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InternalMed_Harrison. Successful therapeutic agents include doxycycline (100 mg bid orally for 1–5 days) and chloramphenicol (500 mg qid orally for 7–10 days). Pregnant patients may be treated with josamycin (3 g/d orally for 5 days). Data on the efficacy of treatment of mildly ill children with clarithromycin or azithromycin should not be extrapolated to adults or to patients with moderate or severe illness. R. akari infects mice and their mites (Liponyssoides sanguineus), which maintain the organisms by transovarial transmission. Epidemiology Rickettsialpox is recognized principally in New York City, but cases have also been reported in other urban and rural locations in the United States and in Ukraine, Croatia, Mexico, and Turkey. Investigation of eschars suspected of representing bioterrorism-associated cutaneous anthrax revealed that rickettsialpox occurs more frequently than previously realized.


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InternalMed_Harrison. Clinical Manifestations A papule forms at the site of the mite’s feeding, develops a central vesicle, and becomes a 1to 2.5-cm painless black crusted eschar surrounded by an erythematous halo (Fig. 211-2). Enlargement of the regional lymph nodes draining the eschar suggests initial lymphogenous spread. After an incubation period of FIGuRE 211-2 Eschar at the site of the mite bite in a patient with rickettsialpox. (Reprinted from A Krusell et al: Emerg Infect Dis 8:727, 2002. Photo obtained by Dr. Kenneth Kaye.)


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InternalMed_Harrison. FIGuRE 211-2 Eschar at the site of the mite bite in a patient with rickettsialpox. (Reprinted from A Krusell et al: Emerg Infect Dis 8:727, 2002. Photo obtained by Dr. Kenneth Kaye.) FIGuRE 211-3 Top: Papulovesicular lesions on the trunk of the patient with rickettsialpox shown in Fig. 211-2. Bottom: Close-up of lesions from the same patient. (Reprinted from A Krusell et al: Emerg Infect Dis 8:727, 2002. Photos obtained by Dr. Kenneth Kaye.) 10–17 days, during which the eschar and regional lymphadenopathy frequently go unnoticed, disease onset is marked by malaise, chills, fever, headache, and myalgia. A macular rash appears 2–6 days after onset and usually evolves sequentially into papules, vesicles, and crusts that heal without scarring (Fig. 211-3); in some cases, the rash remains macular or maculopapular. Some patients develop nausea, vomiting, abdominal pain, cough, conjunctivitis, or photophobia. Without treatment, fever lasts 6–10 days.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis and Treatment Clinical, epidemiologic, and convalescent serologic data establish the diagnosis of a spotted fever–group rickettsiosis that is seldom pursued further. Doxycycline is the drug of choice for treatment. An emerging rickettsiosis caused by R. felis occurs worldwide. Maintained transovarially in the geographically widespread cat flea Ctenocephalides felis, the infection has been described as moderately severe, with fever, rash, and headache as well as CNS, gastrointestinal, and pulmonary symptoms.


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InternalMed_Harrison. EPIDEMIC (LOuSE-BORNE) TYPHuS Epidemiology The human body louse (Pediculus humanus corporis) lives in clothing under poor hygienic conditions and usually in impoverished cold areas. Lice acquire R. prowazekii when they ingest blood from a rickettsemic patient. The rickettsiae multiply in the louse’s mid-gut epithelial cells and are shed in its feces. The infected louse leaves a febrile person and deposits infected feces on its subsequent host during its blood meal; the patient autoinoculates the organisms by scratching. The louse is killed by the rickettsiae and does not pass R. prowazekii to its offspring. ters. An outbreak involved 100,000 people in refugee camps in Burundi in 1997. A small focus was documented in Russia in 1998; sporadic cases were reported from Algeria, and frequent outbreaks occurred in Peru. Eastern flying squirrels (Glaucomys volans) and their lice and fleas maintain R. prowazekii in a zoonotic cycle.


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InternalMed_Harrison. Brill-Zinsser disease is a recrudescent illness occurring years after acute epidemic typhus, probably as a result of waning immunity. R. prowazekii remains latent for years; its reactivation results in sporadic cases of disease in louse-free populations or in epidemics in louse-infested populations. Rickettsiae are potential agents of bioterrorism (Chap. 261e). Infections with R. prowazekii and R. rickettsii have high case–fatality ratios. These organisms cause difficult-to-diagnose diseases and are highly infectious when inhaled as aerosols. Organisms resistant to tetracycline or chloramphenicol have been developed in the laboratory.


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InternalMed_Harrison. Clinical Manifestations After an incubation period of ~1–2 weeks, the onset of illness is abrupt, with prostration, severe headache, and fever rising rapidly to 38.8°–40.0°C (102°–104°F). Cough is prominent, developing in 70% of patients. Myalgias are usually severe. A rash begins on the upper trunk, usually on the fifth day, and then becomes generalized, involving the entire body except the face, palms, and soles. Initially, this rash is macular; without treatment, it becomes maculopapular, petechial, and confluent. The rash often goes undetected in black skin; 60% of African patients have spotless epidemic typhus. Photophobia, with considerable conjunctival injection and eye pain, is common. The tongue may be dry, brown, and furred. Confusion and coma are common. Skin necrosis and gangrene of the digits as well as interstitial pneumonia may occur in severe cases. Untreated disease is fatal in 7–40% of cases, with outcome depending primarily on the condition of the host. Patients


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InternalMed_Harrison. of the digits as well as interstitial pneumonia may occur in severe cases. Untreated disease is fatal in 7–40% of cases, with outcome depending primarily on the condition of the host. Patients with untreated infections develop renal insufficiency and multiorgan involvement in which neurologic manifestations are frequently prominent. Overall, 12% of patients with epidemic typhus have neurologic involvement. Infection associated with North American flying squirrels is a milder illness; whether this milder disease is due to host factors (e.g., better health status) or attenuated virulence is unknown.


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InternalMed_Harrison. Diagnosis and Treatment Epidemic typhus is sometimes misdiagnosed as typhoid fever in tropical countries (Chap. 190). The means even for serologic studies are often unavailable in settings of louse-borne typhus. Epidemics can be recognized by the serologic or immunohistochemical diagnosis of a single case or by detection of R. prowazekii in a louse found on a patient. Doxycycline (200 mg/d, given in two divided doses) is administered orally or—if the patient is comatose or vomiting—intravenously. Although under epidemic conditions a single 200-mg oral dose is effective, treatment is generally continued until 2–3 days after defervescence. Pregnant patients should be evaluated individually and treated with chloramphenicol early in pregnancy or, if necessary, with doxycycline late in pregnancy. Prevention Prevention of epidemic typhus involves control of body lice. Clothes should be changed regularly, and insecticides should be used every 6 weeks to control the louse population.


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InternalMed_Harrison. Prevention Prevention of epidemic typhus involves control of body lice. Clothes should be changed regularly, and insecticides should be used every 6 weeks to control the louse population. ENDEMIC MuRINE TYPHuS Epidemiology R. typhi is maintained in mammalian host/flea cycles, with rats (Rattus rattus and R. norvegicus) and the Oriental rat flea (Xenopsylla cheopis) as the classic zoonotic niche. Fleas acquire R. typhi from rickettsemic rats and carry the organism throughout their life span. Nonimmune rats and humans are infected when rickettsia-laden flea feces contaminate pruritic bite lesions; less frequently, the flea bite transmits the organisms. Transmission can also occur via inhalation of aerosolized rickettsiae from flea feces. Infected rats appear healthy, although they are rickettsemic for ~2 weeks.


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InternalMed_Harrison. Murine typhus occurs mainly in Texas and southern California, where the classic rat/flea cycle is absent and an opossum/cat flea (C. felis) cycle is prominent. Globally, endemic typhus occurs mainly in warm (often coastal) areas throughout the tropics and subtropics, where it is highly prevalent though often unrecognized. The incidence peaks from April through June in southern Texas and during the warm months of summer and early fall in other geographic locations. Patients seldom recall exposure to fleas, although exposure to animals such as cats, opossums, and rats is reported in nearly 40% of cases. Clinical Manifestations The incubation period of experimental murine typhus averages 11 days (range, 8–16 days). Headache, myalgia, arthralgia, nausea, and malaise develop 1–3 days before onset of chills and fever. Nearly all patients experience nausea and vomiting early in the illness.


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InternalMed_Harrison. The duration of untreated illness averages 12 days (range, 9–18 days). Rash is present in only 13% of patients at presentation for medical care (usually ~4 days after onset of fever), appearing an average of 2 days later in half of the remaining patients and never appearing in the others. The initial macular rash is often detected by careful inspection of the axilla or the inner surface of the arm. Subsequently, the rash becomes maculopapular, involving the trunk more often than the extremities; it is seldom petechial and rarely involves the face, palms, or soles. A rash is detected in only 20% of patients with darkly pigmented skin.


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InternalMed_Harrison. Pulmonary involvement is frequently prominent; 35% of patients have a hacking, nonproductive cough, and 23% of patients who undergo chest radiography have pulmonary densities due to interstitial pneumonia, pulmonary edema, and pleural effusions. Bibasilar rales are the most common pulmonary sign. Less common clinical manifestations include abdominal pain, confusion, stupor, seizures, ataxia, coma, and jaundice. Clinical laboratory studies frequently reveal anemia and leukopenia early in the course, leukocytosis late in the course, thrombocytopenia, hyponatremia, hypoalbuminemia, mildly increased serum hepatic aminotransferases, and prerenal azotemia. Complications can include respiratory failure, hematemesis, cerebral hemorrhage, and hemolysis. Severe illness necessitates the admission of 10% of hospitalized patients to an intensive care unit. Greater severity is generally associated with old age, underlying disease, and treatment with a sulfonamide; the case-fatality rate is 1%. In a


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InternalMed_Harrison. 10% of hospitalized patients to an intensive care unit. Greater severity is generally associated with old age, underlying disease, and treatment with a sulfonamide; the case-fatality rate is 1%. In a study of children with murine typhus, 50% suffered only nocturnal fevers, feeling well enough for active daytime play.


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InternalMed_Harrison. Diagnosis and Treatment Serologic studies of acuteand convalescent-phase sera can provide a diagnosis, and an immunohistochemical method for identification of typhus group-specific antigens in biopsy samples has been developed. Cultivation and PCR are used only infrequently and are not widely available. Nevertheless, most patients are treated empirically with doxycycline (100 mg bid orally for 7–15 days) on the basis of clinical suspicion. Ciprofloxacin provides an alternative if doxycycline is contraindicated.


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InternalMed_Harrison. SCRuB TYPHuS Epidemiology O. tsutsugamushi differs substantially from Rickettsia species both genetically and in cell wall composition (i.e., it lacks lipopolysaccharide). O. tsutsugamushi is maintained by transovarial transmission in trombiculid mites. After hatching, infected larval mites (chiggers, the only stage that feeds on a host) inoculate organisms into the skin. Infected chiggers are particularly likely to be found in areas of heavy scrub vegetation during the wet season, when mites lay eggs. Scrub typhus is endemic and reemerging in eastern and south ern Asia, northern Australia, and islands of the western Pacific and Indian Oceans. Infections are prevalent in these regions; in some areas, >3% of the population is infected or reinfected each month. Immunity wanes over 1–3 years, and the organism exhibits remarkable antigenic diversity.


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InternalMed_Harrison. Clinical Manifestations Illness varies from mild and self-limiting to fatal. After an incubation period of 6–21 days, onset is characterized by fever, headache, myalgia, cough, and gastrointestinal symptoms. Some patients recover spontaneously after a few days. The classic case description includes an eschar where the chigger has fed, regional lymphadenopathy, and a maculopapular rash—signs that are seldom seen in indigenous patients. Fewer than 50% of Westerners develop an eschar, and fewer than 40% develop a rash (on day 4–6 of illness). Severe 1159 cases typically manifest with encephalitis and interstitial pneumonia due to vascular injury. The case-fatality rate for untreated classic cases is 7% but would probably be lower if all mild cases were diagnosed.


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InternalMed_Harrison. Diagnosis and Treatment Serologic assays (indirect fluorescent antibody, indirect immunoperoxidase, and enzyme immunoassays) are the mainstays of laboratory diagnosis. PCR amplification of Orientia genes from eschars and blood also is effective. Patients are treated with doxycycline (100 mg bid orally for 7–15 days), azithromycin (500 mg orally for 3 days), or chloramphenicol (500 mg qid orally for 7–15 days). Some cases of scrub typhus in Thailand are caused by strains that have high doxycycline or chloramphenicol minimal inhibitory concentrations (MICs) but that are susceptible to azithromycin and rifampin.


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InternalMed_Harrison. Ehrlichioses are acute febrile infections caused by members of the family Anaplasmataceae, which is made up of obligately intracellular organisms of five genera: Ehrlichia, Anaplasma, Wolbachia, Candidatus Neoehrlichia, and Neorickettsia. The bacteria reside in vertebrate reservoirs and target vacuoles of hematopoietic cells (Fig. 211-4). Three Ehrlichia species and one Anaplasma species are transmitted by ticks to humans and cause infection that can be severe and prevalent. E. chaffeensis, the agent of HME, and an E. muris–like agent (EMLA) infect predominantly mononuclear phagocytes; E. ewingii and A. phagocytophilum infect neutrophils. Infection with Candidatus Neoehrlichia mikurensis is less well characterized, but the agent has been identified in human blood neutrophils.


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InternalMed_Harrison. Ehrlichia, Candidatus Neoehrlichia, and Anaplasma are maintained by horizontal tick-mammal-tick transmission, and humans are only inadvertently infected. Wolbachiae are associated with human filariasis, since they are important for filarial viability and pathogenicity; antibiotic treatment targeting wolbachiae is a strategy for filariasis control. Neorickettsiae parasitize flukes (trematodes) that in turn parasitize aquatic snails, fish, and insects. Only a single human neorickettsiosis has been described: sennetsu fever, an infectious mononucleosis–like illness that was first identified in 1953 and is associated with the ingestion of raw fish containing N. sennetsu–infected flukes. HuMAN MONOCYTOTROPIC EHRLICHIOSIS Epidemiology More than 8404 cases of E. chaffeensis infection had been reported to the Centers for Disease Control and Prevention (CDC) as of April 2013. However, active prospective surveillance has documented an incidence as high as 414 cases per 100,000 population


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InternalMed_Harrison. FIGuRE 211-4 Peripheral-blood smear from a patient with human granulocytotropic anaplasmosis. A neutrophil contains two morulae (vacuoles filled with A. phagocytophilum). (Photo courtesy of Dr. J. Stephen Dumler.) 1160 in some U.S. regions. Most E. chaffeensis infections are identified in the south-central, southeastern, and mid-Atlantic states, but cases have also been recognized in California and New York. All stages of the Lone Star tick (A. americanum) feed on white-tailed deer—a major reservoir. Dogs and coyotes also serve as reservoirs and often lack clinical signs. Tick bites and exposures are frequently reported by patients in rural areas, especially in May through July. The median age of HME patients is 52 years; however, severe and fatal infections in children also are well recognized. Of patients with HME, 60% are male. E. chaffeensis has been detected in South America, Africa, and Asia.


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InternalMed_Harrison. Clinical Manifestations E. chaffeensis disseminates hematogenously from the dermal blood pool created by the feeding tick. After a median incubation period of 8 days, illness develops. Clinical manifestations are undifferentiated and include fever (96% of cases), headache (72%), myalgia (68%), and malaise (77%). Less frequently observed are nausea, vomiting, and diarrhea (25–57%); cough (28%); rash (26% overall, 6% at presentation); and confusion (20%). HME can be severe: 49% of patients with documented cases are hospitalized, and ~2% die. Severe manifestations include a toxic shock–like or septic shock–like syndrome, adult respiratory distress syndrome, cardiac failure, hepatitis, meningoencephalitis, hemorrhage, and—in immunocompromised patients—overwhelming ehrlichial infection. Laboratory findings are valuable in the differential diagnosis of HME; 61% of patients have leukopenia (initially lymphopenia, later neutropenia), 73% have thrombocytopenia, and 84% have elevated serum


InternalMed_Harrison

InternalMed_Harrison. findings are valuable in the differential diagnosis of HME; 61% of patients have leukopenia (initially lymphopenia, later neutropenia), 73% have thrombocytopenia, and 84% have elevated serum levels of hepatic aminotransferases. Despite low blood cell counts, the bone marrow is hypercellular, and noncaseating granulomas can be present. Vasculitis is not a component of HME.


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InternalMed_Harrison. Diagnosis HME can be fatal. Early empirical antibiotic therapy based on clinical diagnosis diminishes adverse outcomes. This diagnosis is suggested by fever with a known tick exposure during the preceding 3 weeks, thrombocytopenia and/or leukopenia, and increased serum aminotransferase levels. Morulae are demonstrated in <10% of peripheral-blood smears. HME can be confirmed during active infection by PCR amplification of E. chaffeensis nucleic acids in blood obtained before the start of doxycycline therapy. Retrospective serodiagnosis requires a consistent clinical picture and a fourfold increase in E. chaffeensis antibody titer to ≥64 in paired sera obtained ~3 weeks apart. Separate specific diagnostic tests are necessary for HME and HGA.


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InternalMed_Harrison. Ehrlichia ewingii, originally a neutrophil pathogen causing fever and lameness in dogs, resembles E. chaffeensis in its tick vector (A. americanum) and vertebrate reservoirs (white-tailed deer and dogs). An E. muris–like agent (EMLA) has been discovered and identified as the cause of human infections in Wisconsin and Minnesota. E. ewingii and EMLA illnesses are similar to but less severe than HME. Many cases occur in immunocompromised patients. No specific serologic diagnostic tests for ewingii or EMLA ehrlichiosis are readily available.


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InternalMed_Harrison. Candidatus Neoehrlichia mikurensis, a bacterium in a phy logenetic clade between Ehrlichia and Anaplasma, was origi nally identified in Ixodes ricinus ticks from the Netherlands and in mice and Ixodes ovatus ticks from Japan. By means of broad-range 16S rRNA gene amplification and sequence analysis, this organism was identified as the cause of severe and sometimes prolonged febrile illnesses in European immunocompromised patients with tick bites or exposures and in Chinese patients with a mild febrile illness after being bitten by Ixodes persulcatus and Haemaphysalis concinna ticks. The clinical presentation is similar to those of HME and HGA. Specific diagnostic methods have been developed but are not widely available.


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InternalMed_Harrison. Doxycycline is effective for HME as well as for ewingii and EMLA ehrlichioses; the use of this drug in Candidatus N. mikurensis infection is associated with disease resolution. Therapy with doxycycline (100 mg given PO or IV twice daily) or tetracycline (250–500 mg given PO every 6 h) lowers hospitalization rates and shortens fever duration. E. chaffeensis is not susceptible to chloramphenicol in vitro, and the use of this drug is controversial. While a few reports document E. chaffeensis persistence in humans, this finding is rare; most infections are cured by short courses of doxycycline (continuing for 3–5 days after defervescence). Although poorly studied, rifampin may be suitable when doxycycline is contraindicated.


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InternalMed_Harrison. HME, ewingii ehrlichiosis, EMLA infection, and Candidatus N. mikurensis infection can be prevented by the avoidance of ticks in endemic areas. The use of protective clothing and tick repellents, careful post-exposure tick searches, and prompt removal of attached ticks probably diminish infection risk. Epidemiology As of April 2013, 10,181 cases of HGA had been reported to the CDC, most in the upper midwestern and northeastern United States; the geographic distribution is similar to that for Lyme disease because of the shared I. scapularis tick vector. White-footed mice, squirrels, and white-tailed deer in the United States and red deer in Europe are natural reservoirs for A. phagocytophilum. HGA incidence peaks in May through July, but the disease can occur throughout the year with exposure to Ixodes ticks. HGA often affects males (59%) and older persons (median age, 51 years).


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InternalMed_Harrison. Clinical Manifestations Seroprevalence rates are high in endemic regions; thus it seems likely that most individuals develop subclinical infections. The incubation period for HGA is 4–8 days, after which the disease manifests as fever (75–100% of cases), myalgia (77%), headache (82%), and malaise (97%). A minority of patients develop nausea, vomiting, or diarrhea (22–39%); cough (27%); or confusion (17%). Rash (6%) is almost invariably concurrent erythema migrans attributable to Lyme disease. Most patients develop thrombocytopenia (75%) and/or leukopenia (55%) with increased serum hepatic aminotransferase levels (83%).


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InternalMed_Harrison. Severe complications occur most often in the elderly and include adult respiratory distress syndrome, a toxic shock–like syndrome, and life-threatening opportunistic infections. Meningoencephalitis is rarely documented with HGA, but brachial plexopathy, cranial nerve involvement, and demyelinating polyneuropathy are reported. For HGA, 7% of patients require intensive care, and the case-fatality rate is 0.6%. Neither vasculitis nor granulomas are components of HGA. While co-infections with Borrelia burgdorferi and Babesia microti (transmitted by the same tick vector[s]) occur, there is little evidence of comorbidity or persistence. HGA is rarely acquired via transfusion.


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InternalMed_Harrison. Diagnosis HGA should be included in the differential diagnosis of influenza-like illnesses during seasons with Ixodes tick activity (May through December), especially with known tick bite or exposure. Concurrent thrombocytopenia, leukopenia, or elevated serum levels of alanine or aspartate aminotransferase further increase the likelihood of HGA. Many HGA patients develop Lyme disease antibodies in the absence of clinical findings consistent with that diagnosis. Thus, HGA should be considered in the differential diagnosis of atypical severe Lyme disease presentations. Peripheral-blood film examination for neutrophil morulae can yield a diagnosis in 20–75% of infections. PCR testing of blood from patients with active disease before doxycycline therapy is sensitive and specific. Serodiagnosis is retrospective, requiring a fourfold increase in A. phagocytophilum antibody titer (to ≥160) in paired serum samples obtained 1 month apart. Since seroprevalence is high in some regions, a single


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InternalMed_Harrison. is retrospective, requiring a fourfold increase in A. phagocytophilum antibody titer (to ≥160) in paired serum samples obtained 1 month apart. Since seroprevalence is high in some regions, a single acute-phase titer should not be used for diagnosis.


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InternalMed_Harrison. No prospective studies of therapy for HGA have been conducted. However, doxycycline (100 mg PO twice daily) is effective. Rifampin therapy is associated with improvement of HGA in pregnant women and children. Most treated patients defervesce within 24–48 h. Prevention HGA prevention requires tick avoidance. Transmission can be documented as few as 4 h after a tick bite.


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InternalMed_Harrison. Prevention HGA prevention requires tick avoidance. Transmission can be documented as few as 4 h after a tick bite. The agent of Q fever is Coxiella burnetii, a small intracellular prokaryote that only recently was grown in cell-free medium. C. burnetii, a pleomorphic coccobacillus with a gram-negative cell wall, survives in harsh environments; it escapes intracellular killing in macrophages by inhibiting the final step in phagosome maturation (cathepsin fusion) and has adapted to the acidic phagolysosome by producing superoxide dismutase. Infection with C. burnetii induces a range of immunomodulatory responses, from immunosuppression in chronic Q fever to the production of autoantibodies, particularly those to smooth muscle and cardiac muscle.


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InternalMed_Harrison. Q fever encompasses two broad clinical syndromes: acute and chronic infection. The host’s immune response (rather than the particular strain) most likely determines whether chronic Q fever develops. C. burnetii survives in monocytes from patients with chronic Q fever but not in monocytes from patients with acute Q fever or from uninfected subjects. Impairment of the bactericidal activity of the C. burnetii–infected monocyte is associated with overproduction of interleukin 10. The CD4+/CD8+ ratio is decreased in Q fever endocarditis. Very few organisms and a strong cellular response are observed in patients with acute Q fever, while many organisms and a moderate cellular response occur in chronic Q fever. Immune control of C. burnetii is T cell–dependent, but 80–90% of bone marrow aspirates obtained years after recovery from Q fever contain C. burnetii DNA. C. burnetii’s ready multiplication within trophoblasts accounts for the high concentrations it can reach in the placenta.


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InternalMed_Harrison. Epidemiology Q fever is a zoonosis. The primary sources of human infection are infected cattle, sheep, and goats. However, cats, rabbits, pigeons, and dogs also serve as sources for transmission of C. burnetii to humans. The wildlife reservoir is extensive and includes ticks, coyotes, gray foxes, skunks, raccoons, rabbits, deer, mice, bears, birds, and opossums. In female animals C. burnetii localizes to the uterus and mammary glands. Infection is reactivated during pregnancy and after radiotherapy in mouse models. High concentrations of C. burnetii are found in the placenta. At the time of parturition, the bacteria are released into the air, and infection follows inhalation of aerosolized organisms by a susceptible host. Windstorms can generate C. burnetii aerosols months after soil contamination during parturition. Individuals up to 18 km from the source have been infected. Because it is easily dispersed as an aerosol, C. burnetii is a potential agent of bioterrorism (Chap. 261e),


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InternalMed_Harrison. during parturition. Individuals up to 18 km from the source have been infected. Because it is easily dispersed as an aerosol, C. burnetii is a potential agent of bioterrorism (Chap. 261e), with a high infectivity rate and pneumonia as the major manifestation.


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InternalMed_Harrison. Determining the source of an outbreak of Q fever can be challenging. An outbreak of Q fever at a horse-boarding ranch in Colorado in 2005 was due to spread of infection from two herds of goats that had been acquired by the owners. PCR testing confirmed the presence of C. burnetii in the soil and among the goats. Of 138 persons who lived within 1 mile of the ranch and who were also tested, 11 (8%) had evidence of C. burnetii infection, and 8 of these 11 individuals had no direct contact with the ranch.


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InternalMed_Harrison. Persons at risk for Q fever include abattoir workers, veterinarians, farmers, and other individuals who have contact with infected animals (particularly newborn animals) or products of conception. The organism is shed in milk for weeks to months after parturition. The ingestion of contaminated milk in some geographic areas probably represents a major route of transmission to humans. A recent outbreak of Q fever associated with ingestion of raw milk confirms the oral route of transmission. In rare instances, person-to-person transmission follows labor and childbirth in an infected woman, autopsy of an infected individual, or blood transfusion. Some evidence suggests that C. bur-1161 netii can be sexually transmitted among humans. Crushing an infected tick between the fingers has resulted in Q fever; the implication is that percutaneous transmission can occur.


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InternalMed_Harrison. Infections due to C. burnetii occur in most geographic locations except New Zealand and Antarctica. Thus Q fever can be associ ated with travel. The number of reported cases of Q fever in the United States ranges from 28 to 54 per year. More than 70% of these cases occur in males, and April, May, and June are the most common months for acquisition. Q fever continues to be common in Australia, with 30 cases per 1 million population per year. Cases among abattoir workers in Australia declined dramatically as a result of a vaccination program. An outbreak of Q fever began in the Netherlands in 2007, and by 2010 more than 4000 cases had been reported. Pneumonia was a common manifestation in this outbreak. The outbreak was due to a combination of high-density goat farming in areas abutting large urban populations and environmental factors. Farms where spread did not occur had high vegetation densities and lower groundwater concentrations.


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InternalMed_Harrison. The primary manifestations of acute Q fever differ geographically (e.g., pneumonia in Nova Scotia and granulomatous hepatitis in Marseille). These differences could reflect the route of infection (i.e., ingestion of contaminated milk for hepatitis and inhalation of contaminated aerosols for pneumonia) or strain differences. In the Netherlands outbreak, sequelae of infection in pregnant women were rare; this was not the case among pregnant women elsewhere. Young age seems to be protective against disease caused by C. burnetii. In a large outbreak in Switzerland, symptomatic infection occurred five times more often among persons >15 years of age than among younger individuals. In many outbreaks, men are affected more commonly than women; the proposed explanation is that female hormones are partially protective.


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InternalMed_Harrison. Clinical Manifestations • acUte Q fever The symptoms of acute Q fever are nonspecific; common among them are fever, extreme fatigue, photophobia, and severe headache that is frequently retro-orbital. Other symptoms include chills, sweats, nausea, vomiting, and diarrhea, each occurring in 5–20% of cases. Cough develops in about half of patients with Q fever pneumonia. Neurologic manifestations of acute Q fever are uncommon; however, in one outbreak in the United Kingdom, 23% of 102 patients had neurologic signs and symptoms as the major manifestation. A nonspecific rash may be evident in 4–18% of patients. The WBC count is usually normal. Thrombocytopenia occurs in ~25% of patients, and reactive thrombocytosis (with platelet counts exceeding 106/μL) frequently develops during recovery. Chest radiography can show opacities similar to those seen in pneumonia caused by other pathogens, but multiple rounded opacities in patients in endemic areas suggest a diagnosis of Q fever pneumonia.


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InternalMed_Harrison. Acute Q fever occasionally complicates pregnancy. In one series, it resulted in premature birth in 35% of cases and in abortion or neonatal death in 43%. Neonatal death (previous or current) and lower infant birth weight are three times more likely among women seropositive for C. burnetii. After the usual incubation period of 3–30 days, 1070 patients with acute Q fever in southern France presented with hepatitis (40%), both pneumonia and hepatitis (20%), pneumonia (17%), isolated fever (14%), CNS involvement (2%), and pericarditis or myocarditis (1%). Acalculous cholecystitis, pancreatitis, lymphadenopathy, spontaneous rupture of the spleen, transient hypoplastic anemia, bone marrow necrosis, hemolytic anemia, histiocytic hemophagocytosis, optic neuritis, and erythema nodosum were less common manifestations.


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InternalMed_Harrison. post–Q fever fatigUe syndrome Prolonged fatigue can follow Q fever and can be accompanied by a constellation of symptoms including headaches, sweats, arthralgia, myalgias, blurred vision, muscle fasciculations, and enlarged and painful lymph nodes. Long-term persistence of a noninfective, nonbiodegraded complex of Coxiella cell components, with its antigens and specific lipopolysaccharide, has been detected in the affected persons. Patients who develop this syndrome have a higher frequency of carriage of HLA-DRB1*11 and of the 2/2 genotype of the interferon γ intron 1 microsatellite.


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InternalMed_Harrison. 1162 cHronic Q fever Chronic Q fever almost always implies endocarditis and usually occurs in patients with previous valvular heart disease, immunosuppression, or chronic renal insufficiency. Fever is usually absent or low grade. Valvular vegetations are detected in only 12% of patients by transthoracic echocardiography, but the rate of detection is higher (21–50%) with transesophageal echocardiography. The vegetations in chronic Q fever endocarditis differ from those in bacterial endocarditis, manifesting as endothelium-covered nodules on the valves. A high index of suspicion is necessary for timely diagnosis. Patients with chronic Q fever are often ill for >1 year before the diagnosis is made. The disease should be suspected in all patients with culture-negative endocarditis. In addition, all patients with valvular heart disease and an unexplained purpuric eruption, renal insufficiency, stroke, and/ or progressive heart failure should be tested for C. burnetii infection. Patients


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InternalMed_Harrison. all patients with valvular heart disease and an unexplained purpuric eruption, renal insufficiency, stroke, and/ or progressive heart failure should be tested for C. burnetii infection. Patients with chronic Q fever have hepatomegaly and/or splenomegaly, which—in combination with rheumatoid factor, elevated erythrocyte sedimentation rate, high C-reactive protein level, and/or increased γ-globulin concentrations (up to 60–70 g/L)—suggests this diagnosis. Other manifestations of chronic Q fever include infection of vascular prostheses, aneurysms, and bone as well as chronic sternal wound infection. Unusual manifestations include chronic thrombocytopenia, mixed cryoglobulinemia, and livedo reticularis.


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InternalMed_Harrison. Diagnosis Isolation of C. burnetii from buffy-coat blood samples or tissue specimens by a shell-vial technique is easy but requires a biosafety level 3 laboratory. PCR detects C. burnetii DNA in tissue specimens, including paraffin-embedded samples. Serology is the most commonly used diagnostic tool. Indirect immunofluorescence is sensitive and specific and is the method of choice. Rheumatoid factor should be adsorbed from the specimen before testing. With chronic infection, the titer to phase I antigen is usually much higher than that to phase II antigen (i.e., C. burnetii that has truncated lipopolysaccharide associated with gene deletions during laboratory passages), and the diagnosis should not be based on serology alone. Rather, the entire clinical setting must be taken into consideration. An anti–phase I IgG titer of ≥6400 would be considered a major criterion for the diagnosis of chronic Q fever, while a titer of ≥800 but ≤6400 would be a minor criterion. In acute Q fever, a


InternalMed_Harrison

InternalMed_Harrison. An anti–phase I IgG titer of ≥6400 would be considered a major criterion for the diagnosis of chronic Q fever, while a titer of ≥800 but ≤6400 would be a minor criterion. In acute Q fever, a fourfold rise in titer can be demonstrated between acuteand convalescent-phase serum samples.


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InternalMed_Harrison. Fluorodeoxyglucose positron emission tomography combined with CT (FDG-PET/CT) can be useful because it can detect not only valvular infection but also intravascular infection elsewhere as well as osteomyelitis. Treatment of acute Q fever with doxycycline (100 mg twice daily for 14 days) is usually successful. Quinolones also are effective. When Q fever is diagnosed during pregnancy, treatment with trimethoprimsulfamethoxazole (TMP-SMX) is recommended for the duration of the pregnancy. One study showed no intrauterine fetal deaths and substantial reduction of obstetric complications in a group of Q fever patients treated with TMP-SMX.


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InternalMed_Harrison. The treatment of chronic Q fever is difficult and requires careful follow-up. Addition of hydroxychloroquine (to alkalinize the phagolysosome) renders doxycycline bactericidal against C. burnetii, and this combination is currently the favored regimen. Treatment with doxycycline (100 mg bid) and hydroxychloroquine (200 mg tid; plasma concentration maintained at 0.8–1.2 μg/mL) for 18 months is superior to a regimen of doxycycline and ofloxacin. Among 21 patients who received doxycycline and hydroxychloroquine, 1 died of a surgical complication, 2 were still being treated at the end of the study, 1 was still being evaluated, and 17 were cured. The mean duration of treatment was 31 months. In the ofloxacin and doxycycline group of 14 patients, 1 had died, 1 was still being treated, 7 had relapsed, and 5 had been cured by the end of the study. Optimal management of Q fever endocarditis entails determining the MIC of doxycycline for the patient’s isolate and measuring serum doxycycline


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InternalMed_Harrison. relapsed, and 5 had been cured by the end of the study. Optimal management of Q fever endocarditis entails determining the MIC of doxycycline for the patient’s isolate and measuring serum doxycycline levels. A serum level–to–doxycycline MIC ratio of ≥1 is associated with a rapid decline in phase I antibodies with the doxycycline-hydroxychloroquine regimen. Patients treated with this regimen must be advised about photosensitivity and retinal toxicity risks. The doxycycline-hydroxychloroquine regimen was successful in one patient with HIV infection and Q fever endocarditis. The Jarisch-Herxheimer reaction occasionally complicates the treatment of chronic Q fever. Treatment of C. burnetii–infected aortic aneurysms is the same as that for Q fever endocarditis. Surgical intervention is often required.


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InternalMed_Harrison. If doxycycline-hydroxychloroquine cannot be used, the regimen chosen should include at least two antibiotics active against C. burnetii. Rifampin (300 mg once daily) combined with doxycycline (100 mg twice daily) or ciprofloxacin (750 mg twice daily) has been used successfully. The management of patients with Q fever endocarditis is complex and should preferably be undertaken by individuals with experience in managing this illness. Monitoring of antibody titers on a quarterly basis is an essential part of the management of these patients. Thus the laboratory should be contacted and asked to save all serum samples from such patients so that the current sample can be run with the previous one. There is incomplete agreement on the antibody titer at which therapy can be stopped. However, it is reasonable to discontinue treatment if IgG antibody levels have decreased by fourfold at 1 year, if IgM antibody to phase II has disappeared, and if the patient is clinically stable.


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InternalMed_Harrison. Patients with acute Q fever and lesions of native heart valves (e.g., bicuspid aortic valve), prosthetic valves, or prosthetic intravascular material should undergo serologic monitoring every 4 months for 2 years. If the phase I IgG titer is >800, further investigation is warranted. Some authorities recommend that patients with valvulopathy and acute Q fever receive doxycycline and hydroxychloroquine to prevent chronic Q fever. For women who exhibit a serologic profile of chronic Q fever after childbirth, hydroxychloroquine and doxycycline should be given for 1 year. Interferon γ was successful in the treatment of a 3-year-old boy with prolonged fever, abdominal pain, and thrombocytopenia due to


InternalMed_Harrison

InternalMed_Harrison. Interferon γ was successful in the treatment of a 3-year-old boy with prolonged fever, abdominal pain, and thrombocytopenia due to C. burnetii that had not been eradicated with conventional antibiotic therapy. Many patients with granulomatous hepatitis due to Q fever have a prolonged febrile illness that is unresponsive to antibiotics. For these individuals, treatment with prednisone (0.5 mg/kg) has resulted in defervescence within 2–15 days. After defervescence, the glucocorticoid dose is tapered over the next month. Prevention A whole-cell vaccine (Q-Vax) licensed in Australia effectively prevents Q fever in abattoir workers. Before administration of the vaccine, skin testing with intradermal diluted C. burnetii vaccine is performed, serologic testing is undertaken, and a history of possible Q fever is sought. Vaccine is given only to patients with no history of Q fever and negative results in serologic and skin testing.


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InternalMed_Harrison. Good animal-husbandry practices are important in preventing widespread contamination of the environment by C. burnetii. These practices include isolating aborting animals for up to 14 days, raising feed bunks to prevent contamination of feed by excreta, destroying aborted materials (by burning and burying fetal membranes and stillborn animals), and wearing masks and gloves when handling aborted materials. Vaccination of sheep and goats and a culling program were effective in the Netherlands outbreak. Only seronegative pregnant animals should be used in research settings, and only seronegative animals should be permitted in petting zoos. During an outbreak of Q fever and for 4 weeks after it ceases, blood donations should not be accepted from individuals who live in the affected area. The contributions of Didier Raoult, MD, to this chapter in previous editions are gratefully acknowledged. Genuine second attacks of M. pneumoniae pneumonia have been 1163


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InternalMed_Harrison. The contributions of Didier Raoult, MD, to this chapter in previous editions are gratefully acknowledged. Genuine second attacks of M. pneumoniae pneumonia have been 1163 Infections due to Mycoplasmas reported infrequently. R. Doug Hardy EPIDEMIOLOGY Mycoplasmas are prokaryotes of the class Mollicutes. Their size (150–350 nm) is closer to that of viruses than to that of bacteria. Unlike viruses, however, mycoplasmas grow in cell-free culture media; in fact, they are the smallest organisms capable of independent replication.


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InternalMed_Harrison. The entire genomes of many Mycoplasma species have been sequenced and have been found to be among the smallest of all prokaryotic genomes. Sequencing information for these genomes has helped define the minimal set of genes necessary for cellular life. The absence of genes related to the synthesis of amino acids, fatty acid metabolism, and cholesterol dictates the mycoplasmas’ parasitic or saprophytic dependence on a host for exogenous nutrients and necessitates the use of complex fastidious media to culture these organisms. Mycoplasmas lack a cell wall and are bound only by a cell membrane. The absence of a cell wall explains the inactivity of β-lactam antibiotics (penicillins and cephalosporins) against infections caused by these organisms.


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InternalMed_Harrison. At least 13 Mycoplasma species, two Acholeplasma species, and two Ureaplasma species have been isolated from humans. Most of these species are thought to be normal inhabitants of oral and urogenital mucous membranes. Only four species—M. pneumoniae, M. hominis, U. urealyticum, and U. parvum—have been shown conclusively to be pathogenic in immunocompetent humans. M. pneumoniae primarily infects the respiratory tract, while M. hominis, U. urealyticum, and U. parvum are associated with a variety of genitourinary tract disorders and neonatal infections. Some data indicate that M. genitalium may be a cause of disease in humans. Other mycoplasmas may cause disease in immunocompromised persons.


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InternalMed_Harrison. M. pneumoniae is generally thought to act as an extracellular pathogen. Although the organism has been shown to exist and replicate within human cells, it is not known whether these intracellular events contribute to the pathogenesis of disease. M. pneumoniae attaches to ciliated respiratory epithelial cells by means of a complex terminal organelle at the tip of one end of the organism. Cytoadherence is mediated by interactive adhesins and accessory proteins clustered on this organelle. After extracellular attachment, M. pneumoniae causes injury to host respiratory tissue. The mechanism of injury is thought to be mediated by the production of hydrogen peroxide and of a recently identified ADP-ribosylating and vacuolating cytotoxin of M. pneumoniae that has many similarities to pertussis toxin. Because mycoplasmas lack a cell wall, they also lack cell wall–derived stimulators of the innate immune system, such as lipopolysaccharide, lipoteichoic acid, and murein (peptidoglycan)


InternalMed_Harrison

InternalMed_Harrison. toxin. Because mycoplasmas lack a cell wall, they also lack cell wall–derived stimulators of the innate immune system, such as lipopolysaccharide, lipoteichoic acid, and murein (peptidoglycan) fragments. However, lipoproteins from the mycoplasmal cell membrane appear to have inflammatory properties, probably acting through Toll-like receptors (primarily TLR2) on macrophages and other cells. Lung biopsy specimens from patients with


InternalMed_Harrison

InternalMed_Harrison. M. pneumoniae respiratory tract infection reveal an inflammatory process involving the trachea, bronchioles, and peribronchial tissue, with a monocytic infiltrate coinciding with a luminal exudate of polymorphonuclear leukocytes. Experimental evidence indicates that innate immunity provides most of the host’s defense against mycoplasmal infection in the lungs, whereas cellular immunity may actually play an immunopathogenic role, exacerbating mycoplasmal lung disease. Humoral immunity appears to provide protection against dissemination of M. pneumoniae infection; patients with humoral immunodeficiencies do not have more severe lung disease than do immunocompetent patients in the early stages of infection but more often develop disseminated infection resulting in syndromes such as arthritis, meningitis, and osteomyelitis. The immunity that follows severe M. pneumoniae infections is more protective and longer-lasting than that following mild infections.


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InternalMed_Harrison. M. pneumoniae infection occurs worldwide. It is likely that the incidence of upper respiratory illness due to M. pneumoniae is up to 20 times that of pneumonia caused by this organism. Infection is spread from one person to another by respiratory droplets expectorated during coughing and results in clinically apparent disease in an estimated 80% of cases. The incubation period for M. pneumoniae is 2–4 weeks; therefore, the time-course of infection in a specific population may be several weeks long. Intrafamilial attack rates are as high as 84% among children and 41% among adults. Outbreaks of M. pneumoniae illness often occur in institutional settings such as military bases, boarding schools, and summer camps. Infections tend to be endemic, with sporadic epidemics every 4–7 years. There is no seasonal pattern.


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InternalMed_Harrison. Most significantly, M. pneumoniae is a major cause of community-acquired respiratory illness in both children and adults and is often grouped with Chlamydia pneumoniae and Legionella species as being among the most important bacterial causes of “atypical” community-acquired pneumonia. For community-acquired pneumonia in adults, M. pneumoniae is the most frequently detected “atypical” organism. Analysis of 13 studies of community-acquired pneumonia published since 1995 (which included 6207 ambulatory and hospitalized adults) showed that the overall prevalence of M. pneumoniae was 22.7%; by comparison, the prevalence of C. pneumoniae was 11.7%, and that of Legionella species was 4.6%. M. pneumoniae pneumonia is also referred to as Eaton agent pneumonia (the organism having first been isolated in the early 1940s by Monroe Eaton), primary atypical pneumonia, and “walking” pneumonia.


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InternalMed_Harrison. CLINICAL MANIFESTATIONS upper Respiratory Tract Infections and Pneumonia Acute M. pneumoniae infections generally manifest as pharyngitis, tracheobronchitis, reactive airway disease/wheezing, or a nonspecific upper respiratory syndrome. Little evidence supports the commonly held belief that this organism is an important cause of otitis media, with or without bullous myringitis. Pneumonia develops in 3–13% of infected individuals; its onset is usually gradual, occurring over several days, but may be more abrupt. Although Mycoplasma pneumonia may begin with a sore throat, the most common presenting symptom is cough. The cough is typically nonproductive, but some patients produce sputum. Headache, malaise, chills, and fever are noted in the majority of patients.


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InternalMed_Harrison. On physical examination, wheezes or rales are detected in ∼80% of patients with M. pneumoniae pneumonia. In many patients, however, pneumonia can be diagnosed only by chest radiography. The most common radiographic pattern is that of peribronchial pneumonia with thickened bronchial markings, streaks of interstitial infiltration, and areas of subsegmental atelectasis. Segmental or lobar consolidation is not uncommon. While clinically evident pleural effusions are infrequent, lateral decubitus views reveal that up to 20% of patients have pleural effusions.


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InternalMed_Harrison. Overall, the clinical presentation of pneumonia in an individual patient is not useful for differentiating M. pneumoniae pneumonia from other types of community-acquired pneumonia. The possibility of M. pneumoniae infection deserves particular consideration when community-acquired pneumonia fails to respond to treatment with a penicillin or a cephalosporin—antibiotics that are ineffective against mycoplasmas. Symptoms usually resolve within 2–3 weeks after the onset of illness. Although M. pneumoniae pneumonia is generally self-limited, appropriate antimicrobial therapy significantly shortens the duration of clinical illness. Infection uncommonly results in critical illness and only rarely in death. In some patients, long-term recurrent wheezing or reactive airway disease may follow the resolution of acute pneumonia. The significance of chronic infection, especially as it relates to asthma, is an area of active investigation.


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InternalMed_Harrison. Extrapulmonary Manifestations An array of extrapulmonary manifestations may develop during M. pneumoniae infection. The most significant are neurologic, dermatologic, cardiac, rheumatologic, and


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InternalMed_Harrison. Infections Due to Mycoplasmas 1164 hematologic in nature. Extrapulmonary manifestations can be a result of disseminated infection, especially in patients with humoral immunodeficiencies (e.g., septic arthritis); postinfectious autoimmune phenomena (e.g., Guillain-Barré syndrome); or possibly ADPribosylating toxin. Overall, these manifestations are uncommon, given the frequency of M. pneumoniae infection. Notably, many patients with extrapulmonary M. pneumoniae disease do not have respiratory disease. Skin eruptions described with M. pneumoniae infection include erythematous (macular or maculopapular), vesicular, bullous, petechial, and urticarial rashes. In some reports, 17% of patients with M. pneumoniae pneumonia have had an exanthem. Erythema multiforme major (Stevens-Johnson syndrome) is the most clinically significant skin eruption associated with M. pneumoniae infection; it appears to occur more commonly with M. pneumoniae than with other infectious agents. A wide spectrum of


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InternalMed_Harrison. is the most clinically significant skin eruption associated with M. pneumoniae infection; it appears to occur more commonly with M. pneumoniae than with other infectious agents. A wide spectrum of neurologic manifestations has been reported with M. pneumoniae infection. The most common are meningoencephalitis, encephalitis, Guillain-Barré syndrome, and aseptic meningitis. M. pneumoniae has been implicated as a likely etiologic agent in 5–7% of cases of encephalitis. Other neurologic manifestations may include cranial neuropathy, acute psychosis, cerebellar ataxia, acute demyelinating encephalomyelitis, cerebrovascular thromboembolic events, and transverse myelitis. Hematologic manifestations of M. pneumoniae infection include hemolytic anemia, aplastic anemia, cold agglutinins, disseminated intravascular coagulation, and hypercoagulopathy. When anemia does occur, it generally develops in the second or third week of illness. In addition, hepatitis, glomerulonephritis, pancreatitis,


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InternalMed_Harrison. intravascular coagulation, and hypercoagulopathy. When anemia does occur, it generally develops in the second or third week of illness. In addition, hepatitis, glomerulonephritis, pancreatitis, myocarditis, pericarditis, rhabdomyolysis, and arthritis (septic and reactive) have been convincingly ascribed to M. pneumoniae infection. Septic arthritis has been described most commonly in hypogammaglobulinemic patients.


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InternalMed_Harrison. Clinical findings, nonmicrobiologic laboratory tests, and chest radiography are not useful for differentiating M. pneumoniae pneumonia from other types of community-acquired pneumonia. In addition, since M. pneumoniae lacks a cell wall, it is not visible on Gram’s stain. Although of historical interest, the measurement of cold agglutinin titers is no longer recommended for the diagnosis of M. pneumoniae infection because the findings are nonspecific and assays specific for M. pneumoniae are now available.


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InternalMed_Harrison. M. pneumoniae are now available. Acute M. pneumoniae infection can be diagnosed by polymerase chain reaction (PCR) detection of the organism in respiratory tract secretions or by isolation of the organism in culture (Table 212-1). Oropharyngeal, nasopharyngeal, and pulmonary specimens are all acceptable for diagnosing M. pneumoniae pneumonia. Other bodily fluids, such cerebrospinal fluid, are acceptable for extrapulmonary infection. M. pneumoniae culture (which requires special media) is not recommended for routine diagnosis because the organism may take weeks to grow and is often difficult to isolate from clinical specimens. In contrast, PCR allows rapid, specific diagnosis earlier in the course of clinical illness. The diagnosis can also be established by serologic tests for IgM and IgG antibodies to M. pneumoniae in paired (acuteand convalescent-phase) serum samples; enzyme-linked immunoassay is


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InternalMed_Harrison. The diagnosis can also be established by serologic tests for IgM and IgG antibodies to M. pneumoniae in paired (acuteand convalescent-phase) serum samples; enzyme-linked immunoassay is Test Sensitivity, % Specificity, % aA combination of PCR and serology is suggested for routine diagnosis. If macrolide resistance is suspected, M. pneumoniae culture may prove useful, providing an isolate for susceptibility testing. bAcuteand convalescent-phase serum samples are recommended. Abbreviation: PCR, polymerase chain reaction. the recommended serologic method. An acute-phase sample alone is not adequate for diagnosis, as antibodies to M. pneumoniae may not develop until 2 weeks into the illness; therefore, it is important to test paired samples. In addition, IgM antibody to M. pneumoniae can persist for up to 1 year after acute infection. Thus its presence may indicate recent rather than acute infection.


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InternalMed_Harrison. The combination of PCR of respiratory tract secretions and serologic testing constitutes the most sensitive and rapid approach to the diagnosis of M. pneumoniae infection.


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InternalMed_Harrison. Although in the majority of untreated cases symptoms resolve within 2–3 weeks without significant associated morbidity, M. pneumoniae pneumonia can be a serious illness that responds to appropriate antimicrobial therapy (Table 212-2). Randomized, double-blind, placebo-controlled trials in adults have demonstrated that antimicrobial treatment significantly decreases the duration of fever, cough, malaise, hospitalization, and radiologic abnormalities in M. pneumoniae pneumonia. Treatment options for acute M. pneumoniae infection include macrolides (e.g., oral azithromycin, 500 mg on day 1, then 250 mg/d on days 2–5), tetracyclines (e.g., oral doxycycline, 100 mg twice daily for 10–14 days), and respiratory fluoroquinolones. However, ciprofloxacin and ofloxacin are not recommended because of their high minimal inhibitory concentrations against M. pneumoniae isolates and their poor performance in experimental studies. A 10to 14-day course of quinolone therapy appears adequate.


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InternalMed_Harrison. In Japan and China, very high levels (up to ≥90%) of M. pneumoniae resistance to macrolides have been reported. In Europe and to a lesser degree in the United States, macrolide-resistant M. pneumoniae is emerging. In investigated outbreaks of respiratory illness due to M. pneumoniae in the United States, macrolide resistance has been reported in 8–27% of isolates. Clinical studies have demonstrated that, when treated with macrolides, patients with community-acquired pneumonia due to macrolideresistant M. pneumoniae experience a significantly longer duration of symptoms than do patients infected with macrolide-sensitive organisms; thus macrolide resistance in M. pneumoniae does appear to have clinical significance. If macrolide resistance is prominent in a particular geographic locale or is suspected, then a nonmacrolide antibiotic should be considered for treatment; in addition, culture of


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InternalMed_Harrison. M. pneumoniae may prove useful in these instances, providing an isolate for susceptibility testing. Clinical observations and experimental data suggest that the addition of glucocorticoids to an antibiotic regimen may be of value for the treatment of severe or refractory M. pneumoniae pneumonia. However, relevant clinical experience is limited. Even though appropriate antibiotic therapy significantly reduces the duration of respiratory illness, it does not appear to shorten the duration of detection of M. pneumoniae by culture or PCR; therefore, a test of cure or eradication is not suggested. The roles of antimicrobial drugs, glucocorticoids, and IV immunoglobulin in the treatment of neurologic disease due to M. pneumoniae remain unknown. aAntimicrobial resistance has been reported in mycoplasmas, as described in the text. uROGENITAL MYCOPLASMAS (SEE ALSO CHAP. 163)


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InternalMed_Harrison. aAntimicrobial resistance has been reported in mycoplasmas, as described in the text. uROGENITAL MYCOPLASMAS (SEE ALSO CHAP. 163) M. hominis, M. genitalium, U. urealyticum, and U. parvum can cause urogenital tract disease. The significance of isolation of these organisms in a variety of other syndromes is unknown and in some cases is being investigated. M. fermentans has not been shown convincingly to cause human disease.


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InternalMed_Harrison. While urogenital mycoplasmas may be transmitted to a fetus during passage through a colonized birth canal, sexual contact is the major mode of transmission, and the risk of colonization increases dramatically with increasing numbers of sexual partners. In asymptomatic women, these mycoplasmas may be found throughout the lower urogenital tract. The vagina yields the largest number of organisms; next most densely colonized are the periurethral area and the cervix. Ureaplasmas are isolated less often from urine than from the cervix, but M. hominis is found with approximately the same frequency at these two sites. Ureaplasmas are isolated from the vagina of 40–80% of sexually active, asymptomatic women and M. hominis from 21–70%. The two microorganisms are found concurrently in 31–60% of women. In men, colonization with each organism is less prevalent. Mycoplasmas have been isolated from urine, semen, and the distal urethra of asymptomatic men.


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InternalMed_Harrison. CLINICAL MANIFESTATIONS urethritis, Pyelonephritis, and urinary Calculi In many episodes of Chlamydia-negative nongonococcal urethritis, ureaplasmas may be the causative agent. These organisms may also cause chronic voiding symptoms in women. The common presence of ureaplasmas in the urethra of asymptomatic men suggests either that only certain serovars are pathogenic or that predisposing factors, such as lack of immunity, must exist in persons who develop symptomatic infection. Alternatively, disease may develop only upon initial exposure to urea-plasmas. Ureaplasmas have been implicated in epididymitis. M. genitalium also appears to cause urethritis. M. genitalium and ureaplasmas do not have a known role in prostatitis. M. hominis does not appear to play a primary etiologic role in urethritis, epididymitis, or prostatitis. Evidence suggests that M. hominis causes up to 5% of cases of acute pyelonephritis. Ureaplasmas have not been associated with this disease.


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InternalMed_Harrison. Evidence suggests that M. hominis causes up to 5% of cases of acute pyelonephritis. Ureaplasmas have not been associated with this disease. Ureaplasmas play a limited role in the production of urinary calculi. The frequency with which ureaplasmas reach the kidney, the predisposing factors that allow them to do so, and the relative frequency of urinary tract calculi induced by this organism (compared with other organisms) are not known. Pelvic Inflammatory Disease M. hominis can cause pelvic inflammatory disease. In most episodes, M. hominis occurs as part of a polymicrobial infection, but the organism may play an independent role in a limited number of cases. Some data also support an association of M. genitalium with pelvic inflammatory disease. Ureaplasmas are not thought to cause pelvic inflammatory disease.


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InternalMed_Harrison. Postpartum and Postabortal Infection Studies implicate M. hominis as the primary pathogen in ∼5–10% of women who have postpartum or postabortal fever; ureaplasmas have been implicated to a lesser degree. These infections are generally self-limited; however, if symptoms persist, specific antimicrobial therapy should be given. Ureaplasmas also appear to play a role in occasional postcesarean wound infections.


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InternalMed_Harrison. Non-urogenital Infection In rare instances, M. hominis causes non-urogenital infections, such as brain abscess, wound infection, poststernotomy mediastinitis, endocarditis, and neonatal meningitis. These infections are most common among immunocompromised and hypogammaglobulinemic patients. Ureaplasmas and M. hominis can cause septic arthritis in immunodeficient patients. Ureaplasmas probably cause neonatal pneumonitis; their significant role in the development of bronchopulmonary dysplasia—the chronic lung disease of premature infants—has been documented in a number of studies. It is unclear whether ureaplasmas and M. hominis cause infertility, spontaneous abortion, premature labor, low birth weight, 1165 or chorioamnionitis.


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InternalMed_Harrison. Culture and PCR are both appropriate methods for the isolation of urogenital mycoplasmas. Culture of these organisms, however, requires special techniques and media that generally are available only at larger medical centers and reference laboratories. Serologic testing is not recommended for the clinical diagnosis of urogenital Mycoplasma infections.


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InternalMed_Harrison. Because colonization with urogenital mycoplasmas is common, it appears at present that their isolation from the urogenital tract in the absence of disease generally does not warrant treatment. Macrolides and doxycycline are considered the antimicrobial agents of choice for Ureaplasma infections (Table 212-2). Ureaplasma resistance to macrolides, doxycycline, quinolones, and chloramphenicol has been reported. M. hominis is resistant to macrolides. Doxycycline is generally the drug of choice for M. hominis infections, although resistance has been reported. Clindamycin is generally active against M. hominis. Quinolones are active in vitro against M. hominis. For M. genitalium, the agent of choice appears to be azithromycin; treatment failures have been reported with other macrolides as well as with quinolones. Charlotte A. Gaydos, Thomas C. Quinn Chlamydiae are obligate intracellular bacteria that cause a wide variety of diseases in humans and animals.


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InternalMed_Harrison. Charlotte A. Gaydos, Thomas C. Quinn Chlamydiae are obligate intracellular bacteria that cause a wide variety of diseases in humans and animals. The chlamydiae were originally classified as four species in the genus Chlamydia: C. trachomatis, C. pneumoniae, C. psittaci, and C. pecorum (the last species being found in ruminants). The C. psittaci group has been separated into three species: C. psittaci, C. felis, and C. abortus. The mouse pneumonitis strain (MoPn) is now classified as C. muridarum, and the guinea pig inclusion conjunctivitis strain (GPIC) is now designated C. caviae.


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InternalMed_Harrison. C. trachomatis is divided into two biovars: trachoma and LGV (lymphogranuloma venereum). The trachoma biovar causes two major types of disease in humans: ocular trachoma, the leading infectious cause of preventable blindness in the developing world; and urogenital infections, which are sexually or neonatally transmitted. The 18 serovars of C. trachomatis fall into three groups: the trachoma serovars A, B, Ba, and C; the oculogenital serovars D–K; and the LGV serovars L1–L3. Serovars can be distinguished by serologic typing with monoclonal antibodies or by molecular gene typing. However, serovar identification usually is not important clinically since the antibiotic susceptibility pattern is the same for all three groups. The one exception applies when LGV is suspected on clinical grounds; in this situation, serovar determination is important because a longer treatment duration is required for LGV strains. BIOLOGY, GROWTH CYCLE, AND PATHOGENESIS


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InternalMed_Harrison. BIOLOGY, GROWTH CYCLE, AND PATHOGENESIS During their intracellular growth, chlamydiae produce characteristic intracytoplasmic inclusions that can be visualized by direct fluorescent antibody (DFA) or Giemsa staining of infected clinical material, such as conjunctival scrapings or cervical or urethral epithelial 1166 cells. Chlamydiae are nonmotile, gram-negative, obligate intracellular bacteria that replicate within the cytoplasm of host cells, forming the characteristic membrane-bound inclusions that are the basis for some diagnostic tests. Originally considered to be large viruses, chlamydiae differ from viruses in possessing RNA and DNA as well as a cell wall that is quite similar in structure to the cell wall of typical gram-negative bacteria. However, chlamydiae lack peptidoglycan; their structural integrity depends on disulfide binding of outer-membrane proteins.


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InternalMed_Harrison. Among the defining characteristics of chlamydiae is a unique growth cycle that involves alternation between two highly specialized morphologic forms (Figs. 213-1 and 213-2): the elementary body (EB), which is the infectious form and is specifically adapted for extracellular survival, and the metabolically active and replicating reticulate body (RB), which is not infectious, is adapted for an intracellular environment, and does not survive well outside the host cell. The biphasic growth cycle begins with attachment of the EB (diameter, 0.25–0.35 μm) at specific sites on the surface of the host cell. The EB enters the cell through a process similar to receptor-mediated endocytosis and resides in an inclusion, where the entire growth cycle is completed. The chlamydiae prevent phagosome-lysosome fusion. The inclusion membrane is modified by insertion of chlamydial antigens. Once the EB has entered the cell, it reorganizes into an RB, which is larger (0.5–1 μm) and contains more RNA. After


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InternalMed_Harrison. fusion. The inclusion membrane is modified by insertion of chlamydial antigens. Once the EB has entered the cell, it reorganizes into an RB, which is larger (0.5–1 μm) and contains more RNA. After ~8 h, the RB starts to divide by binary fission. The intracytoplasmic, membrane-bound inclusion body containing the RBs increases in size as the RBs multiply. Approximately 18–24 h after infection of the cell, these RBs begin to become EBs by a reorganization or condensation process that is poorly understood. After rupture of the inclusion body, the EBs are released to initiate another cycle of infection.


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InternalMed_Harrison. Chlamydiae are susceptible to many broad-spectrum antibiotics and possess a number of enzymes, but they have a very restricted FIGuRE 213-1 Chlamydial intracellular inclusions filled with smaller dense elementary bodies and larger reticulate bodies. (Reprinted with permission from WE Stamm: Chlamydial infections, in Harrison’s Principles of Internal Medicine, 17th ed, AS Fauci et al [eds]. New York, McGraw-Hill, 2008, p 1070.) 2.Initial inclusions 1.Uptake of 3. Fusion of inclusions; chlamydial EBs appearance of RBs 4.Multiplication of RBs; enlargement of inclusion 8. Return to normal removal 7. Persistence associated with IFN-˜ exposure; large aberrant RBs


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 213-2 Chlamydial life cycle. EBs, elementary bodies; RBs, reticulate bodies; IFN-γ, interferon γ. (Reprinted with permission from WE Stamm: Chlamydial infections, in Harrison’s Principles of Internal Medicine, 17th ed, AS Fauci et al [eds]. New York, McGraw-Hill, 2008, p 1071.) 5. Conversion of RBs to EBs 6. Release of EBs cycle with IFN-˜ metabolic capacity. None of these metabolic reactions results in the production of energy. Chlamydiae have thus been considered to be energy parasites that use the ATP produced by the host cell for their own metabolic functions. Many aspects of chlamydial molecular biology are not well understood, but the sequencing of several chlamydial genomes and new proteomics research have provided researchers with many relevant tools for elucidating the biology of the life cycle.


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InternalMed_Harrison. Genital infections are mostly caused by C. trachomatis serovars D–K, with serovars D, E, and F involved most often. Molecular typing of the major outer-membrane protein gene (omp1) from which serovar differences arise has been used to demonstrate that polymorphisms can occur in isolates from patients who are exposed frequently to multiple infections, while less variation is observed in isolates from less sexually active populations. Polymorphisms in the major outer-membrane protein may provide antigenic variation, and the different forms allow persistence in the community because immunity to one is not protective against the others.


InternalMed_Harrison

InternalMed_Harrison. The trachoma biovar is essentially a parasite of squamocolumnar epithelial cells; the LGV biovar is more invasive and involves lymphoid cells. As is typical of chlamydiae, C. trachomatis strains are capable of causing chronic, clinically inapparent, asymptomatic infections. Because the duration of the chlamydial growth cycle is ~48–72 h, the incubation period of sexually transmitted chlamydial infections is relatively long—generally 1–3 weeks. C. trachomatis causes cell death as a result of its replicative cycle and can induce cell damage whenever it persists. However, few toxic effects are demonstrated, and cell death because of chlamydial replication is not sufficient to account for disease manifestations, the majority of which are due to immunopathologic mechanisms or nonspecific host responses to the organism or its byproducts.


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InternalMed_Harrison. In recent years, the entire genomes of various chlamydial species have been sequenced, the field of proteomics has become established, host innate immunity has been more precisely delineated, and innovative host cell–chlamydial interaction studies have been conducted. As a result, many insights have been gained into how chlamydiae adapt and replicate in their intracellular environment and produce disease. These insights into pathogenesis include information on the regulation of gene expression, protein localization, the type III secretion system, the roles of CD4+ and CD8+ T lymphocytes in the host response, and T lymphocyte trafficking.


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InternalMed_Harrison. The chlamydial heat-shock protein, which shares antigenic epitopes with similar proteins of other bacteria and with human heat-shock protein, may sensitize the host, and repeated infections may cause host cell damage. Persistent or recurrent chlamydial infections are associated with fibrosis, scarring, and complications following simple epithelial infections. A common endpoint of these late consequences is scarring of mucous membranes. Genital complications can lead to pelvic inflammatory disease (PID) and its late consequences of infertility, ectopic pregnancy, and chronic pelvic pain, while ocular infections may lead to blinding trachoma. High levels of antibody to human heat-shock protein have been associated with tubal factor infertility and ectopic pregnancy. Without adequate therapy, chlamydial infections may persist for several years, although symptoms—if present—usually abate.


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InternalMed_Harrison. The pathogenic mechanisms of C. pneumoniae have yet to be completely elucidated. The same is true for C. psittaci, except that this agent infects cells very efficiently and causes disease that may reflect direct cytopathic effects. GENITAL INFECTIONS Spectrum Although chlamydiae cause a number of human diseases, localized lower genital tract infections caused by C. trachomatis and the sequelae of such infections are the most important in terms of medical and economic impact. Oculogenital infections due to


InternalMed_Harrison

InternalMed_Harrison. C. trachomatis serovars D–K are transmitted during sexual contact or from mother to baby during childbirth and are associated with many syndromes, including cervicitis, salpingitis, acute urethral syndrome, endometritis, ectopic pregnancy, infertility, and PID in female patients; urethritis, proctitis, and epididymitis in male patients; and conjunctivitis and pneumonia in infants. Women bear the greatest burden of morbidity because of the serious sequelae of these infections. Untreated infections lead to PID, and multiple episodes of PID can lead to tubal factor infertility and chronic pelvic pain. Studies estimate that up to 80–90% of women and >50% of men with C. trachomatis genital infections lack symptoms; other patients have very mild symptoms. Thus a large reservoir of infected persons continues to transmit infection to sexual partners.


InternalMed_Harrison

InternalMed_Harrison. As their designations reflect, the LGV serovars (L1, L2, and L3) cause LGV, an invasive sexually transmitted disease (STD) characterized by acute lymphadenitis with bubo formation and/or acute hemorrhagic proctitis (see “Lymphogranuloma Venereum,” below). Epidemiology C. trachomatis genital infections are global in distribution. The World Health Organization (WHO) esti mated in 2008 that >106.4 million cases occur annually worldwide. This figure makes chlamydial infection the most prevalent sexually transmitted bacterial infection in the world. The associated morbidity is substantial, and economic costs are high.


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InternalMed_Harrison. In the United States, chlamydial infections are the most commonly reported of all infectious diseases. In 2012, 1.3 million cases were reported to the U.S. Centers for Disease Control and Prevention (CDC); however, the CDC estimates that 2–3 million new cases occur per year, with substantial underreporting due to lack of screening in some populations. Rates of infection have increased every year; higher rates among women than among men reflect the focus on expansion of screening programs for women during the past 20 years, the use of increasingly sensitive diagnostic tests, an increased emphasis on case reporting, and improvements in the information systems used for reporting. The CDC and other professional organizations recommend annual screening of all sexually active women ≤25 years of age as well as rescreening of previously infected individuals at 3 months. Young women have the highest infection rates; in 2012, the figures were 3416.5 and 3722.5 cases per 100,000 population at


InternalMed_Harrison

InternalMed_Harrison. of age as well as rescreening of previously infected individuals at 3 months. Young women have the highest infection rates; in 2012, the figures were 3416.5 and 3722.5 cases per 100,000 population at 15–19 and 20–24 years of age, respectively. Age-specific rates among men, while much lower than those among women, were highest in the 20-to 24-year-old age group, at 1343.3 cases per 100,000. In 2012, rates 1167 increased for all racial and ethnic groups, with the highest rates among African Americans. For example, the rate of chlamydial infection among African-American girls 15–19 years of age was 7507.1 cases per 100,000—almost six times the rate among Caucasian girls in the same age group (1301.5/100,000). The rate among African-American women 20–24 years old was 4.8 times the rate among Caucasian women in the same age group. Similar racial disparities in reported rates of chlamydial infection exist among men. For boys 15–19 years of age, the rate among African Americans was 11.1


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InternalMed_Harrison. Caucasian women in the same age group. Similar racial disparities in reported rates of chlamydial infection exist among men. For boys 15–19 years of age, the rate among African Americans was 11.1 times the rate among Caucasians. The rate among Native Americans/Alaska Natives was more than four times the rate among Caucasians (648.3), and the rate among Latinos (383.6) was two times higher than that among Caucasians. These disparities are important reflections of health inequities in the United States.


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InternalMed_Harrison. The above statistics are based on case reporting. Studies based on screening surveys estimate that the U.S. prevalence of C. trachomatis cervical infection is 5% among asymptomatic female college students and prenatal patients, >10% among women seen in family planning clinics, and >20% among women seen in STD clinics. The prevalence of genital C. trachomatis infections varies substantially by geographic locale, with the highest rates in the southeastern United States. However, asymptomatic infections have been detected in >8–10% of young female military recruits from all parts of the country. The prevalence of C. trachomatis in the cervix of pregnant women is 5–10 times higher than that of Neisseria gonorrhoeae. The prevalence of genital infection with either agent is highest among women who are between the ages of 18 and 24, single, and non-Caucasian (e.g., African-American, Latina, Asian, Pacific Islander). Infections recur frequently in these same risk groups and are often acquired


InternalMed_Harrison

InternalMed_Harrison. are between the ages of 18 and 24, single, and non-Caucasian (e.g., African-American, Latina, Asian, Pacific Islander). Infections recur frequently in these same risk groups and are often acquired from untreated sexual partners. The use of oral contraception and the presence of cervical ectopy also confer an increased risk. The proportion of infections that are asymptomatic appears to be higher for C. trachomatis than for


InternalMed_Harrison

InternalMed_Harrison. N. gonorrhoeae, and symptomatic C. trachomatis infections are clinically less severe. Mild or asymptomatic C. trachomatis infections of the fallopian tubes nonetheless cause ongoing tubal damage and infertility. The costs of C. trachomatis infections and their complications to the U.S. health care system have recently been estimated to exceed $516.7 million annually. C. trachomatis is the most common cause of nongonococcal urethritis (NGU) and postgonococcal urethritis (PGU). The designation PGU refers to NGU developing in men 2–3 weeks after treatment of gonococcal urethritis with single doses of agents such as penicillin or cephalosporins, which lack antimicrobial activity against chlamydiae. Since current treatment regimens for gonorrhea have evolved and now include combination therapy with tetracycline, doxycycline, or azithromycin—all of which are effective against concomitant chlamydial infection—both the incidence of PGU and the causative role of


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InternalMed_Harrison. C. trachomatis in this syndrome have declined.


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InternalMed_Harrison. In the United States, most of the estimated 2 million cases of acute urethritis are NGU, and C. trachomatis is implicated in 30–50% of these cases. The cause of most of the remaining cases of NGU is uncertain, but recent evidence suggests that Ureaplasma urealyticum, Mycoplasma genitalium, Trichomonas vaginalis, and herpes simplex virus (HSV) cause some cases. The rate of involvement of C. trachomatis in urethral infection ranges from 3–7% among asymptomatic men to 15–20% among symptomatic men attending STD clinics. A multisite study of men in Baltimore, Seattle, Denver, and San Francisco reported an overall chlamydial prevalence of 7% in urine samples assessed by nucleic acid amplification tests (NAATs). As in women, infection in men is age related, with young age as the greatest risk factor for chlamydial urethritis. The prevalence among men is highest at 20–24 years of age. In STD clinics, urethritis is usually less prevalent among men who have sex with men (MSM) than among


InternalMed_Harrison

InternalMed_Harrison. risk factor for chlamydial urethritis. The prevalence among men is highest at 20–24 years of age. In STD clinics, urethritis is usually less prevalent among men who have sex with men (MSM) than among heterosexual men and is almost always much more common among African-American men than among Caucasian men. One study reported prevalences of 19% and 9% among nonwhite and white heterosexual men, respectively.


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InternalMed_Harrison. 1168 NGU is diagnosed by documentation of a leukocytic urethral exudate and by exclusion of gonorrhea by Gram’s staining or culture. C. trachomatis urethritis is generally less severe than gonococcal urethritis, although in any individual patient these two forms of urethritis cannot reliably be differentiated solely on clinical grounds. Symptoms include urethral discharge (often whitish and mucoid rather than frankly purulent), dysuria, and urethral itching. Physical examination may reveal meatal erythema and tenderness as well as a urethral exudate that is often demonstrable only by stripping of the urethra.


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InternalMed_Harrison. At least one-third of male patients with C. trachomatis urethral infection have no evident signs or symptoms of urethritis. The availability of NAATs for first-void urine specimens has facilitated broader-based testing for asymptomatic infection in male patients. As a result, asymptomatic chlamydial urethritis has been demonstrated in 5–10% of sexually active male adolescents screened at school-based clinics or community centers. Such patients generally have pyuria (≥15 leukocytes per 400× microscopic field in the sediment of first-void urine), a positive leukocyte esterase test, or an increased number of leukocytes on a Gram-stained smear prepared from a urogenital swab inserted 1–2 cm into the anterior urethra. To differentiate between true urethritis and functional symptoms in symptomatic patients or to make a presumptive diagnosis of C. trachomatis infection in high-risk but asymptomatic men (e.g., male patients in STD clinics, sex partners of women with nongonococcal salpingitis


InternalMed_Harrison

InternalMed_Harrison. patients or to make a presumptive diagnosis of C. trachomatis infection in high-risk but asymptomatic men (e.g., male patients in STD clinics, sex partners of women with nongonococcal salpingitis or mucopurulent cervicitis, fathers of children with inclusion conjunctivitis), the examination of an endourethral specimen for increased leukocytes is useful if specific diagnostic tests for chlamydiae are not available. Alternatively, urethritis can be assayed noninvasively by examination of a first-void urine sample for pyuria, either by microscopy or by the leukocyte esterase test. Urine (or a urethral swab) can also be tested directly for chlamydiae by DNA amplification methods, as described below (see “Detection Methods”).


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InternalMed_Harrison. epididymitis Chlamydial urethritis may be followed by acute epididymitis, but this condition is rare, generally occurring in sexually active patients <35 years of age; in older men, epididymitis is usually associated with gram-negative bacterial infection and/or instrumentation procedures. It is estimated that 50–70% of cases of acute epididymitis are caused by C. trachomatis. The condition usually presents as unilateral scrotal pain with tenderness, swelling, and fever in a young man, often occurring in association with chlamydial urethritis. The illness may be mild enough to treat with oral antibiotics on an outpatient basis or severe enough to require hospitalization and parenteral therapy. Testicular torsion should be excluded promptly by radionuclide scan, Doppler flow study, or surgical exploration in a teenager or young adult who presents with acute unilateral testicular pain without urethritis. The possibility of testicular tumor or chronic infection (e.g., tuberculosis)


InternalMed_Harrison

InternalMed_Harrison. surgical exploration in a teenager or young adult who presents with acute unilateral testicular pain without urethritis. The possibility of testicular tumor or chronic infection (e.g., tuberculosis) should be excluded when a patient with unilateral intrascrotal pain and swelling does not respond to appropriate antimicrobial therapy.


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InternalMed_Harrison. reactive artHritis Reactive arthritis consists of conjunctivitis, urethritis (or, in female patients, cervicitis), arthritis, and characteristic mucocutaneous lesions. It may develop in 1–2% of cases of NGU and is thought to be the most common type of peripheral inflammatory arthritis in young men. C. trachomatis has been recovered from the urethra of 16–44% of patients with reactive arthritis and from 69% of men who have signs of urogenital inflammation at the time of examination. Antibodies to C. trachomatis have also been detected in 46–67% of patients with reactive arthritis, and Chlamydia-specific cell-mediated immunity has been documented in 72%. In addition,


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InternalMed_Harrison. C. trachomatis has been isolated from synovial biopsy samples from 15 of 29 patients in a number of small series and from a smaller proportion of synovial fluid specimens. Chlamydial nucleic acids have been identified in synovial membranes and chlamydial EBs in joint fluid. The pathogenesis of reactive arthritis is unclear, but this condition probably represents an abnormal host response to a number of infectious agents, including those associated with bacterial gastroenteritis (e.g., Salmonella, Shigella, Yersinia, or Campylobacter), or to infection with


InternalMed_Harrison

InternalMed_Harrison. C. trachomatis or N. gonorrhoeae. Since >80% of affected patients have the HLA-B27 phenotype and since other mucosal infections produce an identical syndrome, chlamydial infection is thought to initiate an aberrant hyperactive immune response that produces inflammation of the involved target organs in these genetically predisposed individuals. Evidence of exaggerated cell-mediated and humoral immune responses to chlamydial antigens in reactive arthritis supports this hypothesis. The finding of chlamydial EBs and DNA in joint fluid and synovial tissue from patients with reactive arthritis suggests that chlamydiae may actually spread from genital to joint tissues in these patients—perhaps in macrophages.


InternalMed_Harrison

InternalMed_Harrison. NGU is the initial manifestation of reactive arthritis in 80% of patients, typically occurring within 14 days after sexual exposure. The urethritis may be mild and may even go unnoticed by the patient. Similarly, gonococcal urethritis may precede reactive arthritis, but co-infection with an agent of NGU is difficult to rule out. The urethral discharge may be purulent or mucopurulent, and patients may or may not report dysuria. Accompanying prostatitis, usually asymptomatic, has been described. Arthritis usually begins ~4 weeks after the onset of urethritis but may develop sooner or, in a small percentage of cases, may actually precede urethritis. The knees are most frequently involved; next most commonly affected are the ankles and small joints of the feet. Sacroiliitis, either symmetrical or asymmetrical, is documented in two-thirds of patients. Mild bilateral conjunctivitis, iritis, keratitis, or uveitis is sometimes present but lasts for only a few days. Finally, dermatologic


InternalMed_Harrison

InternalMed_Harrison. or asymmetrical, is documented in two-thirds of patients. Mild bilateral conjunctivitis, iritis, keratitis, or uveitis is sometimes present but lasts for only a few days. Finally, dermatologic manifestations occur in up to 50% of patients. The initial lesions— usually papules with a central yellow spot—most often involve the soles and palms and, in ~25% of patients, eventually epithelialize and thicken to produce keratoderma blenorrhagicum. Circinate balanitis is usually painless and occurs in fewer than half of patients. The initial episode of reactive arthritis usually lasts 2–6 months.


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InternalMed_Harrison. proctitis Primary anal or rectal infections with C. trachomatis have been described in women and MSM who practice anal intercourse. In these infections, rectal involvement is initially characterized by severe anorectal pain, a bloody mucopurulent discharge, and tenesmus. Oculogenital serovars D–K and LGV serovars L1, L2, and L3 have been found to cause proctitis. The LGV serovars are far more invasive and cause much more severely symptomatic disease, including severe ulcerative proctocolitis that can be clinically confused with HSV proctitis. Histologically, LGV proctitis may resemble Crohn’s disease in that giant cell formation and granulomas are detected. In the United States and Europe, cases of LGV proctitis occur almost exclusively in MSM, many of whom are positive for HIV infection.


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InternalMed_Harrison. The less invasive non-LGV serovars of C. trachomatis cause mild proctitis. Many infected individuals are asymptomatic, and in these cases infection is diagnosed only by routine culture or NAAT of rectal swabs. The number of fecal leukocytes is usually abnormal in both asymptomatic and symptomatic cases. Sigmoidoscopy may yield normal findings or may reveal mild inflammatory changes or small erosions or follicles in the lower 10 cm of the rectum. Histologic examination of rectal biopsies generally shows anal crypts and prominent follicles as well as neutrophilic infiltration of the lamina propria. Chlamydial proctitis is best diagnosed by isolation of C. trachomatis from the rectum and documentation of a response to appropriate therapy. NAATs are reportedly more sensitive than culture for diagnosis and are also specific.


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InternalMed_Harrison. mUcopUrUlent cervicitis Although many women with chlamydial infections of the cervix have no symptoms, almost half generally have local signs of infection on examination. Cervicitis is usually characterized by the presence of a mucopurulent discharge, with >20 neutrophils per microscopic field visible in strands of cervical mucus in a thinly smeared, gram-stained preparation of endocervical exudate. Hypertrophic ectopy of the cervix may also be evident as an edematous area near the cervical os that is congested and bleeds easily on minor trauma (e.g., when a specimen is collected with a swab). A Papanicolaou smear shows increased numbers of neutrophils as well as a characteristic pattern of mononuclear inflammatory cells including plasma cells, transformed lymphocytes, and histiocytes. Cervical biopsy shows a predominantly mononuclear cell infiltrate of the subepithelial stroma. Clinical experience and collaborative studies indicate that a cutoff of >30 polymorphonuclear neutrophils


InternalMed_Harrison

InternalMed_Harrison. biopsy shows a predominantly mononuclear cell infiltrate of the subepithelial stroma. Clinical experience and collaborative studies indicate that a cutoff of >30 polymorphonuclear neutrophils (PMNs) per 1000× field in a gram-stained smear of cervical mucus correlates best with chlamydial or gonococcal cervicitis.


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InternalMed_Harrison. Clinical recognition of chlamydial cervicitis depends on a high index of suspicion and careful cervical examination. No genital symptoms are specifically correlated with chlamydial cervical infection. The differential diagnosis of a mucopurulent discharge from the endocervical canal in a young, sexually active woman includes gonococcal endocervicitis, salpingitis, endometritis, and intrauterine contraceptive device–induced inflammation. Diagnosis of cervicitis is based on the presence of PMNs on a cervical swab as noted above; the presence of chlamydiae is confirmed by either culture or NAAT.


InternalMed_Harrison

InternalMed_Harrison. pelvic inflammatory disease Inflammation of sections of the fallopian tube is often referred to as salpingitis or PID. The proportion of acute salpingitis cases caused by C. trachomatis varies geographically and with the population studied. It has been estimated that C. trachomatis causes up to 50% of PID cases in the United States. PID occurs via ascending intraluminal spread of C. trachomatis or N. gonorrhoeae from the lower genital tract. Mucopurulent cervicitis is often followed by endometritis, endosalpingitis, and finally pelvic peritonitis. Evidence of mucopurulent cervicitis is often found in women with laparoscopically verified salpingitis. Similarly, endometritis, demonstrated by an endometrial biopsy showing plasma cell infiltration of the endometrial epithelium, is documented in most women with lap-aroscopy-verified chlamydial (or gonococcal) salpingitis. Chlamydial endometritis can also occur in the absence of clinical evidence of salpingitis. Histologic evidence of


InternalMed_Harrison

InternalMed_Harrison. in most women with lap-aroscopy-verified chlamydial (or gonococcal) salpingitis. Chlamydial endometritis can also occur in the absence of clinical evidence of salpingitis. Histologic evidence of endometritis has been correlated with a syndrome consisting of vaginal bleeding, lower abdominal pain, and uterine tenderness in the absence of adnexal tenderness. Chlamydial salpingitis produces milder symptoms than gonococcal salpingitis and may be associated with less marked adnexal tenderness. Thus, mild adnexal or uterine tenderness in a sexually active woman with cervicitis suggests chlamydial PID.


InternalMed_Harrison

InternalMed_Harrison. Chronic untreated endometrial and tubal inflammation can result in tubal scarring, impaired tubal function, tubal occlusion, and infertility, even among women who report no prior treatment for PID. C. trachomatis has been implicated particularly often in “subclinical” PID on the basis of (1) a lack of history of PID among Chlamydiaseropositive women with tubal damage or (2) detection of chlamydial DNA or antigen among asymptomatic women with tubal infertility. These data suggest that the best method to prevent PID and its sequelae is surveillance and control of lower genital tract infections along with diagnosis and treatment of sex partners and prevention of reinfections. Promotion of early symptom recognition and health care presentation may reduce the frequency and severity of sequelae of PID.