline (200 mg), or intramuscular penicillin G procaine (400,000– 800,000 units) is effective. The corresponding doses for children are oral tetracycline at 12.5 mg/kg, oral doxycycline at 5 mg/kg, and intramuscular penicillin G procaine at 200,000–400,000 units. Oral therapy Single dose therapy Intravenous ceftriaxone 2 g qd or Na penicillin G, 5 million U q6h for 14 days First choiceFirst choiceMeningitis/encephalitis Tick-borne relapsing fever Louse-borne relapsing fever


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InternalMed_Harrison. Age š9 years, not pregnant: Age š9 years, not pregnant: doxcycline, 100 mg bid doxycycline 200 mg oral or Age <9 years: erythromycin, tetracycline 500 mg oral or 12.5 mg/kg per day 250–500 mg IV Second choice Age <9 years: erythromycin Age š9 years, not pregnant: 12.5 mg/kg oral tetracycline 500 mg qid Second choice Third choice Penicillin G procaine IM Age š9 years: erythromycin, 800,000 U adults 500 mg qid 200,000–400,000 U children Duration: 10 days Third choice Age š9 years: erythromycin 500 mg oral FIGuRE 209-3 Algorithm for treatment of relapsing fever. If it is not known whether the patient has tick-borne or louse-borne relapsing fever, the patient should be treated for the tick-borne form. The dashed line indicates that central nervous system invasion in louse-borne relapsing fever is uncommon.


InternalMed_Harrison

InternalMed_Harrison. When an adult patient is stuporous or nauseated, the intravenous dose is 250–500 mg. Tetracycline is contraindicated in pregnant and nursing women and in children <9 years old; for individuals in these groups who are allergic to penicillin, oral erythromycin (500 mg for adults and 12.5 mg/kg for children) is an alternative. Tetracycline is marginally superior to penicillin G in terms of time to fever clearance and relapse rate.


InternalMed_Harrison

InternalMed_Harrison. The accumulated anecdotal reports on TBRF therapy indicate a recurrence rate of ≥20% after single-dose treatment. This high rate of recurrence plausibly is due to the greater propensity of tick-borne species than of B. recurrentis to invade the CNS, from which they can reinvade the bloodstream after antibiotic levels decline. Accordingly, multiple antibiotic doses are recommended. The preferred treatment for adults is a 10-day course of tetracycline (500 mg or 12.5 mg/kg orally every 6 h) or doxycycline (100 mg twice daily). When tetracyclines are contraindicated, the alternative is erythromycin (500 mg or 12.5 mg/kg orally every 6 h) for 10 days. If a β-lactam antibiotic is given, it should be administered intravenously rather than orally, especially if CNS involvement is confirmed or suspected. For adults, the regimen is penicillin G (5 million units IV every 6 h) or ceftriaxone (2 g IV daily) for 10–14 days.


InternalMed_Harrison

InternalMed_Harrison. Experience with the treatment of B. miyamotoi infection is limited, but this organism likely has the same antibiotic susceptibilities as other Borrelia species. Until more is known about treatment efficacy, therapy for B. miyamotoi infection can follow the guidelines for Lyme disease—including parenteral therapy for CNS involvement— because it may be difficult to rule out co-infection. The JHR during treatment of relapsing fever can be severe and can even end in death if precautions are not in place for close monitoring and provision of cardiovascular and volume support as needed. Rigors, fever, and hypotension occur within 2–3 h of initiation of antibiotic treatment. The incidence of the JHR is ~80% in LBRF and ~50% in TBRF. Both penicillin and tetracycline can elicit the JHR. The mortality rates for untreated LBRF and TBRF are in the ranges of 10–70% and 4–10%, respectively, and are largely determined by coexisting conditions, such as malnutrition and dehydration.


InternalMed_Harrison

InternalMed_Harrison. Death from untreated relapsing fever is most common during the first fever episode. With prompt antibiotic treatment, the mortality rate is 2–5% for LBRF and <2% for TBRF. Features associated with a poor prognosis include concurrence with malaria, typhus, or typhoid; pregnancy; stupor or coma on admission; diffuse bleeding; poor liver function; myocarditis; and bronchopneumonia. The mortality rate from the JHR in LBRF, in the absence of adequate monitoring and resuscitation measures, is ~5%. Some patients have survived the crisis or the JHR only to die suddenly either later that day or on the next day. Relapsing fever during pregnancy frequently leads to abortion or stillbirth, but congenital malformations have not been reported. Although it is possible that spirochetes may persist in the CNS or other sequestered sites after bacteremia has resolved, chronic disease or disability from a persistent infection has not been attributed to relapsing fever. Partial immunity against


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InternalMed_Harrison. in the CNS or other sequestered sites after bacteremia has resolved, chronic disease or disability from a persistent infection has not been attributed to relapsing fever. Partial immunity against reinfection seems to develop in residents of endemic areas.


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InternalMed_Harrison. There is no vaccine for either LBRF or TBRF. Reduction of exposure to lice and ticks is the key strategy for prevention. LBRF can be prevented through improved personal hygiene, reduction of crowding, better access to washing facilities, and selected use of pesticides. Infested clothing is an important factor in maintaining body lice. The risk of TBRF can be reduced by construction of houses with concrete or sealed plank floors and without thatched roofs or mud walls. Log cabins pose a particular risk in North America when rodents nest in the roof or beneath the house or porch. Interiors of buildings infested with Ornithodoros ticks can be treated with pesticides. If residing in a high-risk environment, individuals should not sleep on the floor, and beds should be moved away from the wall. With an exposure to TBRF, postexposure treatment with doxycycline (200 mg on day 1 followed by 100 mg/d for 4 days) was efficacious in preventing infection in a placebo-controlled trial.


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InternalMed_Harrison. Lyme Borreliosis Allen C. Steere DEFINITION Lyme borreliosis is caused by a spirochete, Borrelia burgdorferi sensu lato, that is transmitted by ticks of the Ixodes ricinus complex. The infec-tion usually begins with a characteristic expanding skin lesion, erythema 210 migrans (EM; stage 1, localized infection). After several days or weeks, the spirochete may spread to many different sites (stage 2, disseminated infection). Possible manifestations of disseminated infection include secondary annular skin lesions, meningitis, cranial neuritis, radiculoneuritis, peripheral neuritis, carditis, atrioventricular nodal block, or migratory musculoskeletal pain. Months or years later (usually after periods of latent infection), intermittent or persistent arthritis, chronic encephalopathy or polyneuropathy, or acrodermatitis may develop (stage 3, persistent infection). Most patients experience early symptoms of the illness during the summer, but the infection may not become symptomatic until it


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InternalMed_Harrison. or acrodermatitis may develop (stage 3, persistent infection). Most patients experience early symptoms of the illness during the summer, but the infection may not become symptomatic until it progresses to stage 2 or 3.


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InternalMed_Harrison. Lyme disease was recognized as a separate entity in 1976 because of a geographic cluster of children in Lyme, Connecticut, who were thought to have juvenile rheumatoid arthritis. It became apparent that Lyme disease was a multisystemic illness that affected primarily the skin, nervous system, heart, and joints. Epidemiologic studies of patients with EM implicated certain Ixodes ticks as vectors of the disease. Early in the twentieth century, EM had been described in Europe and attributed to I. ricinus tick bites. In 1982, a previously unrecognized spirochete, now called Borrelia burgdorferi, was recovered from Ixodes scapularis ticks and then from patients with Lyme disease. The entity is now called Lyme disease or Lyme borreliosis.


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InternalMed_Harrison. B. burgdorferi, the causative agent of Lyme disease, is a fastidious microaerophilic bacterium. The spirochete’s genome is quite small (~1.5 Mb) and consists of a highly unusual linear chromo some of 950 kb as well as 17–21 linear and circular plasmids. The most remarkable aspect of the B. burgdorferi genome is that there are sequences for more than 100 known or predicted lipoproteins—a larger number than in any other organism. The spirochete has few proteins with biosynthetic activity and depends on its host for most of its nutritional requirements. It has no sequences for recognizable toxins.


InternalMed_Harrison

InternalMed_Harrison. Currently, 13 closely related borrelial species are collectively referred to as Borrelia burgdorferi sensu lato (i.e., “B. burgdor feri in the general sense”). The human infection Lyme borreliosis is caused primarily by three pathogenic genospecies: B. burgdorferi sensu stricto (“B. burgdorferi in the strict sense,” hereafter referred to simply as B. burgdorferi), Borrelia garinii, and Borrelia afzelii. B. burgdorferi is the sole cause of the infection in the United States; all three genospecies are found in Europe, and the latter two species occur in Asia.


InternalMed_Harrison

InternalMed_Harrison. Strains of B. burgdorferi have been subdivided according to several typing schemes: one based on sequence variation of outer-surface protein C (OspC), a second based on differences in the 16S–23S rRNA intergenic spacer region (RST or IGS), and a third called multilocus sequence typing. From these typing systems, it is apparent that strains of B. burgdorferi differ in pathogenicity. OspC type A (RST1) strains seem to be particularly virulent and may have played a role in the emergence of Lyme disease in epidemic form in the northeastern United States in the late twentieth century. The 13 known genospecies of B. burgdorferi sensu lato live in nature in enzootic cycles involving 14 species of ticks that are part of the I. ricinus complex. I. scapularis (Fig. 475-1) is the principal vector in the eastern United States from Maine to Georgia and in the midwestern states of Wisconsin, Minnesota, and Michigan.


InternalMed_Harrison

InternalMed_Harrison. I. pacificus is the vector in the western states of California and Oregon. The disease is acquired throughout Europe (from Great Britain to Scandinavia to European Russia), where I. ricinus is the vector, and in Asian Russia, China, and Japan, where I. persulcatus is the vector. These ticks may transmit other agents as well. In the United States, I. scapularis also transmits Babesia microti; Anaplasma phagocytophilum; Ehrlichia species Wisconsin; Borrelia miyamotoi; and, in rare instances, Powassan encephalitis virus (the deer tick virus) (see “Differential Diagnosis,” below). In Europe and Asia, I. ricinus and I. persulcatus also transmit tick-borne encephalitis virus.


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InternalMed_Harrison. Ticks of the I. ricinus complex have larval, nymphal, and adult stages. They require a blood meal at each stage. The risk of infection in a given area depends largely on the density of these ticks as well as their feeding habits and animal hosts, which have evolved differently in different locations. For I. scapularis in the northeastern United States, the white-footed mouse and certain other rodents are the preferred hosts of the immature larvae and nymphs. It is critical that both of the tick’s immature stages feed on the same host because the life cycle of the spirochete depends on horizontal transmission: in early summer from infected nymphs to mice and in late summer from infected mice to larvae, which then molt to become the infected nymphs that will begin the cycle again the following year. It is the tiny nymphal tick that is primarily responsible for transmission of the disease to humans during the early summer months. White-tailed deer, which are not involved in the life


InternalMed_Harrison

InternalMed_Harrison. year. It is the tiny nymphal tick that is primarily responsible for transmission of the disease to humans during the early summer months. White-tailed deer, which are not involved in the life cycle of the spirochete, are the preferred host for the adult stage of I. scapularis and seem to be critical to the tick’s survival.


InternalMed_Harrison

InternalMed_Harrison. Lyme disease is now the most common vector-borne infection in the United States and Europe. Since surveillance was begun by the Centers for Disease Control and Prevention (CDC) in 1982, the number of cases in the United States has increased dramatically. More than 30,000 new cases are now reported each summer, but the actual number of new cases is probably closer to 300,000 annually. In Europe, reported frequencies of the disease are highest in the middle of the continent and in Scandinavia.


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InternalMed_Harrison. 1150 PATHOGENESIS AND IMMuNITY To maintain its complex enzootic cycle, B. burgdorferi must adapt to two markedly different environments: the tick and the mammalian host. The spirochete expresses outer-surface protein A (OspA) in the midgut of the tick, whereas OspC is upregulated as the organism travels to the tick’s salivary gland. There, OspC binds a tick salivary-gland protein (Salp15), which is required for infection of the mammalian host. The tick usually must be attached for at least 24 h for transmission of B. burgdorferi. After injection into the human skin, the spirochete downregulates OspC and upregulates the VlsE lipoprotein. This protein undergoes extensive antigenic variation, which is necessary for spirochetal survival. After several days to weeks, B. burgdorferi may migrate outward in the skin, producing EM, and may spread hematogenously or in the lymph to other organs. The only known virulence factors of B. burgdorferi are surface proteins that allow the spirochete to


InternalMed_Harrison

InternalMed_Harrison. outward in the skin, producing EM, and may spread hematogenously or in the lymph to other organs. The only known virulence factors of B. burgdorferi are surface proteins that allow the spirochete to attach to mammalian proteins, integrins, glycosaminoglycans, or glycoproteins. For example, spread through the skin and other tissue matrices may be facilitated by the binding of human plasminogen and its activators to the surface of the spirochete. Some Borrelia strains bind complement regulator–acquiring surface proteins (FHL-1/reconectin, or factor H), which help to protect spirochetes from complement-mediated lysis. Dissemination of the organism in the blood is facilitated by binding to the fibrinogen receptor on activated platelets (αIIbβ3) and the vitronectin receptor (αvβ3) on endothelial cells. As the name indicates, spirochetal decorin-binding proteins A and B bind decorin, a glycosaminoglycan on collagen fibrils; this binding may explain why the organism is commonly aligned with


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InternalMed_Harrison. cells. As the name indicates, spirochetal decorin-binding proteins A and B bind decorin, a glycosaminoglycan on collagen fibrils; this binding may explain why the organism is commonly aligned with collagen fibrils in the extracellular matrix in the heart, nervous system, or joints. To control and eradicate B. burgdorferi, the host mounts both innate and adaptive immune responses, resulting in macrophageand antibody-mediated killing of the spirochete. As part of the innate immune response, complement may lyse the spirochete in the skin. Cells at affected sites release potent proinflammatory cytokines, including interleukin 6, tumor necrosis factor α, interleukin 1β, and interferon γ. Patients who are homozygous for a Toll-like receptor 1 polymorphism (1805GG), particularly when infected with highly inflammatory B. burgdorferi RST1 strains, have exceptionally high levels of proinflammatory cytokines. The purpose of the adaptive immune response appears to be the production of specific


InternalMed_Harrison

InternalMed_Harrison. with highly inflammatory B. burgdorferi RST1 strains, have exceptionally high levels of proinflammatory cytokines. The purpose of the adaptive immune response appears to be the production of specific antibodies, which opsonize the organism—a step necessary for optimal spirochetal killing. Studies with protein arrays expressing ~1200 B. burgdorferi proteins detected antibody responses to a total of 120 spirochetal proteins (particularly outer-surface lipoproteins) in a population of patients with Lyme arthritis. Histologic examination of all affected tissues reveals an infiltration of lymphocytes, macrophages, and plasma cells with some degree of vascular damage, including mild vasculitis or hypervascular occlusion. These findings suggest that the spirochete may have been present in or around blood vessels. In enzootic infection, B. burgdorferi spirochetes must survive this immune assault only during the summer months before returning to larval ticks to begin the cycle again the


InternalMed_Harrison

InternalMed_Harrison. or around blood vessels. In enzootic infection, B. burgdorferi spirochetes must survive this immune assault only during the summer months before returning to larval ticks to begin the cycle again the following year. In contrast, infection of humans is a dead-end event for the spirochete. Within several weeks or months, innate and adaptive immune mechanisms— even without antibiotic treatment—control widely disseminated infection, and generalized systemic symptoms wane. However, without antibiotic therapy, spirochetes may survive in localized niches for several more years. For example, B. burgdorferi infection in the United States may cause persistent arthritis or, in rare cases, subtle encephalopathy or polyneuropathy. Thus, immune mechanisms seem to succeed eventually in the near or total eradication of B. burgdorferi from selected niches, including the joints or nervous system, and symptoms resolve in most patients.


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InternalMed_Harrison. CLINICAL MANIFESTATIONS Early Infection: Stage 1 (Localized Infection) Because of the small size of nymphal ixodid ticks, most patients do not remember the preceding tick bite. After an incubation period of 3–32 days, EM usually begins as a red macule or papule at the site of the tick bite that expands slowly to form a large annular lesion (Fig. 210-1). As the lesion increases in size, it often develops a bright red outer border and partial central clearing. The center of the lesion sometimes becomes intensely erythematous and indurated, vesicular, or necrotic. In other instances, the expanding lesion remains an even, intense red; several red rings are found within an outside ring; or the central area turns blue before the lesion clears. Although EM can be located anywhere, the thigh, groin, and axilla are particularly common sites. The lesion is warm but not often painful. Approximately 20% of patients do not exhibit this characteristic skin manifestation.


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InternalMed_Harrison. FIGuRE 210-1 A classic erythema migrans lesion (9 cm in diameter) is shown near the right axilla. The lesion has partial central clearing, a bright red outer border, and a target center. (Courtesy of Vijay K. Sikand, MD; with permission.)


InternalMed_Harrison

InternalMed_Harrison. Early Infection: Stage 2 (Disseminated Infection) In cases in the United States, B. burgdorferi often spreads hematogenously to many sites within days or weeks after the onset of EM. In these cases, patients may develop secondary annular skin lesions similar in appearance to the initial lesion. Skin involvement is commonly accompanied by severe headache, mild stiffness of the neck, fever, chills, migratory musculoskeletal pain, arthralgias, and profound malaise and fatigue. Less common manifestations include generalized lymphadenopathy or splenomegaly, hepatitis, sore throat, nonproductive cough, conjunctivitis, iritis, or testicular swelling. Except for fatigue and lethargy, which are often constant, the early signs and symptoms of Lyme disease are typically intermittent and changing. Even in untreated patients, the early symptoms usually become less severe or disappear within several weeks. In ~15% of patients, the infection presents with these nonspecific systemic symptoms.


InternalMed_Harrison

InternalMed_Harrison. Symptoms suggestive of meningeal irritation may develop early in Lyme disease when EM is present but usually are not associated with cerebrospinal fluid (CSF) pleocytosis or an objective neurologic deficit. After several weeks or months, ~15% of untreated patients develop frank neurologic abnormalities, including meningitis, subtle encephalitic signs, cranial neuritis (including bilateral facial palsy), motor or sensory radiculoneuropathy, peripheral neuropathy, mononeuritis multiplex, cerebellar ataxia, or myelitis—alone or in various combinations. In children, the optic nerve may be affected because of inflammation or increased intracranial pressure, and these effects may lead to blindness. In the United States, the usual pattern consists of fluctuating symptoms of meningitis accompanied by facial palsy and peripheral radiculoneuropathy. Lymphocytic pleocytosis (~100 cells/μL) is found in CSF, often along with elevated protein levels and normal or slightly low glucose


InternalMed_Harrison

InternalMed_Harrison. accompanied by facial palsy and peripheral radiculoneuropathy. Lymphocytic pleocytosis (~100 cells/μL) is found in CSF, often along with elevated protein levels and normal or slightly low glucose concentrations. In Europe and Asia, the first neurologic sign is characteristically radicular pain, which is followed by the development of CSF pleocytosis (meningopolyneuritis or Bannwarth’s syndrome); meningeal or encephalitic signs are frequently absent. These early neurologic abnormalities usually resolve completely within months, but in rare cases chronic neurologic disease may occur later.


InternalMed_Harrison

InternalMed_Harrison. Within several weeks after the onset of illness, ~8% of patients develop cardiac involvement. The most common abnormality is a fluctuating degree of atrioventricular block (first-degree, Wenckebach, or complete heart block). Some patients have more diffuse cardiac involvement, including electrocardiographic changes indicative of acute myopericarditis, left ventricular dysfunction evident on radionuclide scans, or (in rare cases) cardiomegaly or fatal pancarditis. Cardiac involvement lasts for only a few weeks in most patients but may recur in untreated patients. Chronic cardiomyopathy caused by B. burgdorferi has been reported in Europe. During this stage, musculoskeletal pain is common. The typical pattern consists of migratory pain in joints, tendons, bursae, muscles, or bones (usually without joint swelling) lasting for hours or days and affecting one or two locations at a time.


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InternalMed_Harrison. Late Infection: Stage 3 (Persistent Infection) Months after the onset of infection, ~60% of patients in the United States who have received no antibiotic treatment develop frank arthritis. The typical pattern comprises intermittent attacks of oligoarticular arthritis in large joints (especially the knees), lasting for weeks or months in a given joint. A few small joints or periarticular sites also may be affected, primarily during early attacks. The number of patients who continue to have recurrent attacks decreases each year. However, in a small percentage of cases, involvement of large joints—usually one or both knees—is persistent and may lead to erosion of cartilage and bone.


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InternalMed_Harrison. White cell counts in joint fluid range from 500 to 110,000/μL (average, 25,000/μL); most of these cells are polymorphonuclear leukocytes. Tests for rheumatoid factor or antinuclear antibodies usually give negative results. Examination of synovial biopsy samples reveals fibrin deposits, villous hypertrophy, vascular proliferation, microangiopathic lesions, and a heavy infiltration of lymphocytes and plasma cells.


InternalMed_Harrison

InternalMed_Harrison. Although most patients with Lyme arthritis respond well to antibiotic therapy, a small percentage in the northeastern United States have persistent (antibiotic-refractory) arthritis for months or even for several years after receiving oral and IV antibiotic therapy for 2 or 3 months. Although more often these patients are initially infected with RST1 strains of B. burgdorferi, this complication is not thought to result from persistent infection. Results of culture and polymerase chain reaction (PCR) for B. burgdorferi in synovial tissue obtained in the postantibiotic period have been uniformly negative. Rather, infection-induced autoimmunity, retained spirochetal antigens, or both may play a role in this outcome. Antibiotic-refractory arthritis is associated with a higher frequency of certain class II major histocompatibility complex molecules (particularly HLA-DRBI*0401 or -*0101 molecules); the Toll-like receptor 1 polymorphism 1805GG, which leads to exceptionally high levels of


InternalMed_Harrison

InternalMed_Harrison. certain class II major histocompatibility complex molecules (particularly HLA-DRBI*0401 or -*0101 molecules); the Toll-like receptor 1 polymorphism 1805GG, which leads to exceptionally high levels of cytokines and chemokines in affected joints; and low frequencies of FoxP3+ T regulatory cells in synovial fluid, which correlate with longer posttreatment durations of arthritis. The recent identification of a novel human autoantigen, endothelial cell growth factor, as a target of T and B cell responses in patients with Lyme disease provided the first direct evidence of autoimmune T and B cell responses in this illness. However, multiple spirochetal or additional yet-to-be identified auto-antigens may have a role in antibiotic-refractory arthritis.


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InternalMed_Harrison. Although rare, chronic neurologic involvement also may become apparent from months to several years after the onset of infection, sometimes after long periods of latent infection. The most common form of chronic central nervous system involvement is subtle encephalopathy affecting memory, mood, or sleep, and the most common form of peripheral neuropathy is an axonal polyneuropathy manifested as either distal paresthesia or spinal radicular pain. Patients with encephalopathy frequently have evidence of memory impairment in neuropsychological tests and abnormal results in CSF analyses. In cases of polyneuropathy, electromyography generally shows extensive abnormalities of proximal and distal nerve segments. Encephalomyelitis or leukoencephalitis, a rare manifestation of Lyme borreliosis associated primarily with B. garinii infection in Europe, is a severe neurologic disorder that may include spastic paraparesis, upper motor-neuron bladder dysfunction, and, rarely, lesions in the


InternalMed_Harrison

InternalMed_Harrison. associated primarily with B. garinii infection in Europe, is a severe neurologic disorder that may include spastic paraparesis, upper motor-neuron bladder dysfunction, and, rarely, lesions in the periventricular white matter.


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InternalMed_Harrison. Acrodermatitis chronica atrophicans, the late skin manifesta tion of Lyme borreliosis, has been associated primarily with B. afzelii infection in Europe and Asia. It has been observed especially often in elderly women. The skin lesions, which are usually 1151 found on the acral surface of an arm or leg, begin insidiously with reddish-violaceous discoloration; they become sclerotic or atrophic over a period of years.


InternalMed_Harrison

InternalMed_Harrison. The basic patterns of Lyme borreliosis are similar worldwide, but there are regional variations, primarily between the illness found in North America, which is caused exclusively by B. burgdorferi, and that found in Europe, which is caused primarily by B. afzelii and B. garinii. With each of the Borrelia species, the infection usually begins with EM. However, B. burgdorferi strains in the eastern United States often disseminate widely; they are particularly arthritogenic, and they may cause antibiotic-refractory arthritis. B. garinii typically disseminates less widely, but it is especially neurotropic and may cause borrelial encephalomyelitis. B. afzelii often infects only the skin but may persist in that site, where it may cause several different dermatoborrelioses, including acrodermatitis chronica atrophicans.


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InternalMed_Harrison. Post–Lyme Syndrome (Chronic Lyme Disease) Despite resolution of the objective manifestations of the infection with antibiotic therapy, ~10% of patients (although the reported percentages vary widely) continue to have subjective pain, neurocognitive manifestations, or fatigue symptoms. These symptoms usually improve and resolve within months but may last for years. At the far end of the spectrum, the symptoms may be similar to or indistinguishable from chronic fatigue syndrome (Chap. 464e) and fibromyalgia (Chap. 396). Compared with symptoms of active Lyme disease, post-Lyme symptoms tend to be more generalized or disabling. They include marked fatigue, severe headache, diffuse musculoskeletal pain, multiple symmetric tender points in characteristic locations, pain and stiffness in many joints, diffuse paresthesias, difficulty with concentration, and sleep disturbances. Patients with this condition lack evidence of joint inflammation, have normal neurologic test results, and may


InternalMed_Harrison

InternalMed_Harrison. joints, diffuse paresthesias, difficulty with concentration, and sleep disturbances. Patients with this condition lack evidence of joint inflammation, have normal neurologic test results, and may exhibit anxiety and depression. In contrast, late manifestations of Lyme disease, including arthritis, encephalopathy, and neuropathy, are usually associated with minimal systemic symptoms. Currently, no evidence indicates that persistent subjective symptoms after recommended courses of antibi otic therapy are caused by active infection.


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InternalMed_Harrison. The culture of B. burgdorferi in Barbour-Stoenner-Kelly (BSK) medium permits definitive diagnosis, but this method has been used primarily in research studies. Moreover, with a few exceptions, positive cultures have been obtained only early in the illness—particularly from biopsy samples of EM skin lesions, less often from plasma samples, and occasionally from CSF samples. Later in the infection, PCR is greatly superior to culture for the detection of B. burgdorferi DNA in joint fluid; this is the major use for PCR testing in Lyme disease. However, because B. burgdorferi DNA may persist for at least weeks after spirochetal killing with antibiotics, detection of spirochetal DNA in joint fluid is not an accurate test of active joint infection in Lyme disease and cannot be used reliably to determine the adequacy of antibiotic therapy. The sensitivity of PCR determinations in CSF from patients with neuroborreliosis has been much lower than that in joint fluid. There seems to be little if


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InternalMed_Harrison. the adequacy of antibiotic therapy. The sensitivity of PCR determinations in CSF from patients with neuroborreliosis has been much lower than that in joint fluid. There seems to be little if any role for PCR in the detection of B. burgdorferi DNA in blood or urine samples. Moreover, this procedure must be carefully controlled to prevent contamination.


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InternalMed_Harrison. Because of the problems associated with direct detection of B. burgdorferi, Lyme disease is usually diagnosed by the recognition of a characteristic clinical picture accompanied by serologic confirmation. Although serologic testing may yield negative results during the first several weeks of infection, almost all patients have a positive antibody response to B. burgdorferi after that time. The limitation of serologic tests is that they do not clearly distinguish between active and inactive infection. Patients with previous Lyme disease—particularly in cases progressing to late stages—often remain seropositive for years, even after adequate antibiotic treatment. In addition, ~10% of patients are seropositive because of asymptomatic infection. If these individuals subsequently develop another illness, the positive serologic test for Source: Adapted from the recommendations of the American College of Physicians (G Nichol et al: Ann Intern Med 128:37, 1998, with permission).


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InternalMed_Harrison. Source: Adapted from the recommendations of the American College of Physicians (G Nichol et al: Ann Intern Med 128:37, 1998, with permission). Lyme disease may cause diagnostic confusion. According to an algorithm published by the American College of Physicians (Table 210-1), serologic testing for Lyme disease is recommended only for patients with at least an intermediate pretest probability of Lyme disease, such as those with oligoarticular arthritis. It should not be used as a screening procedure in patients with pain or fatigue syndromes. In such patients, the probability of a false-positive serologic result is higher than that of a true-positive result.


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InternalMed_Harrison. For serologic analysis of Lyme disease in the United States, the CDC recommends a two-step approach in which samples are first tested by enzyme-linked immunosorbent assay (ELISA) and equivocal or positive results are then tested by western blotting. During the first weeks of infection, both IgM and IgG responses to the spirochete should be determined, preferably in both acuteand convalescent-phase serum samples. Approximately 20–30% of patients have a positive response detectable in acute-phase samples, whereas ~70–80% have a positive response during convalescence (2–4 weeks later). After 4–8 weeks of infection (by which time most patients with active Lyme disease have disseminated infection), the sensitivity and specificity of the IgG response to the spirochete are both very high—in the range of 99%—as determined by the two-test approach of ELISA and western blot. At this point and thereafter, a single test (that for IgG) is usually sufficient. In persons with illness of >2 months’


InternalMed_Harrison

InternalMed_Harrison. range of 99%—as determined by the two-test approach of ELISA and western blot. At this point and thereafter, a single test (that for IgG) is usually sufficient. In persons with illness of >2 months’ duration, a positive IgM test result alone is likely to be false-positive and therefore should not be used to support the diagnosis.


InternalMed_Harrison

InternalMed_Harrison. According to current criteria adopted by the CDC, an IgM western blot is considered positive if two of the following three bands are present: 23, 39, and 41 kDa. However, the combination of two such bands may still represent a false-positive result. Misuse or misinterpretation of IgM blots has been a factor in the incorrect diagnosis of Lyme disease in patients with other illnesses. An IgG blot is considered positive if 5 of the following 10 bands are present: 18, 23, 28, 30, 39, 41, 45, 58, 66, and 93 kDa. In European cases, no single set of criteria for the interpretation of immunoblots results in high levels of sensitivity and specificity in all countries.


InternalMed_Harrison

InternalMed_Harrison. The most promising second-generation serologic test is the VlsE C6 peptide IgG ELISA, which employs a 26-mer of the sixth invariant region of the VlsE lipoprotein of B. burgdorferi. The results achieved with this test are similar to those obtained with the standard two-test approach (sonicate IgM and IgG ELISA and western blot). The principal advantage of the C6 peptide ELISA is the early detection of an IgG response, which renders an IgM test unnecessary. However, not all patients with late Lyme disease have a response to the C6 peptide, and this test is not quite as specific as sonicate western blot. Thus, at present, a two-test approach that includes western blot is still recommended. Blotting can also be helpful in assessing the duration of current or past disease.


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InternalMed_Harrison. After successful antibiotic treatment, antibody titers decline slowly but responses (including that to the VlsE C6 peptide) may persist for years. Moreover, not only the IgG but also the IgM response may persist for years after therapy. Therefore, even a positive IgM response cannot be interpreted as confirmation of recent infection or reinfection unless the clinical picture is appropriate.


InternalMed_Harrison

InternalMed_Harrison. Classic EM is a slowly expanding erythema, often with partial central clearing. If the lesion expands little, it may represent the red papule of an uninfected tick bite. If the lesion expands rapidly, it may represent cellulitis (e.g., streptococcal cellulitis) or an allergic reaction, perhaps to tick saliva. Patients with secondary annular lesions may be thought to have erythema multiforme, but neither the development of blistering mucosal lesions nor the involvement of the palms or soles is a feature of B. burgdorferi infection. In the eastern United States, an EM-like skin lesion, sometimes with mild systemic symptoms, may be associated with Amblyomma americanum tick bites. However, the cause of this Southern tick-associated rash illness (STARI) has not yet been identified. This tick may also transmit Ehrlichia chaffeensis, a rickettsial agent (Chap. 211).


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InternalMed_Harrison. As stated above, I. scapularis ticks in the United States may transmit not only B. burgdorferi but also B. microti, a red blood cell parasite (Chap. 249); A. phagocytophilum, the agent of human granulocytotropic anaplasmosis (Chap. 211); Ehrlichia species Wisconsin; B. miyamotoi, a relapsing fever spirochete (Chap. 209); or (rarely) Powassan encephalitis virus (the deer tick virus, which is closely related to European tick-borne encephalitis virus) (Chap. 233). Although babesiosis and anaplasmosis are most often asymptomatic, infection with any of these agents may cause nonspecific systemic symptoms, particularly in the young or elderly, and co-infected patients may have more severe or persistent symptoms than patients infected with a single agent. Standard blood counts may yield clues regarding the presence of co-infection with Anaplasma or Babesia. Anaplasmosis may cause leukopenia or thrombocytopenia, and babesiosis may cause thrombocytopenia or (in severe cases) hemolytic anemia.


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InternalMed_Harrison. the presence of co-infection with Anaplasma or Babesia. Anaplasmosis may cause leukopenia or thrombocytopenia, and babesiosis may cause thrombocytopenia or (in severe cases) hemolytic anemia. IgM serologic responses may confuse the diagnosis. For example, A. phagocytophilum may elicit a positive IgM response to B. burgdorferi. The frequency of co-infection in different studies has been variable. In one prospective study, 4% of patients with EM had evidence of co-infection.


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InternalMed_Harrison. Facial palsy caused by B. burgdorferi, which occurs in the early disseminated phase of the infection (often in July, August, or September), is usually recognized by its association with EM. However, in rare cases, facial palsy without EM may be the presenting manifestation of Lyme disease. In such cases, both the IgM and the IgG responses to the spirochete are usually positive. The most common infectious agents that cause facial palsy are herpes simplex virus type 1 (Bell’s palsy; Chap. 216) and varicella-zoster virus (Ramsay Hunt syndrome; Chap. 217). Later in the infection, oligoarticular Lyme arthritis most resembles reactive arthritis in an adult or the pauciarticular form of juvenile idiopathic arthritis in a child. Patients with Lyme arthritis usually have the strongest IgG antibody responses seen in Lyme borreliosis, with reactivity to many spirochetal proteins.


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InternalMed_Harrison. The most common problem in diagnosis is to mistake Lyme disease for chronic fatigue syndrome (Chap. 464e) or fibromyalgia (Chap. 396). This difficulty is compounded by the fact that a small percentage of patients do in fact develop these chronic pain or fatigue syndromes in association with or soon after Lyme disease. Moreover, a counterculture has emerged that ascribes pain and fatigue syndromes to chronic Lyme disease when there is little or no evidence of B. burgdorferi infection. In such cases, the term chronic Lyme disease, which is equated with chronic B. burgdorferi infection, is a misnomer, and the use of prolonged, dangerous, and expensive antibiotic treatment is not warranted.


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InternalMed_Harrison. As outlined in the algorithm in Fig. 210-2, the various manifestations of Lyme disease can usually be treated successfully with orally administered antibiotics; the exceptions are objective neurologic abnormalities and third-degree atrioventricular heart block, which are generally treated with IV antibiotics, and arthritis that does not Joint Arthritis* Heart AV block Nervous system Facial palsy alone Meningitis Radiculoneuritis Encephalopathy Polyneuropathy Intravenous therapy First choice: ceftriaxone, 2 g qd Second choice: cefotaxime, 2 g q8h Third choice: Na penicillin G, 5 million U q6h 1°, 2° 3° First choice Age ˜ 9 years, not pregnant: doxycycline, 100 mg bid Age < 9 years: amoxicillin, 50 mg/kg per day Second choice for adults: amoxicillin, 500 mg tid Third choice for all ages: cefuroxime axetil, 500 mg bid Fourth choice for all ages: erythromycin, 250 mg qid Neurologic involvement: 14–28 days


InternalMed_Harrison

InternalMed_Harrison. Second choice for adults: amoxicillin, 500 mg tid Third choice for all ages: cefuroxime axetil, 500 mg bid Fourth choice for all ages: erythromycin, 250 mg qid Neurologic involvement: 14–28 days Cardiac involvement: 28 days complete course with oral therapy when patient is no longer in high-degree AV block FIGuRE 210-2 Algorithm for the treatment of the various early or late manifestations of Lyme borreliosis. AV, atrioventricular. *For arthritis, oral therapy should be tried first; if arthritis is unresponsive, IV therapy should be administered. **For Lyme arthritis, IV ceftriaxone (2 g given once a day for 14–28 days) also is effective and is necessary for a small percentage of patients; however, compared with oral treatment, this regimen is less convenient to administer, has more side effects, and is more expensive.


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InternalMed_Harrison. respond to therapy. For early Lyme disease, doxycycline is effective and can be administered to men and nonpregnant women. An advantage of this regimen is that it is also effective against A. phagocytophilum, which is transmitted by the same tick that transmits the Lyme disease agent. Amoxicillin, cefuroxime axetil, and erythromycin or its congeners are second-, third-, and fourth-choice alternatives, respectively. In children, amoxicillin is effective (not more than 2 g/d); in cases of penicillin allergy, cefuroxime axetil or erythromycin may be used. In contrast to secondor third-generation cephalosporin antibiotics, first-generation cephalosporins, such as cephalexin, are not effective. For patients with infection localized to the skin, a 14-day course of therapy is generally sufficient; in contrast, for patients with disseminated infection, a 21-day course is recommended. Approximately 15% of patients experience a Jarisch-Herxheimer-like reaction during the first 24 h of therapy.


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InternalMed_Harrison. in contrast, for patients with disseminated infection, a 21-day course is recommended. Approximately 15% of patients experience a Jarisch-Herxheimer-like reaction during the first 24 h of therapy. In multicenter studies, more than 90% of patients whose early Lyme disease was treated with these regimens had satisfactory outcomes. Although some patients reported symptoms after treatment, objective evidence of persistent infection or relapse was rare, and re-treatment was usually unnecessary.


InternalMed_Harrison

InternalMed_Harrison. Oral administration of doxycycline or amoxicillin for 30 days is recommended for the initial treatment of Lyme arthritis in patients who do not have concomitant neurologic involvement. Among patients with arthritis who do not respond to oral antibiotics, re-treatment with IV ceftriaxone for 28 days is appropriate. In patients with arthritis in whom joint inflammation persists for months or even several years after both oral and IV antibiotics, treatment with nonsteroidal anti-inflammatory agents, therapy with disease-1153 modifying antirheumatic drugs, or synovectomy may be successful.


InternalMed_Harrison

InternalMed_Harrison. In the United States, parenteral antibiotic therapy is usually used for objective neurologic abnormalities (with the exception of facial palsy alone). Patients with neurologic involvement are most commonly treated with IV ceftriaxone for 14–28 days, but IV cefotaxime or IV penicillin G for the same duration also may be effective. In Europe, similar results have been obtained with oral doxycycline and IV antibiotics in the treatment of acute neuroborreliosis. In patients with high-degree atrioventricular block or a PR interval of >0.3 s, IV therapy for at least part of the course and cardiac monitoring are recommended, but the insertion of a permanent pacemaker is not necessary.


InternalMed_Harrison

InternalMed_Harrison. It is unclear how and whether asymptomatic infection should be treated, but patients with such infection are often given a course of oral antibiotics. Because maternal-fetal transmission of B. burgdorferi seems to occur rarely (if at all), standard therapy for the manifestations of the illness is recommended for pregnant women. Long-term persistence of B. burgdorferi has not been documented in any large series of patients after treatment with currently recommended regimens. Although an occasional patient requires a second course of antibiotics, there is no indication for multiple, repeated antibiotic courses in the treatment of Lyme disease. After appropriately treated Lyme disease, a small percentage of patients continue to have subjective symptoms, primarily musculoskeletal pain, neurocognitive difficulties, or fatigue. This chronic


InternalMed_Harrison

InternalMed_Harrison. After appropriately treated Lyme disease, a small percentage of patients continue to have subjective symptoms, primarily musculoskeletal pain, neurocognitive difficulties, or fatigue. This chronic Lyme disease or post–Lyme syndrome is sometimes a disabling condition that is similar to chronic fatigue syndrome or fibromyalgia. In a large study, one group of patients with post–Lyme syndrome received IV ceftriaxone for 30 days followed by oral doxycycline for 60 days, while another group received IV and oral placebo preparations for the same durations. No significant differences were found between groups in the numbers of patients reporting that their symptoms had improved, become worse, or stayed the same. Such patients are best treated for the relief of symptoms rather than with prolonged courses of antibiotics.


InternalMed_Harrison

InternalMed_Harrison. The risk of infection with B. burgdorferi after a recognized tick bite is so low that antibiotic prophylaxis is not routinely indicated. However, if an attached, engorged I. scapularis nymph is found or if follow-up is anticipated to be difficult, a single 200-mg dose of doxycycline, which usually prevents Lyme disease when given within 72 h after the tick bite, may be administered. The response to treatment is best early in the disease. Later treatment of Lyme borreliosis is still effective, but the period of convalescence may be longer. Eventually, most patients recover with minimal or no residual deficits.


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InternalMed_Harrison. Reinfection may occur after EM when patients are treated with antimicrobial agents. In such cases, the immune response is not adequate to provide protection from subsequent infection. However, patients who develop an expanded immune response to the spirochete over a period of months (e.g., those with Lyme arthritis) have protective immunity for a period of years and rarely, if ever, acquire the infection again. Protective measures for the prevention of Lyme disease may include the avoidance of tick-infested areas, the use of repellents and acaricides, tick checks, and modification of landscapes in or near residential areas. Although a vaccine for Lyme disease used to be available, the manufacturer has discontinued its production. Therefore, no vaccine is now commercially available for the prevention of this infection.


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InternalMed_Harrison. 1154 Rickettsial diseases David H. Walker, J. Stephen Dumler, Thomas Marrie The rickettsiae are a heterogeneous group of small, obligately intra-cellular, 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 211 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 appropriate geographic region (spotted fever and typhus rickettsioses, scrub typhus, ehrlichioses, anaplasmosis); (2) travel to or residence in an endemic geographic region during the incubation period (Table 211-1); (3) expo-sure 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


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InternalMed_Harrison. 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 sECTIOn 10 dIsEAsEs CAusEd By RICKETTsIAE, MyCOPLAsMAs, And CHLAMydIAE rickettsiae, Coxiella burnetii, Rickettsia prowazekii, and R. 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.


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InternalMed_Harrison. 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, Neorickettsia, 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 occurrence of a macular, maculopapular, or vesicular rash; eschar; pneumonitis; and meningoencephalitis—vary from one disease to another. Given the 15 etiologic agents with varied mechanisms of transmission, geographic distributions, and associated disease manifestations, the consideration of rickettsial diseases as a single entity poses complex challenges (Table 211-1).


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InternalMed_Harrison. Establishing the etiologic diagnosis of rickettsioses is very difficult during the acute stage of illness, and definitive diagnosis usually requires the examination of paired serum samples after convalescence. Heightened clinical suspicion is based on epidemiologic data, history of exposure to vectors or reservoir animals, travel to endemic locations, clinical manifestations (sometimes including 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 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.


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InternalMed_Harrison. Rickettsial infections dominated by fever may resolve without further 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; (3) development of a vesicular rash (often in rickettsialpox and African tick-bite fever); (4) development of pneumonitis with chest radiographic opacities 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) development 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


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InternalMed_Harrison. 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).


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InternalMed_Harrison. in spotted fever and typhus rickettsioses, ehrlichioses, anaplasmosis, and scrub typhus), normal or low WBC counts, mild to moderate serum elevations of hepatic aminotransferases, and hyponatremia, suggest some common pathophysiologic mechanisms. Application of these clinical, epidemiologic, and laboratory principles requires consideration of a rickettsial diagnosis and knowledge of the individual diseases. TICK-, MITE-, LOuSE-, AND FLEA-BORNE RICKETTSIOSES


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InternalMed_Harrison. TICK-, MITE-, LOuSE-, AND FLEA-BORNE RICKETTSIOSES These diseases, caused by organisms of the genera Rickettsia and Orientia 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 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. R. massiliae, R. helvetica, R. heilongjiangensis, R. aeschlimannii, and R. monacensis) have never been documented to cause a fatal illness. Epidemiology 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 and A. aureolatum in Central and/or 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.


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InternalMed_Harrison. 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. Pathogenesis R. rickettsii organisms are inoculated into the dermis along with secretions of the tick’s salivary glands after ≥6 h of feeding.


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InternalMed_Harrison. The rickettsiae spread lymphohematogenously throughout the body course and treated appropriately as outpatients. In the tertiary-care and infect numerous foci of contiguous endothelial cells. The dose-setting, RMSF is all too often recognized only when late severe dependent incubation period is ~1 week (range, 2–14 days). Occlusive manifestations, developing at the end of the first week or during the thrombosis and ischemic necrosis are not the fundamental pathologic second week of illness in patients without appropriate treatment, bases for tissue and organ injury. Instead, increased vascular perme-prompt return to a physician or hospital and admission to an intenability, with resulting edema, hypovolemia, and ischemia, is responsi-sive care unit. ble. Consumption of platelets results in thrombocytopenia in 32–52% The progressive nature of the infection is clearly manifested in the of patients, but disseminated intravascular coagulation with hypofi-skin. Rash is evident in only 14%


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InternalMed_Harrison. thrombocytopenia in 32–52% The progressive nature of the infection is clearly manifested in the of patients, but disseminated intravascular coagulation with hypofi-skin. Rash is evident in only 14% of patients on the first day of illness brinogenemia is rare. Activation of platelets, generation of thrombin, and in only 49% during the first 3 days. Macules (1–5 mm) appear first and activation of the fibrinolytic system all appear to be homeostatic on the wrists and ankles and then on the remainder of the extremities physiologic responses to endothelial injury. and the trunk. Later, more severe vascular damage results in frank hemorrhage at the center of the maculopapule, producing a petechia Clinical Manifestations Early in the illness, when medical attention that does not disappear upon compression (Fig. 211-1). This sequence usually is first sought, RMSF is difficult to distinguish from many self-of events is sometimes delayed or aborted by effective treatment. limiting viral


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InternalMed_Harrison. upon compression (Fig. 211-1). This sequence usually is first sought, RMSF is difficult to distinguish from many self-of events is sometimes delayed or aborted by effective treatment. limiting viral illnesses. Fever, headache, malaise, myalgia, nausea, vom-However, the rash is a variable manifestation, appearing on day 6 iting, and anorexia are the most common symptoms during the first or later in 20% of cases and not appearing at all in 9–16% of cases. 3 days. The patient becomes progressively more ill as vascular Petechiae occur in 41–59% of cases, appearing on or after day 6 in 74% infection and injury advance. In one large series, only one-third of of cases that manifest a rash. Involvement of the palms and soles, often patients were diagnosed with presumptive RMSF early in the clinical considered diagnostically important, usually develops relatively late in


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InternalMed_Harrison. FIGuRE 211-1 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.) 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) 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 stool or vomitus of 10% of patients, and death has followed massive upper-gastrointestinal hemorrhage.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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. Diagnosis 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 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.


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InternalMed_Harrison. 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 can masquerade as bacterial or viral meningoencephalitis. Cough, pulmonary signs, and chest radiographic opacities can lead to a diagnostic consideration of bronchitis or pneumonia.


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InternalMed_Harrison. 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 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 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.


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InternalMed_Harrison. 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 ≥64 usually detectable. The sensitivity and specificity of the indirect immunofluorescence IgG assay are 89–100% and 99–100%, 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.


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InternalMed_Harrison. The only diagnostic test that has proven useful during the acute illness 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. 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. Few cases are specifically determined to be caused by R. rickettsii. Currently, many febrile persons who do not have RMSF present with cross-reactive


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InternalMed_Harrison. cross-reactive enzyme immunoassay serology. 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 spotted fever–group rickettsia R. amblyommii.


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InternalMed_Harrison. 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,


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InternalMed_Harrison. 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 associated with more adverse outcomes than no treatment at all. 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 treatment of tick bites has no proven role in preventing RMSF. MEDITERRANEAN SPOTTED FEVER (BOuTONNEuSE FEVER), AFRICAN TICKBITE FEVER, AND OTHER TICK-BORNE SPOTTED FEVERS Epidemiology R. conorii is prevalent in southern Europe,


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InternalMed_Harrison. MEDITERRANEAN SPOTTED FEVER (BOuTONNEuSE FEVER), AFRICAN TICKBITE FEVER, AND OTHER TICK-BORNE SPOTTED FEVERS Epidemiology 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.


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InternalMed_Harrison. 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 rickettsiosis most frequently imported into Europe and North America. A similar disease caused by the closely related species R. parkeri is transmitted by 1157 A. maculatum in the United States and by 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


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InternalMed_Harrison. 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 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 after a wintertime Dermacentor tick bite manifest an afebrile illness with an eschar (usually on the scalp) and painful regional lymphadenopathy.


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InternalMed_Harrison. 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, or blood samples. Serologic diagnosis detects antibodies to antigens shared among spotted fever–group rickettsiae, hindering identification of the etiologic species. In an endemic area, a possible diagnosis of rickettsial spotted fevers should be considered when patients present with fever, rash, and/or a skin lesion consisting of a black necrotic area or a crust surrounded by erythema.