InternalMed_Harrison

InternalMed_Harrison. The course of untreated syphilis was studied retrospectively in a group of nearly 2000 patients with primary or secondary disease diagnosed clinically (the Oslo Study, 1891–1951) and was assessed prospectively in 431 African-American men with seropositive latent syphilis of ≥3 years’ duration (the notorious Tuskegee Study, 1932–1972). In the Oslo Study, 24% of patients developed relapsing secondary lesions within 4 years, and 28% eventually developed one or more manifestations of tertiary syphilis. Cardiovascular syphilis, including aortitis, was detected in 10% of patients; 7% of patients developed symptomatic neurosyphilis, and 16% developed benign tertiary gummatous syphilis. Syphilis was the primary cause of death in 15% of men and 8% of women. Cardiovascular syphilis was documented in 35% of men and 22% of women who eventually came to autopsy. In general, serious late complications were nearly twice as common among men as among women.


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InternalMed_Harrison. The Tuskegee Study showed that the death rate among untreated African-American men with syphilis (25–50 years old) was 17% higher than the rate among uninfected subjects and that 30% of all deaths were attributable to cardiovascular or, to a lesser extent, CNS syphilis. Anatomic evidence of aortitis was found in 40–60% of autopsied subjects with syphilis (vs 15% of control subjects), whereas CNS syphilis was found in only 4%. Rates of hypertension were also higher among the infected subjects. The ethical issues eventually raised by this study, begun in the preantibiotic era but continuing into the early 1970s, had a major influence on the development of current guidelines for human medical experimentation, and the history of the study may still contribute to a reluctance of some African Americans to participate as subjects in clinical research.


InternalMed_Harrison

InternalMed_Harrison. Primary Syphilis The typical primary chancre usually begins as a single painless papule that rapidly becomes eroded and usually becomes indurated, with a characteristic cartilaginous consistency on palpation of the edge and base of the ulcer. Multiple primary lesions are seen in a minority of patients. In heterosexual men the chancre is usually located on the penis (Fig. 206-2; see also Fig. 25e-17), whereas in MSM it may be found in the anal canal or rectum, in the mouth, or on the external genitalia. Oral sex has been identified as the source of infection in some MSM. In women, common primary sites are the cervix and labia. Consequently, primary syphilis goes unrecognized in women and homosexual men more often than in heterosexual men. FIGuRE 206-2 Primary syphilis with a firm, nontender chancre.


InternalMed_Harrison

InternalMed_Harrison. Atypical primary lesions are common. The clinical appearance depends on the number of treponemes inoculated and on the immunologic status of the patient. A large inoculum produces a dark-fieldpositive ulcerative lesion in nonimmune volunteers but may produce a small dark-field-negative papule, an asymptomatic but seropositive latent infection, or no response at all in some individuals with a history of syphilis. A small inoculum may produce only a papular lesion, even in nonimmune individuals. Therefore, syphilis should be considered even in the evaluation of trivial or atypical dark-field-negative genital lesions. The genital lesions that most commonly must be differentiated from those of primary syphilis include those caused by herpes simplex virus infection (Chap. 216), chancroid (Chap. 182), traumatic injury, and donovanosis (Chap. 198e). Regional (usually inguinal) lymphadenopathy accompanies the primary syphilitic lesion, appearing within 1 week of lesion onset. The nodes are


InternalMed_Harrison

InternalMed_Harrison. 182), traumatic injury, and donovanosis (Chap. 198e). Regional (usually inguinal) lymphadenopathy accompanies the primary syphilitic lesion, appearing within 1 week of lesion onset. The nodes are firm, nonsuppurative, and painless. Inguinal lymphadenopathy is bilateral and may occur with anal as well as with external genital chancres. The chancre generally heals within 4–6 weeks (range, 2–12 weeks), but lymphadenopathy may persist for months.


InternalMed_Harrison

InternalMed_Harrison. Secondary Syphilis The protean manifestations of the secondary stage usually include mucocutaneous lesions and generalized nontender lymphadenopathy. The healing primary chancre may still be present in ∼15% of cases, and the stages may overlap more frequently in persons with concurrent HIV infection. The skin rash consists of macular, papular, papulosquamous, and occasionally pustular syphilides; often more than one form is present simultaneously. The eruption may be very subtle, and 25% of patients with a discernible rash may be unaware that they have dermatologic manifestations. Initial lesions are pale red or pink, nonpruritic, discrete macules distributed on the trunk and proximal extremities; these macules progress to papular lesions that are distributed widely and that frequently involve the palms and soles (Fig. 206-3; see also Figs. 25e-18 and 25e-19). Rarely, severe necrotic lesions (lues maligna) may appear; they are more commonly reported in HIV-infected individuals.


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InternalMed_Harrison. involve the palms and soles (Fig. 206-3; see also Figs. 25e-18 and 25e-19). Rarely, severe necrotic lesions (lues maligna) may appear; they are more commonly reported in HIV-infected individuals. Involvement of the hair follicles may result in patchy alopecia of the scalp hair, eyebrows, or beard in up to 5% of cases.


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InternalMed_Harrison. In warm, moist, intertriginous areas (commonly the perianal region, vulva, and scrotum), papules can enlarge to produce broad, moist, pink or gray-white, highly infectious lesions (condylomata lata; see Fig. 25e-20) in 10% of patients with secondary syphilis. Superficial mucosal erosions (mucous patches) occur in 10–15% of patients and commonly involve the oral or genital mucosa (see Fig. 25e-21). The typical mucous patch is a painless silver-gray erosion surrounded by a red periphery.


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InternalMed_Harrison. Constitutional signs and symptoms that may accompany or precede secondary syphilis include sore throat (15–30%), fever (5–8%), weight loss (2–20%), malaise (25%), anorexia (2–10%), headache (10%), and meningismus (5%). Acute meningitis occurs in only 1–2% of cases, but CSF cell and protein concentrations are increased in up to 40% of cases, and viable T. pallidum organisms have been recovered from CSF during primary and secondary syphilis in 30% of cases; the latter finding is 1135 often but not always associated with other CSF abnormalities.


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InternalMed_Harrison. Less common complications of secondary syphilis include hepatitis, nephropathy, gastrointestinal involvement (hypertrophic gastritis, patchy proctitis, or a rectosigmoid mass), arthritis, and periostitis. Ocular findings associated with secondary syphilis include pupillary abnormalities and optic neuritis as well as the classic iritis or uveitis. The diagnosis of ocular syphilis is often considered in affected patients only after they fail to respond to steroid therapy. Anterior uveitis has been reported in 5–10% of patients with secondary syphilis, and T. pallidum has been demonstrated in aqueous humor from such patients. Hepatic involvement is common in syphilis; although it is usually asymptomatic, up to 25% of patients may have abnormal liver function tests. Frank syphilitic hepatitis may be seen. Renal involvement usually results from immune complex deposition and produces proteinuria associated with an acute nephrotic syndrome. Like those of primary syphilis, the manifestations


InternalMed_Harrison

InternalMed_Harrison. may be seen. Renal involvement usually results from immune complex deposition and produces proteinuria associated with an acute nephrotic syndrome. Like those of primary syphilis, the manifestations of the secondary stage resolve spontaneously, usually within 1–6 months.


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InternalMed_Harrison. Latent Syphilis Positive serologic tests for syphilis, together with a normal CSF examination and the absence of clinical manifestations of syphilis, indicate a diagnosis of latent syphilis in an untreated person. The diagnosis is often suspected on the basis of a history of primary or secondary lesions, a history of exposure to syphilis, or the delivery of an infant with congenital syphilis. A previous negative serologic test or a history of lesions or exposure may help establish the duration of latent infection, which is an important factor in the selection of appropriate therapy. Early latent syphilis is limited to the first year after infection, whereas late latent syphilis is defined as that of ≥1 year’s duration (or of unknown duration). T. pallidum may still seed the bloodstream intermittently during the latent stage, and pregnant women with latent syphilis may infect the fetus in utero. Moreover, syphilis has been transmitted through blood transfusion or organ donation from


InternalMed_Harrison

InternalMed_Harrison. intermittently during the latent stage, and pregnant women with latent syphilis may infect the fetus in utero. Moreover, syphilis has been transmitted through blood transfusion or organ donation from patients with latent syphilis. It was previously thought that untreated late latent syphilis had three possible outcomes: (1) persistent lifelong infection; (2) development of late syphilis; or (3) spontaneous cure, with reversion of serologic tests to negative. It is now apparent, however, that the more sensitive treponemal antibody tests rarely, if ever, become nonreactive without treatment. Although progression to clinically evident late syphilis is very rare today, the occurrence of spontaneous cure is in doubt.


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InternalMed_Harrison. Involvement of the CNS Traditionally, neurosyphilis has been considered a late manifestation of syphilis, but this view is inaccurate. CNS syphilis represents a continuum encompassing early invasion (usually within the first weeks or months of infection), months to years of asymptomatic involvement, and, in some cases, development of early or late neurologic manifestations.


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InternalMed_Harrison. asymptomatic neUrosypHilis The diagnosis of asymptomatic neurosyphilis is made in patients who lack neurologic symptoms and signs but who have CSF abnormalities including mononuclear pleocytosis, increased protein concentrations, or CSF reactivity in the Venereal Disease Research Laboratory (VDRL) test. CSF abnormalities are demon- strated in up to 40% of cases of primary or secondary syphilis and in 25% of cases of latent syphilis. T. pallidum has been recovered by inoculation into rab-bits of CSF from up to 30% of patients with primary or secondary syphilis but less frequently by inoculation of CSF from patients with latent syphilis. The presence of T. pallidum in CSF is often associated with other CSF abnormali-ties, but organisms can be recovered from patients with otherwise normal CSF. Although the prognostic implica-tions of these findings in early syphilis


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InternalMed_Harrison. FIGuRE 206-3 Secondary syphilis. Left: Maculopapular truncal eruption. Middle: Papules on the are uncertain, it may be appropriate palms. Right: Papules on the soles. (Courtesy of Jill McKenzie and Christina Marra.) to conclude that even patients with 1136 early syphilis who have such findings do indeed have asymptomatic neurosyphilis and should be treated for neurosyphilis; such treatment is particularly important in patients with concurrent HIV infection. Before the advent of penicillin, the risk of development of clinical neurosyphilis in untreated asymptomatic persons was roughly proportional to the intensity of CSF changes, with the overall cumulative probability of progression to clinical neurosyphilis ∼20% in the first 10 years but increasing with time. Most experts agree that neurosyphilis is more common in HIV-infected persons, while immunocompetent patients with untreated latent syphilis and normal CSF probably run a very low risk of subsequent neurosyphilis. In several


InternalMed_Harrison

InternalMed_Harrison. neurosyphilis is more common in HIV-infected persons, while immunocompetent patients with untreated latent syphilis and normal CSF probably run a very low risk of subsequent neurosyphilis. In several recent studies, neurosyphilis was associated with a rapid plasma reagin (RPR) titer of ≥1:32, regardless of clinical stage or HIV infection status.


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InternalMed_Harrison. symptomatic neUrosypHilis The major clinical categories of symptomatic neurosyphilis include meningeal, meningovascular, and parenchymatous syphilis. The last category includes general paresis and tabes dorsalis. The onset of symptoms usually occurs <1 year after infection for meningeal syphilis, up to 10 years after infection for meningovascular syphilis, at ∼20 years for general paresis, and at 25–30 years for tabes dorsalis. Neurosyphilis is more frequently symptomatic in patients who are co-infected with HIV, particularly in the setting of a low CD4+ T lymphocyte count. In addition, recent evidence suggests that syphilis infection worsens the cognitive impairment seen in HIV-infected persons and that this effect persists even after treatment for syphilis.


InternalMed_Harrison

InternalMed_Harrison. Meningeal syphilis may present as headache, nausea, vomiting, neck stiffness, cranial nerve involvement, seizures, and changes in mental status. This condition may be concurrent with or may follow the secondary stage. Patients presenting with uveitis, iritis, or hearing loss often have meningeal syphilis, but these clinical findings can also be seen in patients with normal CSF. Meningovascular syphilis reflects meningitis together with inflammatory vasculitis of small, medium, or large vessels. The most common presentation is a stroke syndrome involving the middle cerebral artery of a relatively young adult. However, unlike the usual thrombotic or embolic stroke syndrome of sudden onset, meningovascular syphilis often becomes manifest after a subacute encephalitic prodrome (with headaches, vertigo, insomnia, and psychological abnormalities), which is followed by a gradually progressive vascular syndrome.


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InternalMed_Harrison. The manifestations of general paresis reflect widespread late parenchymal damage and include abnormalities corresponding to the mnemonic paresis: personality, affect, reflexes (hyperactive), eye (e.g., Argyll Robertson pupils), sensorium (illusions, delusions, hallucinations), intellect (a decrease in recent memory and in the capacity for orientation, calculations, judgment, and insight), and speech. Tabes dorsalis is a late manifestation of syphilis that presents as symptoms and signs of demyelination of the posterior columns, dorsal roots, and dorsal root ganglia. Symptoms include ataxic wide-based gait and foot drop; paresthesia; bladder disturbances; impotence; areflexia; and loss of positional, deep-pain, and temperature sensations. Trophic joint degeneration (Charcot’s joints) and perforating ulceration of the feet can result from loss of pain sensation. The small, irregular Argyll Robertson pupil, a feature of both tabes dorsalis and paresis, reacts to accommodation but not to


InternalMed_Harrison

InternalMed_Harrison. ulceration of the feet can result from loss of pain sensation. The small, irregular Argyll Robertson pupil, a feature of both tabes dorsalis and paresis, reacts to accommodation but not to light. Optic atrophy also occurs frequently in association with tabes.


InternalMed_Harrison

InternalMed_Harrison. Other Manifestations of Late Syphilis The slowly progressive inflammatory process leading to tertiary disease begins early during infection, although these manifestations may not become clinically apparent for years or decades. Early syphilitic aortitis becomes evident soon after secondary lesions subside, and treponemes that trigger the development of gummas may have seeded the tissue years earlier.


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InternalMed_Harrison. cardiovascUlar sypHilis Cardiovascular manifestations, usually appearing 10–40 years after infection, are attributable to endarteritis obliterans of the vasa vasorum, which provide the blood supply to large vessels; T. pallidum DNA has been detected by PCR in aortic tissue. Cardiovascular involvement results in uncomplicated aortitis, aortic regurgitation, saccular aneurysm (usually of the ascending aorta), or coronary ostial stenosis. In the preantibiotic era, symptomatic cardiovascular complications developed in ∼10% of persons with late untreated syphilis. Today, this form of late syphilis is rarely seen in the developed world. Linear calcification of the ascending aorta on chest x-ray films suggests asymptomatic syphilitic aortitis, as arteriosclerosis seldom produces this sign. Only 1 in 10 aortic aneurysms of syphilitic origin involves the abdominal aorta.


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InternalMed_Harrison. late benign sypHilis (gUmma) Gummas are usually solitary lesions ranging from microscopic to several centimeters in diameter. Histologic examination shows a granulomatous inflammation, with a central area of necrosis due to endarteritis obliterans. Although rarely demonstrated microscopically, T. pallidum has been detected by PCR or recovered from these lesions, and penicillin treatment results in rapid resolution, confirming the treponemal stimulus for the inflammation. Common sites include the skin and skeletal system; however, any organ (including the brain) may be involved. Gummas of the skin produce indolent, painless, indurated nodular or ulcerative lesions that may resemble other chronic granulomatous conditions, including tuberculosis, sarcoidosis, leprosy, and deep fungal infections. Skeletal gummas most frequently involve the long bones, although any bone may be affected. Upper respiratory gummas can lead to perforation of the nasal septum or palate.


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InternalMed_Harrison. Congenital Syphilis Transmission of T. pallidum across the placenta from a syphilitic woman to her fetus may occur at any stage of pregnancy, but fetal damage generally does not occur until after the fourth month of gestation, when fetal immunologic competence begins to develop. This timing suggests that the pathogenesis of congenital syphilis, like that of adult syphilis, depends on the host immune response rather than on a direct toxic effect of T. pallidum. The risk of fetal infection during untreated early maternal syphilis is ∼75–95%, decreasing to ∼35% for maternal syphilis of >2 years’ duration. Adequate treatment of the woman before the 16th week of pregnancy should prevent fetal damage, and treatment before the third trimester should adequately treat the infected fetus. Untreated maternal infection may result in a rate of fetal loss of up to 40% (with stillbirth more common than abortion because of the late onset of fetal pathology), prematurity, neonatal death, or nonfatal


InternalMed_Harrison

InternalMed_Harrison. maternal infection may result in a rate of fetal loss of up to 40% (with stillbirth more common than abortion because of the late onset of fetal pathology), prematurity, neonatal death, or nonfatal congenital syphilis. Among infants born alive, only fulminant congenital syphilis is clinically apparent at birth, and these babies have a very poor prognosis. The most common clinical problem is the healthy-appearing baby born to a mother with a positive serologic test


InternalMed_Harrison

InternalMed_Harrison. Routine serologic testing in early pregnancy is considered cost-effective in virtually all populations, even in areas with a low prenatal prevalence of syphilis. Low-tech point-of-care tests have been developed and are being widely implemented to facilitate antenatal testing in resource-poor settings. A recent study demonstrated the high cost-effectiveness of using these tests for screening (with subsequent treatment) in sub-Saharan Africa. Adverse outcomes were reduced, with 64,000 fewer stillbirths, 25,000 fewer neonatal deaths, and up to 25,000 fewer live births of infants with syphilis. The intervention would remain cost-effective even if the current syphilis seroprevalence among pregnant women declined from its present 3.1% to 0.4%. Where the prevalence of syphilis is high or when the patient is at high risk of reinfection, serologic testing should be repeated in the third trimester and at delivery. Neonatal congenital syphilis must be differentiated from other generalized


InternalMed_Harrison

InternalMed_Harrison. the patient is at high risk of reinfection, serologic testing should be repeated in the third trimester and at delivery. Neonatal congenital syphilis must be differentiated from other generalized congenital infections, including rubella, cytomegalovirus or herpes simplex virus infection, and toxoplasmosis, as well as from erythroblastosis fetalis.


InternalMed_Harrison

InternalMed_Harrison. The manifestations of congenital syphilis include (1) early manifestations, which appear within the first 2 years of life (often at 2–10 weeks of age), are infectious, and resemble the manifestations of secondary syphilis in the adult; (2) late manifestations, which appear after 2 years and are noninfectious; and (3) residual stigmata. The earliest manifestations of congenital syphilis include rhinitis, or “snuffles” (23%); mucocutaneous lesions (35–41%); bone changes (61%), including osteochondritis, osteitis, and periostitis detectable by x-ray examination of long bones; hepatosplenomegaly (50%); lymphadenopathy (32%); anemia (34%); jaundice (30%); thrombocytopenia; and leukocytosis. CNS invasion by T. pallidum is detectable in 22% of infected neonates. Neonatal death is usually due to pulmonary hemorrhage, secondary bacterial infection, or severe hepatitis.


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InternalMed_Harrison. Late congenital syphilis (untreated after 2 years of age) is subclinical in 60% of cases; the clinical spectrum in the remainder of cases may include interstitial keratitis (which occurs at 5–25 years of age), eighth-nerve deafness, and recurrent arthropathy. Bilateral knee effusions are known as Clutton’s joints. Neurosyphilis was present in about one-quarter of untreated patients with late congenital syphilis in the preantibiotic era. Gummatous periostitis occurs at 5–20 years of age and, as in nonvenereal endemic syphilis, tends to cause destructive lesions of the palate and nasal septum. Classic stigmata include Hutchinson’s teeth (centrally notched, widely spaced, peg-shaped upper central incisors), “mulberry” molars (sixth-year molars with multiple, poorly developed cusps), saddle nose, and saber shins.


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InternalMed_Harrison. Demonstration of the Organism T. pallidum cannot be detected by culture. Historically, dark-field microscopy and immunofluorescence antibody staining have been used to identify this spirochete in samples from moist lesions such as chancres or condylomata lata, but these tests are rarely available outside of research laboratories. Sensitive and specific PCR tests have been developed but are not commercially available, although a number of laboratories perform in-house validated PCR testing. T. pallidum can be found in tissue with appropriate silver stains, but these results should be interpreted with caution because artifacts resembling T. pallidum are often seen. Tissue treponemes can be demonstrated more reliably in research laboratories by PCR or by immunofluorescence or immunohistochemical methods using specific monoclonal or polyclonal antibodies to T. pallidum.


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InternalMed_Harrison. Serologic Tests for Syphilis There are two types of serologic test for syphilis: nontreponemal and treponemal. Both are reactive in persons with any treponemal infection, including yaws, pinta, and endemic syphilis.


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InternalMed_Harrison. The most widely used nontreponemal antibody tests for syphilis are the RPR and VDRL tests, which measure IgG and IgM directed against a cardiolipin-lecithin-cholesterol antigen complex. The RPR test is easier to perform and uses unheated serum or plasma; it is the test of choice for rapid serologic diagnosis in a clinical setting. The VDRL test remains the standard for examining CSF and is superior to the RPR for this purpose. The RPR and VDRL tests are recommended for screening or for quantitation of serum antibody. The titer reflects disease activity, rising during the evolution of early syphilis, often exceeding 1:32 in secondary syphilis, and declining thereafter without therapy. After treatment for early syphilis, a persistent fall by fourfold or more (e.g., a decline from 1:32 to 1:8) is considered an adequate response. VDRL titers do not correspond directly to RPR titers, and sequential quantitative testing (as for response to therapy) must employ a single test. As will be


InternalMed_Harrison

InternalMed_Harrison. 1:8) is considered an adequate response. VDRL titers do not correspond directly to RPR titers, and sequential quantitative testing (as for response to therapy) must employ a single test. As will be discussed (see “Evaluation for Neurosyphilis,” below), the RPR titer may be useful in determining which patients will benefit from CSF examination.


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InternalMed_Harrison. Treponemal tests measure antibodies to native or recombinant T. pallidum antigens and include the fluorescent treponemal antibody– absorbed (FTA-ABS) test and the T. pallidum particle agglutination (TPPA) test, both of which are more sensitive for primary syphilis than the previously used hemagglutination tests. The T. pallidum hemagglutination (TPHA) test is widely used in Europe but is not available in the United States. When used to confirm positive nontreponemal test results, treponemal tests have a very high positive predictive value for diagnosis of syphilis. Treponemal enzyme or chemiluminescence immunoassays (EIAs/CIAs), based largely on reactivity to recombinant antigens, have also been developed and are now widely used as screening tests by large laboratories. In a screening setting, however, treponemal tests give false-positive results at rates as high as 1–2%, and the rate is higher with the EIA/CIA tests. Treponemal tests are likely to remain reactive even after adequate


InternalMed_Harrison

InternalMed_Harrison. however, treponemal tests give false-positive results at rates as high as 1–2%, and the rate is higher with the EIA/CIA tests. Treponemal tests are likely to remain reactive even after adequate treatment and cannot differentiate


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InternalMed_Harrison. EIA+ RPR+ Consistent with past or current syphilis EIA+ RPR– TPPA– Unconfirmed EIA. Unlikely to be syphilis. If pt is at risk for syphilis, retest in 1 month. EIA+ RPR– TPPA+ Possible syphilis infection. Requires historical and clinical evaluation. EIA+ RPR– TPPA or FTA-ABS (Different platform and target antigens) EIA– Negative for syphilis antibodies Syphilis EIA EIA+ Quantitative RPR or VDRL FIGuRE 206-4 Algorithm for interpretation of results from syphilis enzyme immunoassays (EIAs) used for screening. FTA-ABS, fluores-cent treponemal antibody–absorbed; RPR, rapid plasma reagin; TPPA, Treponema pallidum particle agglutination; VDRL, Venereal Disease Research Laboratory. (Based on the 2010 Sexually Transmitted Diseases Treatment Guidelines from the Centers for Disease Control and Prevention.) past from current T. pallidum infection. Figure 206-4 provides a suggested algorithm for management of such cases.


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InternalMed_Harrison. Both nontreponemal and treponemal tests may be nonreactive in early primary syphilis, although treponemal tests are slightly more sensitive (85–90%) during this stage than nontreponemal tests (∼80%). All tests are reactive during secondary syphilis. (Fewer than 1% of patients with high titers have a nontreponemal test that is nonreactive or weakly reactive with undiluted serum but is reactive with diluted serum—the prozone phenomenon.) VDRL and RPR sensitivity and titers may decline in untreated persons with late latent syphilis, but treponemal tests remain sensitive in these stages. After treatment for early syphilis, nontreponemal test titers will generally decline or the tests will become nonreactive, whereas treponemal tests often remain reactive after therapy and are not helpful in determining the infection status of persons with past syphilis.


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InternalMed_Harrison. For practical purposes, most clinicians need to be familiar with three uses of serologic tests for syphilis recommended by the Centers for Disease Control and Prevention (CDC): (1) screening or diagnosis (RPR or VDRL), (2) quantitative measurement of antibody to assess clinical syphilis activity or to monitor response to therapy (RPR or VDRL), and (3) confirmation of a syphilis diagnosis in a patient with a reactive RPR or VDRL test (FTA-ABS, TPPA, EIA/CIA). Studies have not demonstrated the utility of IgM testing for adult syphilis. Whereas IgM titers appear to decline after therapy, the presence or absence of specific IgM does not strictly correlate with T. pallidum infection. Moreover, no commercially available IgM test is recommended, even for evaluation of infants with suspected congenital syphilis.


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InternalMed_Harrison. False-Positive Serologic Tests for Syphilis The lipid antigens of nontreponemal tests are similar to those found in human tissues, and the tests may be reactive (usually with titers ≤1:8) in persons without treponemal infection. Among patients being screened for syphilis because of risk factors, clinical suspicion, or history of exposure, ∼1% of reactive tests are falsely positive. Modern VDRL and RPR tests are highly specific, and false-positive reactions are largely limited to persons with 1138 autoimmune conditions or injection drug use. The prevalence of false-positive results increases with advancing age, approaching 10% among persons >70 years old. In a patient with a false-positive nontreponemal test, syphilis is excluded by a nonreactive treponemal test. False-positive reactions may also occur with the treponemal tests, particularly the new, very sensitive EIA/CIA tests. When a low-prevalence population for syphilis is screened, the number of false-positive reactions may


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InternalMed_Harrison. may also occur with the treponemal tests, particularly the new, very sensitive EIA/CIA tests. When a low-prevalence population for syphilis is screened, the number of false-positive reactions may outnumber true positives, leading to unnecessary treatment. Although the precise reason is not known, it has been shown that sera from patients with periodontal disease react with antigens used in the EIA/CIA tests, presumably as a result of cross-reactive epitopes in the many treponemes that infect the gingival crevices during periodontal disease.


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InternalMed_Harrison. Evaluation for Neurosyphilis Involvement of the CNS is detected by examination of CSF for pleocytosis (>5 white blood cells/μL), increased protein concentration (>45 mg/dL), or VDRL reactivity. Elevated CSF cell counts and protein concentrations are not specific for neurosyphilis and may be confounded by HIV co-infection. Because CSF pleocytosis may also be due to HIV, some studies have suggested using a CSF white-cell cutoff of 20 cells/μL as diagnostic of neurosyphilis in HIV-infected patients with syphilis. The CSF VDRL test is highly specific and, when reactive, is considered diagnostic of neurosyphilis; however, this test is insensitive and may be nonreactive even in cases of symptomatic neurosyphilis. The FTA-ABS test on CSF is reactive far more often than the VDRL test on CSF in all stages of syphilis, but reactivity may reflect passive transfer of serum antibody into the CSF. A nonreactive FTA-ABS test on CSF, however, may be used to rule out asymptomatic neurosyphilis. The


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InternalMed_Harrison. all stages of syphilis, but reactivity may reflect passive transfer of serum antibody into the CSF. A nonreactive FTA-ABS test on CSF, however, may be used to rule out asymptomatic neurosyphilis. The utility of measuring CXCL13 in CSF to distinguish between neurosyphilis and HIV-related CSF abnormalities has been demonstrated.


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InternalMed_Harrison. Clearly, all T. pallidum–infected patients who have signs or symptoms consistent with neurologic disease (e.g., meningitis, hearing loss) or ophthalmic disease (e.g., uveitis, iritis) should have a CSF examination, regardless of disease stage. The appropriate management of asymptomatic persons is less clear. Lumbar puncture on all asymptomatic patients with untreated syphilis is impractical and unnecessary. Because standard therapy with penicillin G benzathine fails to result in treponemicidal drug levels in CSF, however, it is important to identify those persons at higher risk for having or developing neurosyphilis so that appropriate therapy may be given. Viable T. pallidum has been isolated from the CSF of several patients (with and without concurrent HIV infection) after penicillin G benzathine therapy for early syphilis. Large-scale prospective studies have now provided evidence-based guidelines for determining which syphilis patients may benefit most from CSF examination for


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InternalMed_Harrison. G benzathine therapy for early syphilis. Large-scale prospective studies have now provided evidence-based guidelines for determining which syphilis patients may benefit most from CSF examination for evidence of neurosyphilis. Specifically, patients with RPR titers of ≥1:32 are at higher risk of having neurosyphilis (11-fold and 6-fold higher in HIV-infected and HIV-uninfected persons, respectively), as are HIV-infected patients with CD4+ T cell counts of ≤350/μL. Guidelines for CSF examination are shown in Table 206-1.


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InternalMed_Harrison. Evaluation of HIV-Infected Patients for Syphilis Because persons at highest risk for syphilis are also at increased risk for HIV infection, these Signs or symptoms of nervous system involvement (e.g., meningitis, hearing loss, cranial nerve dysfunction, altered mental status, ophthalmic disease [e.g., uveitis, iritis, pupillary abnormalities], ataxia, loss of vibration sense), or RPR or VDRL titer ≥1:32, or Active tertiary syphilis, or Suspected treatment failure CD4+ T cell count ≤350/μL, or All HIV-infected persons (recommended by some experts) Source: Adapted from the 2010 Sexually Transmitted Diseases Treatment Guidelines from the Centers for Disease Control and Prevention.


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InternalMed_Harrison. All HIV-infected persons (recommended by some experts) Source: Adapted from the 2010 Sexually Transmitted Diseases Treatment Guidelines from the Centers for Disease Control and Prevention. two infections frequently coexist. There is evidence that syphilis and other genital ulcer diseases are important risk factors for acquisition and transmission of HIV infection. Some manifestations of syphilis may be altered in patients with concurrent HIV infection, and multiple cases of neurologic relapse after standard therapy have been reported in these patients.


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InternalMed_Harrison. Persons with newly diagnosed HIV infection should be tested for syphilis; conversely, all patients with newly diagnosed syphilis should be tested for HIV infection. Some authorities, persuaded by reports of persistent T. pallidum in CSF of HIV-infected persons after standard therapy for early syphilis, recommend CSF examination for evidence of neurosyphilis for all co-infected patients, regardless of the stage of syphilis, with treatment for neurosyphilis if CSF abnormalities are found. Others, on the basis of their own clinical experience, believe that standard therapy—without CSF examination—is sufficient for all cases of early syphilis in HIV-infected patients without neurologic signs or symptoms. As described above, RPR titer and CD4+ T cell count can be used to identify patients at higher risk of neurosyphilis for lumbar puncture, although some cases of neurosyphilis will be missed, even when these criteria are used. Table 206-1 summarizes guidelines suggested by published


InternalMed_Harrison

InternalMed_Harrison. at higher risk of neurosyphilis for lumbar puncture, although some cases of neurosyphilis will be missed, even when these criteria are used. Table 206-1 summarizes guidelines suggested by published studies. Serologic testing after treatment is important for all patients with syphilis, particularly for those also infected with HIV.


InternalMed_Harrison

InternalMed_Harrison. The CDC’s 2010 guidelines for the treatment of syphilis are summarized in Table 206-2 and are discussed below. Penicillin G is the drug of choice for all stages of syphilis. T. pallidum is killed by very low concentrations of penicillin G, although a long period of exposure to penicillin is required because of the unusually slow rate of multiplication of the organism. The efficacy of penicillin against syphilis remains undiminished after 60 years of use, and there is no evidence of penicillin resistance in T. pallidum. Other antibiotics effective in syphilis include the tetracyclines and the cephalosporins. Aminoglycosides and spectinomycin inhibit T. pallidum only in very large doses, and the sulfonamides and the quinolones are inactive. Azithromycin has shown significant promise as an effective oral agent against


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InternalMed_Harrison. T. pallidum; however, strains harboring 23S rRNA mutations that confer macrolide resistance are widespread; such strains represent >80% of recent isolates from Seattle and San Francisco and have now been identified in multiple North American and European sites. Macrolide resistance mutations have been identified in nearly all samples reported from some regions of China. In contrast, a study based in Madagascar documented the equivalence of benzathine penicillin and azithromycin for treatment of early syphilis, although a sample from one azithromycin clinical failure in that study showed the presence of a 23S rRNA resistance mutation. A more recent survey from South Africa showed a very low (1%) frequency of known 23s rRNA resistance mutations. In short, the prevalence of resistant strains varies widely by geographic location, and routine treatment of syphilis with azithromycin is not recommended. In all cases, careful follow-up of any patient treated for syphilis with azithromycin


InternalMed_Harrison

InternalMed_Harrison. varies widely by geographic location, and routine treatment of syphilis with azithromycin is not recommended. In all cases, careful follow-up of any patient treated for syphilis with azithromycin must be ensured.


InternalMed_Harrison

InternalMed_Harrison. Early Syphilis Patients and Their Contacts Penicillin G benzathine is the most widely used agent for the treatment of early syphilis; a single dose of 2.4 million units is recommended. Preventive treatment is also recommended for individuals who have been exposed to infectious syphilis within the previous 3 months. The regimens recommended for prevention are the same as those recommended for early syphilis. Penicillin G benzathine cures >95% of cases of early syphilis, although clinical relapse can follow treatment, particularly in patients with concurrent HIV infection. Because the risk of neurologic relapse may be higher in HIV-infected patients, CSF examination is recommended in HIV-seropositive individuals with syphilis of any stage, particularly those with a serum RPR titer of ≥1:32 or a Stage of Syphilis Patients without Penicillin Allergy Patients with Confirmed Penicillin Allergyb Primary, secondary, or early latent


InternalMed_Harrison

InternalMed_Harrison. Stage of Syphilis Patients without Penicillin Allergy Patients with Confirmed Penicillin Allergyb Primary, secondary, or early latent Late latent (or latent of uncertain duration), cardiovascular, or benign tertiary Syphilis in pregnancy CSF normal or not examined: Penicillin G benzathine (single dose of 2.4 mU IM) CSF abnormal: Treat as neurosyphilis CSF normal or not examined: Penicillin G benzathine (2.4 mU IM weekly for 3 weeks) CSF abnormal: Treat as neurosyphilis Aqueous crystalline penicillin G (18–24 mU/d IV, given as 3–4 mU q4h or continuous infusion) for 10–14 days Aqueous procaine penicillin G (2.4 mU/d IM) plus oral probenecid (500 mg qid), both for 10–14 days According to stage CSF normal or not examined: Tetracycline HCl (500 mg PO qid) or doxycycline (100 mg PO bid) for 2 weeks CSF abnormal: Treat as neurosyphilis CSF normal and patient not infected with HIV: Tetracycline HCl (500 mg PO qid) or doxycycline (100 mg PO bid) for 4 weeks


InternalMed_Harrison

InternalMed_Harrison. CSF abnormal: Treat as neurosyphilis CSF normal and patient not infected with HIV: Tetracycline HCl (500 mg PO qid) or doxycycline (100 mg PO bid) for 4 weeks CSF normal and patient infected with HIV: Desensitization and treatment with penicillin if compliance cannot be ensured CSF abnormal: Treat as neurosyphilis Desensitization and treatment with penicillinc Desensitization and treatment with penicillin aSee Table 206-1 and text for indications for CSF examination. bBecause of the documented presence of macrolide resistance in many T. pallidum strains in North America, Europe, and China, azithromycin or other macrolides should be used with caution only when treatment with penicillin or doxycycline is not feasible. Azithromycin should not be used for men who have sex with men or for pregnant women. cLimited data suggest that ceftriaxone (2 g/d either IM or IV for 10–14 days) can be used; however, cross-reactivity between penicillin and ceftriaxone is possible.


InternalMed_Harrison

InternalMed_Harrison. Abbreviations: CSF, cerebrospinal fluid; mU, million units. Source: Adapted from the 2010 Sexually Transmitted Diseases Treatment Guidelines from the Centers for Disease Control and Prevention. CD4+ T cell count of ≤350/μL. Therapy appropriate for neurosyphilis should be given if there is any evidence of CNS infection. Late Latent Syphilis or Syphilis of unknown Duration If the CSF is normal or is not examined, the recommended treatment is penicillin G benzathine (7.2 million units total; Table 206-2). If CSF abnormalities are found, the patient should be treated for neurosyphilis.


InternalMed_Harrison

InternalMed_Harrison. Tertiary Syphilis CSF examination should be performed. If the CSF is normal, the recommended treatment is penicillin G benzathine (7.2 million units total; Table 206-2). If CSF abnormalities are found, the patient should be treated for neurosyphilis. The clinical response to treatment for benign tertiary syphilis is usually impressive. However, responses to therapy for cardiovascular syphilis are not dramatic because aortic aneurysm and aortic regurgitation cannot be reversed by antibiotics.


InternalMed_Harrison

InternalMed_Harrison. Syphilis in Penicillin-Allergic Patients For penicillin-allergic patients with syphilis, a 2-week (early syphilis) or 4-week (late or late latent syphilis) course of therapy with doxycycline or tetracycline is recommended (Table 206-2). These regimens appear to be effective in early syphilis but have not been tested for late or late latent syphilis, and compliance may be problematic. Limited studies suggest that ceftriaxone (1 g/d, given IM or IV for 8–10 days) is effective for early syphilis. These nonpenicillin regimens have not been carefully evaluated in HIV-infected individuals and should be used with caution. If compliance and follow-up cannot be ensured, penicillin-allergic HIV-infected persons with late latent or late syphilis should be desensitized and treated with penicillin.


InternalMed_Harrison

InternalMed_Harrison. Neurosyphilis Penicillin G benzathine, given in total doses of up to 7.2 million units, does not produce detectable concentrations of penicillin G in CSF and should not be used for treatment of neurosyphilis. Asymptomatic neurosyphilis may relapse as symptomatic disease after treatment with benzathine penicillin, and the risk of relapse may be higher in HIV-infected patients. Both symptomatic and asymptomatic neurosyphilis should be treated with aqueous penicillin (Table 206-2). Administration either of IV aqueous crystalline penicillin G or of IM aqueous procaine penicillin G plus oral probenecid in recommended doses is thought to ensure treponemicidal concentrations of penicillin G in CSF. The clinical response to penicillin therapy for meningeal syphilis is dramatic, but treatment of neurosyphilis with existing parenchymal damage may only arrest disease progression. No data suggest that additional therapy (e.g., penicillin G benzathine for 3 weeks) is beneficial after treatment for


InternalMed_Harrison

InternalMed_Harrison. with existing parenchymal damage may only arrest disease progression. No data suggest that additional therapy (e.g., penicillin G benzathine for 3 weeks) is beneficial after treatment for neurosyphilis.


InternalMed_Harrison

InternalMed_Harrison. The use of antibiotics other than penicillin G for the treatment of neurosyphilis has not been studied, although very limited data suggest that ceftriaxone may be used. In patients with penicillin allergy demonstrated by skin testing, desensitization and treatment with penicillin are recommended. Management of Syphilis in Pregnancy Every pregnant woman should undergo a nontreponemal test at her first prenatal visit and, if at high risk of exposure, again in the third trimester and at delivery. In the untreated pregnant patient with presumed syphilis, expeditious treatment appropriate to the stage of the disease is essential. Patients should be warned of the risk of a Jarisch-Herxheimer reaction, which may be associated with mild premature contractions but rarely results in premature delivery.


InternalMed_Harrison

InternalMed_Harrison. Penicillin is the only recommended agent for the treatment of syphilis in pregnancy. If the patient has a documented penicillin allergy, desensitization and penicillin therapy should be undertaken according to the CDC’s 2010 guidelines. After treatment, a quantitative nontreponemal test should be repeated monthly throughout pregnancy to assess therapeutic efficacy. Treated women whose antibody titers rise by fourfold or whose titers do not decrease by fourfold over a 3-month period should be re-treated.


InternalMed_Harrison

InternalMed_Harrison. Whether or not they are infected, newborn infants of mothers with reactive serologic tests may themselves have reactive tests because of transplacental transfer of maternal IgG antibody. For asymptomatic infants born to women treated adequately with penicillin during the first or second trimester of pregnancy, monthly quantitative nontreponemal tests may be performed to monitor for appropriate reduction in antibody titers. Rising or persistent titers indicate infection, and the infant should be treated. Detection of neonatal IgM antibody may be useful, but no commercially available test is currently recommended.


InternalMed_Harrison

InternalMed_Harrison. An infant should be treated at birth if the treatment status of the seropositive mother is unknown; if the mother has received inadequate or nonpenicillin therapy; if the mother received penicillin therapy in the third trimester; or if the infant may be difficult to follow. The CSF should be examined to obtain baseline values before treatment. Penicillin is the only recommended drug for the treatment of syphilis in infants. Specific recommendations for the treatment of infants and older children are included in the CDC’s 2010 treatment guidelines.


InternalMed_Harrison

InternalMed_Harrison. 1140 ARISCH-HERXHEIMER REACTIoN A dramatic although usually mild reaction consisting of fever, chills, myalgias, headache, tachycardia, increased respiratory rate, increased circulating neutrophil count, and vasodilation with mild hypotension may follow the initiation of treatment for syphilis. This reaction is thought to be a response to lipoproteins released by dying T. pallidum organisms. The arisch-Herxheimer reaction occurs in 50of patients with primary syphilis, of those with secondary syphilis, and a lower proportion of persons with later-stage disease. Defervescence takes place within 12–2 h. In patients with secondary syphilis, erythema and edema of the mucocutaneous lesions may increase. Patients should be warned to expect such symptoms, which can be managed with symptom-based treatment. Steroid or other anti-inflammatory therapy is not reuired for this mild transient reaction.


InternalMed_Harrison

InternalMed_Harrison. Efficacy of treatment should be assessed by clinical evaluation and monitoring of the uantitative L or P titer for a fourfold decline (e.g., from 12 to 1). Patients with primary or secondary syphilis should be examined and 12 months after treatment and persons with latent or late syphilis at , 12, and 2 months. More freuent clinical and serologic examination (, , 12, and 2 months) is recommended for patients concurrently infected with HI regardless of the stage of syphilis.


InternalMed_Harrison

InternalMed_Harrison. After successful treatment of seropositive first-episode primary or secondary syphilis, the L or P titer progressively declines, becoming negative by 12 months in 0–75of seropositive primary cases and in 20–0of secondary cases. Patients with HIinfection or a history of prior syphilis are less likely to become nonreactive in the L or P test. ates of decline of serologic titers appear to be slower, and serologically defined treatment failures more common, among HIinfected patients than among those without HI co-infectionhowever, effective antiretroviral therapy may reduce these differences. e-treatment should be considered if serologic responses are not adeuate or if clinical signs persist or recur. ecause it is difficult to differentiate treatment failure from reinfection, the CSF should be examined, with treatment for neurosyphilis if CSF is abnormal and treatment for late latent syphilis if CSF is normal. A minority of patients treated for early syphilis may experience a one-dilution


InternalMed_Harrison

InternalMed_Harrison. examined, with treatment for neurosyphilis if CSF is abnormal and treatment for late latent syphilis if CSF is normal. A minority of patients treated for early syphilis may experience a one-dilution titer increase within 1 days after treatmenthowever, this early elevation does not significantly affect the serologic outcome at months after treatment. Patients treated for late latent syphilis freuently have low initial L or P titers and may not have a fourfold decline after therapy with penicillin. In such patients, re-treatment is not warranted unless the titer rises or signs and symptoms of syphilis appear. ecause treponemal tests may remain reactive despite treatment for seropositive syphilis, these tests are not useful in following the response to therapy.


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InternalMed_Harrison. The activity of neurosyphilis (symptomatic or asymptomatic) correlates best with CSF pleocytosis, and this measure provides the most sensitive index of response to treatment. epeat CSF examinations should be performed every months until the cell count is normal. An elevated CSF cell count falls to normal in –12 months in adeuately treated HIuninfected patients. The persistence of mild pleocytosis in HIinfected patients may be due to the presence of HIin CSFthis scenario may be difficult to distinguish from treatment failure. Elevated levels of CSF protein fall more slowly, and the CSF L titer declines gradually over several years. In patients treated for neurosyphilis, a fourfold reduction in serum P titer has been positively correlated with normalization of CSF abnormalitiesthis correlation is stronger in HIuninfected patients and in HIinfected patients receiving effective antiretroviral therapy.


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InternalMed_Harrison. The rate of development of acquired resistance to T. pallidum after natural or experimental infection is related to the size of the antigenic stimulus, which depends on both the size of the infecting inoculum and the duration of infection before treatment. Both humoral and cellular responses are considered to be of major importance in immunity and in the healing of early lesions. Cellular infiltration, predominantly by T lymphocytes and macrophages, produces a TH1 cytokine milieu consistent with the clearance of organisms by activated macrophages. Specific antibody enhances phagocytosis and is required for macrophage-mediated killing of T. pallidum. Recent studies demonstrate antigenic variation of the TprK protein, which may lead to persistence of infection and determine susceptibility to reinfection with another strain. Comparative genomic studies have revealed some sequence variations among T. pallidum strains, which can be differentiated by molecular typing methods. Possible


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InternalMed_Harrison. to reinfection with another strain. Comparative genomic studies have revealed some sequence variations among T. pallidum strains, which can be differentiated by molecular typing methods. Possible correlations between molecular type and clinical manifestations are being examined.


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InternalMed_Harrison. are thought to persist in Haiti and other Caribbean islands, Peru, 207e-1 Endemic Treponematoses Colombia, Ecuador, Brazil, Guyana, and Surinam, although recent data are lacking. Pinta is limited to Central America and northern South Sheila A. Lukehart America, where it is found rarely and only in very remote villages.


InternalMed_Harrison

InternalMed_Harrison. The endemic treponematoses are chronic diseases that are transmitted by direct contact, usually during childhood, and, like syphilis, can cause severe late manifestations years after initial infection. These diseases are caused by very close relatives of Treponema pallidum subspecies pallidum, the etiologic agent of venereal syphilis (Chap. 206). Yaws, pinta, and endemic syphilis are traditionally distinguished from venereal syphilis by mode of transmission, age of acquisition, geographic distribution, and clinical features; however, there is some overlap for each of these factors. Generally, yaws flourishes in moist tropical areas of several regions, endemic syphilis is found primarily in arid climates, and pinta is found in temperate foci in the Americas (Fig. 207e-1). These infections are usually limited to rural areas of developing nations and are seen in developed countries only among recent immigrants from endemic regions. Our “knowledge” about the endemic treponematoses is


InternalMed_Harrison

InternalMed_Harrison. are usually limited to rural areas of developing nations and are seen in developed countries only among recent immigrants from endemic regions. Our “knowledge” about the endemic treponematoses is based on observations by health care workers who have visited endemic areas; virtually no well-designed studies of the natural history, diagnosis, or treatment of these infections have been conducted. The treponemal infections are compared and contrasted in Table 207e-1.


InternalMed_Harrison

InternalMed_Harrison. eradication campaign from 1952 to 1969, more than 160 mil lion people in Africa, Asia, and South America were examined for treponemal infections, and more than 50 million cases, contacts, and persons with latent infections were treated. This campaign reduced the prevalence of active yaws from >20% to <1% in many areas. In recent decades, lack of focused surveillance and diversion of resources have resulted in documented resurgence of these infections in some regions. The most recent WHO global estimate (1995) suggested that there are 460,000 new cases per year (mostly yaws) and a prevalence of 2.5 million infected persons; during subsequent years, an increased incidence was documented in some countries. Recent areas of resurgent yaws morbidity include West Africa (Ivory Coast, Ghana, Togo, Benin), the Central African Republic, Nigeria, and rural Democratic Republic of the Congo. The prevalence of endemic syphilis is estimated to be >10% in some regions of northern Ghana, Mali, Niger,


InternalMed_Harrison

InternalMed_Harrison. Benin), the Central African Republic, Nigeria, and rural Democratic Republic of the Congo. The prevalence of endemic syphilis is estimated to be >10% in some regions of northern Ghana, Mali, Niger, Burkina Faso, and Senegal. In Asia and the Pacific Islands, reports suggest active outbreaks of yaws in Indonesia, Papua New Guinea, the Solomon Islands, East Timor, Vanuatu, Laos, and Kampuchea. India actively renewed its focus on yaws control in 1996, achieved zero-case status in 2003, and declared elimination in 2006. In the Americas, foci of yaws


InternalMed_Harrison

InternalMed_Harrison. Evidence of yaws-like and venereal diseases, with treponemal seroreactivity, in wild gorillas and baboons in Africa has led to speculation that there may be an animal reservoir for yaws. The etiologic agents of the endemic treponematoses are listed in Table 207e-1. These little-studied organisms are morphologically identical to T. pallidum subspecies pallidum (the agent of venereal syphilis), and no definitive antigenic differences among them have been identified to date. A controversy has existed about whether the pathogenic treponemes are truly separate organisms, as genome sequencing indicates that yaws and syphilis treponemes are 99.8% identical. Three of the four organisms are classified as subspecies of


InternalMed_Harrison

InternalMed_Harrison. T. pallidum; the fourth (T. carateum) remains a separate species simply because no organisms have been available for genetic studies. Based on analysis of the small number of strains currently available, molecular signatures—assessed by polymerase chain reaction (PCR) amplification of tpr genes and restriction digestion—have been identified that can differentiate the T. pallidum subspecies. Whether these genetic differences are related to distinct clinical characteristics of these diseases has not been determined. Full genome sequencing of an unclassified strain (Fribourg-Blanc) isolated from a baboon in 1966 shows a very high degree of homology with available strains of T. pallidum subspecies pertenue. This observation is consistent with an earlier report that the Fribourg-Blanc strain can cause experimental infection of humans. Molecular analyses of additional samples from affected baboons suggests that the nonhuman primate samples diverge from the evolutionary tree prior to the


InternalMed_Harrison

InternalMed_Harrison. can cause experimental infection of humans. Molecular analyses of additional samples from affected baboons suggests that the nonhuman primate samples diverge from the evolutionary tree prior to the clade that contains the human isolates, but uncertainty remains about the importance of the nonhuman primate reservoir for human infection.


InternalMed_Harrison

InternalMed_Harrison. All of the treponemal infections, including syphilis, are chronic and are characterized by defined disease stages, with a localized primary lesion, disseminated secondary lesions, periods of latency, and possible late lesions. Primary and secondary stages are more frequently overlapping in yaws and endemic syphilis than in venereal syphilis, and the late manifestations of pinta are very mild relative to the destructive lesions of the other treponematoses. The current preference is to divide the clinical course of the endemic treponematoses into “early” and “late” stages.


InternalMed_Harrison

InternalMed_Harrison. The major clinical distinctions made between venereal syphilis and the nonvenereal infections are the apparent lack of congenital transmission and of central nervous system (CNS) involvement in the nonvenereal infections. It is not known whether these distinctions are entirely accurate. Because of the high degree of genetic relatedness among the organisms, there is little biological reason to think that T. pallidum subspecies endemicum and T. pallidum subspecies pertenue would be unable to cross the blood-brain barrier or to invade the placenta. These organisms are like T. pallidum subspecies pallidum in that they obviously disseminate from the site of initial infection and can persist for decades. The lack of recognized congenital infection may be due to the fact that childhood infections often reach the latent stage (low bacterial load) before girls reach sexual maturity. Neurologic involvement may go unrecognized because of the lack of trained


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InternalMed_Harrison. FIGURE 207e-1 Geographic distribution of endemic treponematoses.(Courtesy of the World medical personnel in endemic regions, Health Organization; updated from www.who.int/yaws/epidemiology/Map_yaws_90s.jpg.) the delay of many years between infection Organism T. pallidum subsp. pallidum Common modes of Sexual, transplacental transmission Usual age of acquisition Sexual maturity or in utero Primary lesion Cutaneous ulcer (chancre) Common location Genital, oral, anal Late complications Gummas, cardiovascular and central nervous system involvementa T. pallidum subsp. pertenue Skin-to-skin Early childhood Papilloma, often ulcerative Cutaneous papulosquamous lesions; condylomata lata, osteoperiostitis Destructive gummas of skin, bone, cartilage T. pallidum subsp. endemicum T. carateum


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InternalMed_Harrison. Cutaneous papulosquamous lesions; condylomata lata, osteoperiostitis Destructive gummas of skin, bone, cartilage T. pallidum subsp. endemicum T. carateum Mouth-to-mouth or via shared Skin-to-skin drinking/eating utensils Early childhood Late childhood Mucosal papule, rarely seen Nonulcerating papule with satellites, pruritic Oral Extremities, face Mucocutaneous lesions Pintides, pigmented, pruritic (mucous patch, split papule, condylomata lata); osteoperiostitis Unknown Unknown Destructive gummas of skin, Nondestructive, dyschromic, bone, cartilage achromic macules aCentral nervous system involvement and congenital infection in the endemic treponematoses have been postulated by some investigators (see text).


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InternalMed_Harrison. and possible CNS manifestations, or a low rate of symptomatic CNS disease. Some published evidence supports congenital transmission as well as cardiovascular, ophthalmologic, and CNS involvement in yaws and endemic syphilis. Although the reported studies have been small, have failed to control for other causes of CNS abnormalities, and in some instances have not included serologic confirmation, it may be erroneous to accept unquestioningly the frequently repeated belief that these organisms fail to cause such manifestations. Yaws Also known as pian, framboesia, or bouba, yaws is characterized by the development of one or several primary lesions (“mother yaw”) followed by multiple disseminated skin lesions. All early skin lesions are infectious and may persist for many months; cutaneous relapses are common during the first 5 years. Late manifestations, affecting ~10% of untreated persons, are destructive and can involve skin, bone, and joints.


InternalMed_Harrison

InternalMed_Harrison. The infection is transmitted by direct contact with infectious lesions, often during play or group sleeping, and may be enhanced by disruption of the skin by insect bites or abrasions. After an average of 3–4 weeks, the first lesion begins as a papule—usually on an extremity— and then enlarges (particularly during moist warm weather) to become papillomatous or “raspberry-like” (thus the name “framboesia”) (Fig. 207e-2A). Regional lymphadenopathy develops, and the lesion usually heals within 6 months; dissemination is thought to occur during the early weeks of infection. A generalized secondary eruption (Fig. 207e-2B), accompanied by generalized lymphadenopathy, appears either concurrent with or after the primary lesion; may take several forms (macular, papular, or papillomatous); and may become secondarily infected with other bacteria. Painful papillomatous lesions on the soles of the feet result in a crablike gait (“crab yaws”), and periostitis may result in nocturnal bone pain and


InternalMed_Harrison

InternalMed_Harrison. become secondarily infected with other bacteria. Painful papillomatous lesions on the soles of the feet result in a crablike gait (“crab yaws”), and periostitis may result in nocturnal bone pain and polydactylitis. Late yaws is manifested by gummas of the skin and long bones, hyperkeratoses of the palms and soles, osteitis and periostitis, and hydrarthrosis. The late gummatous lesions are characteristically extensive. Destruction of the nose, maxilla, palate, and pharynx is termed gangosa and is similar to the destructive lesions seen in leprosy and leishmaniasis.


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InternalMed_Harrison. Endemic Syphilis The early lesions of endemic syphilis (bejel, siti, dichuchwa, njovera, skerljevo) are localized primarily to mucocutaneous and mucosal surfaces. The infection is reportedly transmitted by direct contact, by kissing, by premastication of food, or by sharing of drinking and eating utensils. A role for insects in transmission has been suggested but is unproven. The initial lesion, usually an intraoral papule, often goes unrecognized and is followed by mucous patches (Fig. 207e-2C) on the oral mucosa and mucocutaneous lesions resembling the condylomata lata of secondary syphilis. This eruption may last for months or even years, and treponemes can readily be demonstrated in early lesions. Periostitis and regional lymphadenopathy are common. After a variable period of latency, late manifestations may appear, including osseous and cutaneous gummas. Destructive gummas, osteitis, and gangosa are more common in endemic syphilis than in yaws.


InternalMed_Harrison

InternalMed_Harrison. Pinta Pinta (mal del pinto, carate, azul, purupuru) is the most benign of the treponemal infections. This disease has three stages that are characterized by marked changes in skin color (Fig. 207e-2D), but pinta does not appear to cause destructive lesions or to involve


InternalMed_Harrison

InternalMed_Harrison. FIGURE 207e-2 Clinical manifestations of endemic treponematoses. A. Papillomatous initial lesion of early yaws. B. Disseminated lesions of early yaws. C. Mucous patches of endemic syphilis. D. Pigmented macules of pinta. (Photos published with permission from Dr. David Fegan, Brisbane, Australia [A and B]; and from PL Perine et al: Handbook of Endemic Treponematoses, Geneva, World Health Organization, 1984 [C and D].) tissues other than the skin. The initial papule is most often located on the extremities or face and is pruritic. After one to many months of infection, numerous disseminated secondary lesions (pintides) appear. These lesions are initially red but become deeply pigmented, ultimately turning a dark slate blue. The secondary lesions are infectious and highly pruritic and may persist for years. Late pigmented lesions are called dyschromic macules and contain treponemes. Over time, most pigmented lesions show varying degrees of depigmentation, becoming brown and eventually


InternalMed_Harrison

InternalMed_Harrison. persist for years. Late pigmented lesions are called dyschromic macules and contain treponemes. Over time, most pigmented lesions show varying degrees of depigmentation, becoming brown and eventually white and giving the skin a mottled appearance. White achromic lesions are characteristic of the late stage.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis of the endemic treponematoses is based on clinical manifestations and, when available, dark-field microscopy and serologic testing. The same serologic tests that are used for venereal syphilis (Chap. 206) become reactive during all treponemal infections. Although several targets have been evaluated for specific serodiagnosis, to date there is no antibody test that can discriminate among the different infections. The nonvenereal treponemal infections should be considered in the evaluation of a reactive syphilis serology in any person who has emigrated from an endemic area. Sensitive PCR assays can be used to confirm treponemal infection and to identify the etiologic agent in research laboratories.


InternalMed_Harrison

InternalMed_Harrison. The WHO-recommended therapy for patients and their contacts is benzathine penicillin G (1.2 million units IM for adults; 600,000 units for children <10 years old). This dose is half of that recommended for early venereal syphilis, and no controlled efficacy studies have been conducted. Definitive evidence of resistance to penicillin is lacking, although relapsing lesions have been reported after penicillin treatment in Papua New Guinea. A recent study in that nation demonstrated equivalence between IM benzathine penicillin G and a single oral dose of azithromycin (30 mg/kg, up to a maximum of 2 g). This 207e-3 finding provided the WHO’s revitalized yaws eradication program with a much easier regimen for use in mass treatment. Although macrolide resistance mutations are common in circulating strains of


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InternalMed_Harrison. T. pallidum subspecies pallidum in many parts of the world, analysis of a limited number of yaws samples from Papua New Guinea has yielded no evidence of resistance mutations to date. Limited data suggest the efficacy of tetracycline for treatment of yaws, but no data exist for other endemic treponematoses. Solely on the basis of experience with venereal syphilis, it is thought that doxycycline or tetracycline (at doses appropriate for syphilis; Chap. 206) are alternatives for patients allergic to penicillin. A Jarisch-Herxheimer reaction (Chap. 206) may follow treatment of endemic treponematoses. Nontreponemal serologic titers (in the Venereal Disease Research Laboratory [VDRL] slide test or the rapid plasma reagin [RPR] test) usually decline after effective therapy, but patients may not become seronegative.


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InternalMed_Harrison. Buoyed by the successful elimination of yaws in India in 2006 and the availability of an inexpensive, single-dose oral drug for treatment, in 2012 the WHO renewed its efforts to eradicate yaws globally by 2020. Enthusiasm is high; several planning meetings have been held to develop country-specific plans of action; and resources are being sought. Some caution is warranted: The possible animal reservoir will need to be evaluated. There may be only a window of time during which countries can successfully use azithromycin for yaws eradication before resistance begins to appear in yaws organisms. Given the ongoing lower-dose azithromycin mass treatment campaigns against trachoma, often in populations also at high risk for yaws, development of macrolide resistance is likely at some point. Complete drug coverage and continued careful surveillance by health centers (the weak link in prior control efforts) will be essential for success.


InternalMed_Harrison

InternalMed_Harrison. Leptospirosis Rudy A. Hartskeerl, Jiři F. P. Wagenaar Leptospirosis is a globally important zoonotic disease whose apparent reemergence is illustrated by recent outbreaks on virtually all continents. The disease is caused by pathogenic Leptospira species and is charac-terized by a broad spectrum of clinical manifestations, varying from 208 asymptomatic infection to fulminant, fatal disease. In its mild form, leptospirosis may present as nonspecific symptoms such as fever, headache, and myalgia. Severe leptospirosis, characterized by jaundice, renal dysfunction, and hemorrhagic diathesis, is often referred to as Weil’s syndrome. With or without jaundice, severe pulmonary hemorrhage is increasingly recognized as an important presentation of severe disease. Leptospira species are spirochetes belonging to the order Spirochaetales and the family Leptospiraceae. Traditionally, the genus Leptospira comprised two species: the pathogenic L. interrogans and the free-living


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InternalMed_Harrison. L. biflexa, now designated L. interrogans sensu lato and L. biflexa sensu lato, respectively. Twenty-two Leptospira species with pathogenic (10 species), intermediate (5 species), and nonpathogenic (7 species) status have now been described on the basis of phylogenetic and virulence analyses (Fig. 208-1). Genome sequences of five Leptospira species 0.005 FIGuRE 208-1 Differentiation of pathogenic, intermediate, and nonpathogenic (saprophytic) Leptospira species by molecular phyloge-netic analysis using the rrs gene and including the potentially new pathogenic species Leptospira borgpetersenii group B and the saprophytic species Leptospira idonii. Scale bar indicates the rate of nucleotide substitutions per base pair. (Figure prepared and provided by Dr. A. Ahmed, KIT Biomedical Research, Amsterdam, The Netherlands.) (L. biflexa, L. interrogans, L. santarosai, L. borgpetersenii, and


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InternalMed_Harrison. L. licerasiae) have been published, and the availability of genome sequences of a wide variety of Leptospira strains will undoubtedly lead to a better understanding of the pathogenesis of leptospirosis. However, classification based on serologic differences better serves clinical, diagnostic, and epidemiologic purposes. Pathogenic Leptospira species are divided into serovars according to their antigenic composition. More than 250 serovars make up the 26 serogroups. Leptospires are coiled, thin, highly motile organisms that have hooked ends and two periplasmic flagella, with polar extrusions from the cytoplasmic membrane that are responsible for motility (Fig. 208-2). These organisms are 6–20 μm long and ~0.1 μm wide; they stain poorly but can be seen microscopically by dark-field examination and after silver impregnation staining of tissues. Leptospires require special media and conditions for growth; it may take weeks to months for cultures to become positive.


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InternalMed_Harrison. commonly in the tropics and subtropics because the climate and occasionally poor hygienic conditions favor the pathogen’s survival and distribution. In most countries, leptospirosis is an underappreciated problem. Most cases occur in men, with a peak incidence during the summer and fall in both the Northern and Southern Hemispheres and during the rainy season in the tropics. FIGuRE 208-2 Transmission electron microscopic image of Leptospira interrogans invading equine conjunctival tissue. (Image kindly provided by Dr. JE Nally, National Animal Disease Center, U.S. Department of Agriculture, Ames, IA. This image appears on the homepage of the European Leptospirosis Society website [http://eurolepto.ucd.ie/].) Reliable data on morbidity and mortality from leptospirosis have gradually started to appear. Current information on global human leptospirosis varies but indicates that approximately 1 million severe cases occur per year, with a mean case–fatality rate of nearly 10%.


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InternalMed_Harrison. As a zoonosis, leptospirosis affects almost all mammalian species and represents a significant veterinary burden. Rodents, especially rats, are the most important reservoir, although other wild mammals as well as domestic and farm animals may also harbor these microorganisms. Leptospires establish a symbiotic relationship with their host and can persist in the urogenital tract for years. Some serovars are generally associated with particular animals—e.g., Icterohaemorrhagiae and Copenhageni with rats, Grippotyphosa with voles, Hardjo with cattle, Canicola with dogs, and Pomona with pigs—but may occur in other animals as well.


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InternalMed_Harrison. Leptospirosis presents as both an endemic and an epidemic disease. Transmission of leptospires may follow direct contact with urine, blood, or tissue from an infected animal or, more commonly, exposure to environmental contamination. The dogma that human-to-human transmission is very rare is challenged by recent findings on household clustering, asymptomatic renal colonization, and prolonged excretion of leptospires. (Both of the latter features imply human infection sources that are not recognized.) Because leptospires can survive in a humid environment for many months, water is an important vehicle in their transmission. Epidemics of leptospirosis are not well understood. Outbreaks may result from exposure to flood waters contaminated by urine from infected animals, as has been reported from several countries. However, it is also true that outbreaks may occur without floods, and floods often occur without outbreaks.


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InternalMed_Harrison. The vast majority of infections with Leptospira cause no or only mild disease in humans. A small percentage of infections (~1%) lead to severe, potentially fatal complications. The proportion of leptospirosis cases that are mild is unknown because patients either do not seek or do not have access to medical care or because the nonspecific symptoms are interpreted as an influenza-like illness. Reported cases surely represent a significant underestimation of the total number. Certain occupational groups are at especially high risk, including veterinarians, agricultural workers, sewage workers, slaughterhouse employees, and workers in the fishing industry. Risk factors include direct or indirect contact with animals, including exposure to water and soil contaminated with animal urine. Leptospirosis has also been recognized in deteriorating inner cities and suburban areas where rat populations are expanding.


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InternalMed_Harrison. Recreational exposure and domestic-animal contact are prominent sources of leptospirosis. Recreational freshwater activities, such as canoeing, windsurfing, swimming, and waterskiing, place persons at risk for infection. Several outbreaks have followed sporting events. For example, an outbreak took place in 1998 among athletes after a triathlon in Springfield, Illinois. Ingestion of one or more swallows of lake water during the swimming leg of the triathlon was a prominent risk factor for illness. Heavy rains that preceded the triathlon, with consequent agricultural runoff, are likely to have increased the level of leptospiral contamination in the lake water. In another outbreak, 42% of participants contracted leptospirosis during the 2000 Eco-Challenge-Sabah multisport endurance race in Malaysian Borneo. Swimming in the Segama River was shown to be an independent risk factor.


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InternalMed_Harrison. In addition, leptospirosis is a traveler’s disease. Large proportions of patients acquire the infection while traveling in tropical countries, usually during adventurous activities such as whitewater rafting, jungle trekking, and caving. Transmission via laboratory accidents has been reported but is rare. New data indicate that leptospirosis may develop after unanticipated immersion in contaminated water (e.g., in an automobile accident) more frequently than has generally been thought and can also result from an animal bite.


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InternalMed_Harrison. Transmission occurs through cuts, abraded skin, or mucous membranes, especially the conjunctival and oral mucosa. After entry, the organisms proliferate, cross tissue barriers, and disseminate hematogenously to all organs (leptospiremic phase). During this initial incubation period, leptospires can be isolated from the bloodstream (Fig. 208-3). The organisms are able to survive in the nonimmune host: they evade complement-mediated killing by binding factor H, a strong inhibitor of the complement system, on their surface. Moreover, pathogenic leptospires resist ingestion and killing by neutrophils, monocytes, and macrophages. During the immune phase, the appearance of antibodies coincides with the disappearance of leptospires from the blood. However, the bacteria persist in various organs, including liver, lung, kidney, heart, and brain. Autopsy findings illustrate the involvement of multiple organ systems in severe disease. Renal pathology shows both acute tubular damage and


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InternalMed_Harrison. organs, including liver, lung, kidney, heart, and brain. Autopsy findings illustrate the involvement of multiple organ systems in severe disease. Renal pathology shows both acute tubular damage and interstitial nephritis. Acute tubular lesions progress in time to interstitial edema and acute tubular necrosis. Severe nephritis is observed in patients who survive long enough to develop it and seems to be a secondary response to acute epithelial damage. The reported deregulation of the expression of several transporters along the nephron, including the proximal sodium-hydrogen exchanger 3 (NHE3), aquaporins 1 and 2 (AQP1 and AQP2), Na+-K+ ATPase, and the Na-K-2Cl cotransporter NKCC2, contributes to tubular potassium wasting, hypokalemia, and polyuria. Histopathology of the liver shows focal necrosis, foci of inflammation, and plugging of bile canaliculi. Widespread hepatocellular necrosis is not found. Petechiae and hemorrhages are observed in the heart, lungs (Fig. 208-4), kidneys (and


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InternalMed_Harrison. necrosis, foci of inflammation, and plugging of bile canaliculi. Widespread hepatocellular necrosis is not found. Petechiae and hemorrhages are observed in the heart, lungs (Fig. 208-4), kidneys (and adrenals), pancreas, liver, gastrointestinal tract (including retro-peritoneal fat, mesentery, and omentum), muscles, prostate, testis, and brain (subarachnoid bleeding). Several studies show an association between hemorrhage and thrombocytopenia. Although the underlying mechanisms of thrombocytopenia have not been elucidated, it seems likely that platelet consumption plays an important role. A consumptive coagulopathy may occur, with elevated markers of coagulation activation (thrombin–antithrombin complexes, prothrombin fragments 1 and 2, d-dimer), diminished anticoagulant markers (antithrombin, protein C), and deregulated fibrinolytic activity. Overt disseminated intravascular coagulation (DIC) has been documented in patients from Thailand and Indonesia. Elevated plasma levels of


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InternalMed_Harrison. protein C), and deregulated fibrinolytic activity. Overt disseminated intravascular coagulation (DIC) has been documented in patients from Thailand and Indonesia. Elevated plasma levels of soluble E-selectin and von Willebrand factor in patients with leptospirosis reflect endothelial cell activation. Experimental models show that pathogenic leptospires or leptospiral proteins are able to activate endothelial cells in vitro and to disrupt endothelial-cell barrier function, promoting dissemination. Platelets have been shown to aggregate on activated endothelium in the human lung, whereas histology reveals swelling of activated endothelial cells but no evident vasculitis or necrosis. Immunoglobulin and complement deposition have been demonstrated in lung tissue involved in pulmonary hemorrhage.


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InternalMed_Harrison. Approximate time scale Week 1 Acute stage Convalescent stage Convalescent shedder Normal response fever Titers decline at varying rates Early treatment Leptospiremia Leptospiruria and immunity Anamnestic Delayed Reservoir host Uveitis ? Interstitial nephritis 2 3 4 months-years years Incubation period Inoculation Leptospires present in Blood CSF CSF 1 2 3 4 5 Urine Blood Urine Antibody titers High Low “Negative” Laboratory investigations Culture Serology Phases 2–20 days FIGuRE 208-3 Biphasic nature of leptospirosis and relevant investigations at different stages of disease. Note that an incubation period of up to 1 month has now been documented. Specimens 1 and 2 for serology are acute-phase serum samples; specimen 3 is a convalescent-phase serum sample that may facilitate detection of a delayed immune response; and specimens 4 and 5 are follow-up serum samples that can pro-vide epidemiologic information, such as the presumptive infecting serogroup. CSF, cerebrospinal fluid.


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InternalMed_Harrison. of a delayed immune response; and specimens 4 and 5 are follow-up serum samples that can pro-vide epidemiologic information, such as the presumptive infecting serogroup. CSF, cerebrospinal fluid. (Reprinted as adapted by PN Levett: Clin Microbiol Rev 14:296, 2001 [from LH Turner: Leptospirosis. BMJ 1:231, 1969] with permission from the American Society for Microbiology and the BMJ Publishing Group.)


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InternalMed_Harrison. Leptospira species have a typical double-membrane cell wall structure harboring a variety of membrane-associated proteins, including an unusually high number of lipoproteins. The peptidoglycan layer is located close to the cytoplasmic membrane. The lipopolysaccharide (LPS) in the outer membrane has an unusual structure with a relatively low endotoxic potency. Pathogenic leptospires contain a variety of genes coding for proteins involved in motility and in cell and tissue adhesion and invasion that represent potential virulence factors. Many of these are surface-exposed outer-membrane proteins (OMPs). To date, the only leptospiral virulence factor shown to satisfy Koch’s molecular postulates is loa22 encoding a surface-exposed protein with an unknown function. However, the gene is not confined to pathogenic Leptospira species.


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InternalMed_Harrison. Immunity to Leptospira depends on the production of circulating antibodies to serovar-specific LPS. It is unclear whether other antigens play a significant role in protective humoral immunity. Moreover, immunity may not be confined to antibody responses; involvement of the innate-immune Toll-like receptor 2 (TLR2) and TLR4 activation pathways in controlling infection has been demonstrated, whereas in vaccinated cattle a cell-mediated immune response is correlated with protection. It is likely that several surface-exposed proteins mediate leptospire–host cell interactions, and these proteins may represent candidate vaccine components. Although animal-model studies have shown various degrees of vaccine efficacy for various putative virulence-associated OMPs, it is not yet clear whether such proteins elicit acceptable levels of sterilizing immunity.


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InternalMed_Harrison. FIGuRE 208-4 Severe pulmonary hemorrhage in leptospirosis. Left panel: Chest x-ray. Right panel: Gross appearance of right lower lobes of lung at autopsy. This patient, a 15-year-old from the Peruvian Amazonian city of Iqitos, died several days after presentation with acute illness, jaundice, and hemoptysis. Blood culture yielded Leptospira interrogans serovar Copenhageni/Icterohaemorrhagiae. (Adapted with permission from E Segura et al: Clin Infect Dis 40:343, 2005. © 2005 by the Infectious Diseases Society of America.) 1144 CLINICAL MANIFESTATIONS Although leptospirosis is a potentially fatal disease with bleeding and multiorgan failure as its clinical hallmarks, the majority of cases are thought to be relatively mild, presenting as the sudden onset of a febrile illness. The incubation period is usually 1–2 weeks but ranges from 1 to 30 days. (Figure 208-3 indicates a slightly different range, but an incubation period of up to 1 month has now been documented.) Leptospirosis is


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InternalMed_Harrison. period is usually 1–2 weeks but ranges from 1 to 30 days. (Figure 208-3 indicates a slightly different range, but an incubation period of up to 1 month has now been documented.) Leptospirosis is classically described as biphasic. The acute leptospiremic phase is characterized by fever of 3–10 days’ duration, during which time the organism can be cultured from blood. During the immune phase, resolution of symptoms may coincide with the appearance of antibodies, and leptospires can be cultured from the urine. The distinction between the first and second phases is not always clear: milder cases do not always include the second phase, and severe disease may be monophasic and fulminant. The idea that distinct clinical syndromes are associated with specific serogroups has been refuted, although some serovars tend to cause more severe disease than others.


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InternalMed_Harrison. Mild Leptospirosis Most patients are asymptomatic or only mildly ill and do not seek medical attention. Serologic evidence of past inapparent infection is frequently found in persons who have been exposed but have not become ill. Mild symptomatic leptospirosis usually presents as a flu-like illness of sudden onset, with fever, chills, headache, nausea, vomiting, abdominal pain, conjunctival suffusion (redness without exudate), and myalgia. Muscle pain is intense and especially affects the calves, back, and abdomen. The headache is intense, localized to the frontal or retroorbital region (resembling that occurring in dengue), and sometimes accompanied by photophobia. Aseptic meningitis may be present and is more common among children than among adults. Although Leptospira can be cultured from the cerebrospinal fluid (CSF) in the early phase, the majority of cases follow a benign course with regard to the central nervous system; symptoms disappear within a few days but may persist for


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InternalMed_Harrison. from the cerebrospinal fluid (CSF) in the early phase, the majority of cases follow a benign course with regard to the central nervous system; symptoms disappear within a few days but may persist for weeks.


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InternalMed_Harrison. Physical examination may include any of the following findings, none of which is pathognomonic for leptospirosis: fever, conjunctival suffusion, pharyngeal injection, muscle tenderness, lymphadenopathy, rash, meningismus, hepatomegaly, and splenomegaly. If present, the rash is often transient; may be macular, maculopapular, erythematous, or hemorrhagic (petechial or ecchymotic); and may be misdiagnosed as due to scrub typhus or viral infection. Lung auscultation may reveal crackles, and mild jaundice may be present. The natural course of mild leptospirosis usually involves spontaneous resolution within 7–10 days, but persistent symptoms have been documented. In the absence of a clinical diagnosis and antimicrobial therapy, the mortality rate in mild leptospirosis is low.


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InternalMed_Harrison. Severe Leptospirosis Although the onset of severe leptospirosis may be no different from that of mild leptospirosis, severe disease is often rapidly progressive and is associated with a case–fatality rate ranging from 1 to 50%. Higher mortality rates are associated with an age >40, altered mental status, acute renal failure, respiratory insufficiency, hypotension, and arrhythmias. The classic presentation, often referred to as Weil's syndrome, encompasses the triad of hemorrhage, jaundice, and acute kidney injury.


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InternalMed_Harrison. Patients die of septic shock with multiorgan failure and/or severe bleeding complications that most commonly involve the lungs (pulmonary hemorrhage), gastrointestinal tract (melena, hemoptysis), urogenital tract (hematuria), and skin (petechiae, ecchymosis, and bleeding from venipuncture sites). Pulmonary hemorrhage (with or without jaundice) is now recognized as a widespread public health problem, presenting with cough, chest pain, respiratory distress, and hemoptysis that may not be apparent until patients are intubated. Jaundice occurs in 5–10% of all patients with leptospirosis; it can be profound and give an orange cast to the skin but usually is not associated with fulminant hepatic necrosis. Physical examination may reveal an enlarged and tender liver.


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InternalMed_Harrison. Acute kidney injury is common in severe disease, presenting after several days of illness, and can be either nonoliguric or oliguric. Typical electrolyte abnormalities include hypokalemia and hyponatremia. Loss of magnesium in the urine is uniquely associated with leptospiral nephropathy. Hypotension is associated with acute tubular necrosis, oliguria, or anuria, requiring fluid resuscitation and sometimes vasopressor therapy. Hemodialysis can be life-saving, with renal function typically returning to normal in survivors.


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InternalMed_Harrison. Other syndromes include (necrotizing) pancreatitis, cholecystitis, skeletal muscle involvement, rhabdomyolysis (with moderately elevated serum creatine kinase levels), and neurologic manifestations including aseptic meningitis. Cardiac involvement is commonly reflected on the electrocardiogram as nonspecific STand T-wave changes. Repolarization abnormalities and arrhythmias are considered poor prognostic factors. Myocarditis has been described. Rare hematologic complications include hemolysis, thrombotic thrombocytopenic purpura, and hemolytic-uremic syndrome. Long-term symptoms following severe leptospirosis include fatigue, myalgia, malaise, and headache and may persist for years. Autoimmune-associated uveitis, a potentially chronic condition, is a recognized sequela of leptospirosis.


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InternalMed_Harrison. The clinical diagnosis of leptospirosis should be based on an appropriate exposure history combined with any of the protean manifestations of the disease. Returning travelers from endemic areas usually have a history of recreational freshwater activities or other mucosal or percutaneous contact with contaminated surface waters or soil. For nontravelers, recreational water contact and occupational hazards that involve direct or indirect animal contact should be explored (see “Epidemiology,” above).


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InternalMed_Harrison. Although biochemical, hematologic, and urinalysis findings in acute leptospirosis are nonspecific, certain patterns may suggest the diagnosis. Laboratory results usually show signs of a bacterial infection, including leukocytosis with a left shift and elevated markers of inflammation (C-reactive protein level and erythrocyte sedimentation rate). Thrombocytopenia (platelet count ≤100 × 109/L) is common and is associated with bleeding and renal failure. In severe disease, signs of coagulation activation may be present, varying from borderline abnormalities to a serious derangement compatible with DIC as defined by international criteria. The kidneys are invariably involved in leptospirosis. Related findings range from urinary sediment changes (leukocytes, erythrocytes, and hyaline or granular casts) and mild proteinuria in mild disease to renal failure and azotemia in severe leptospirosis. Nonoliguric hypokalemic renal insufficiency (see “Clinical Manifestations,” above) is


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InternalMed_Harrison. or granular casts) and mild proteinuria in mild disease to renal failure and azotemia in severe leptospirosis. Nonoliguric hypokalemic renal insufficiency (see “Clinical Manifestations,” above) is characteristic of early leptospirosis. Serum bilirubin levels may be high, whereas rises in aminotransferase and alkaline phosphatase levels are usually moderate. Although clinical symptoms of pancreatitis are not a common finding, amylase levels are often elevated. When symptoms of aseptic meningitis develop, examination of the CSF shows pleocytosis that can range from a few cells to >1000 cells/μL, with a polymorphonuclear cell predominance. The protein concentration in the CSF may be elevated; CSF glucose levels are normal.


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InternalMed_Harrison. In severe leptospirosis, pulmonary radiographic abnormalities are more common than would be expected on the basis of physical examination (Fig. 208-4). The most common radiographic finding is a patchy bilateral alveolar pattern that corresponds to scattered alveolar hemorrhage. These abnormalities predominantly affect the lower lobes. Other findings include pleura-based densities (representing areas of hemorrhage) and diffuse ground-glass attenuation typical of acute respiratory distress syndrome (ARDS).


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InternalMed_Harrison. A definitive diagnosis of leptospirosis is based on isolation of the organism from the patient, on a positive result in the polymerase chain reaction (PCR), or on seroconversion or a rise in antibody titer. In cases with strong clinical evidence of infection, a single antibody titer of 1:200–1:800 (depending on whether the case occurs in a low-or high-endemic area) in the microscopic agglutination test (MAT) is required. Preferably, a fourfold or greater rise in titer is detected between acuteand convalescent-phase serum specimens. Antibodies generally do not reach detectable levels until the second week of illness. The antibody response can be affected by early treatment with antibiotics.


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InternalMed_Harrison. The MAT, which uses a battery of live leptospiral strains, and the enzyme-linked immunosorbent assay (ELISA), which uses a broadly reacting antigen, are the standard serologic procedures. The MAT usually is available only in specialized laboratories and is used for determination of the antibody titer and for tentative identification of the involved leptospiral serogroup—and, when epidemiologic background information is available, the putative serovar. This point underscores the importance of testing antigens representative of the serovars prevalent in the particular geographic area. However, cross-reactions occur frequently, and thus definitive identification of the infecting serovar or serogroup is not possible without isolation of the causative organism. Because serologic testing lacks sensitivity in the early acute phase of the disease (up to day 5), it cannot be used as the basis for a timely decision about whether to start treatment.


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InternalMed_Harrison. In addition to the MAT and the ELISA, various rapid tests with diagnostic value have been developed, and some of these are commercially available. These rapid tests mainly apply lateral flow, (latex) agglutination, or ELISA methodology and are reasonably sensitive and specific, although results reported in the literature vary, probably as a consequence of differences in test interpretation, (re)exposure risks, serovar distribution, and the use of biased serum panels. These methods do not require culture or MAT facilities and are useful in settings that lack a strong medical infrastructure. PCR methodologies, notably real-time PCR, have become increasingly widely implemented. Compared with serology, PCR offers a great advantage: the capacity to confirm the diagnosis of leptospirosis with a high degree of accuracy during the first 5 days of illness.