More than 150 species of NTM have been identified. Only a minority of these environmental organisms, which are found in soil and water, are important human pathogens. NTM cause extensive disease, primarily in persons with preexisting pulmonary disease or immunocompromise, but also can cause nodular/bronchiectatic disease in otherwise seemingly healthy hosts. NTM are also important causes of infections in surgical settings. The two major classes of NTM are the slow-growing and rapidly growing species; subcultures of the latter grow within 1 week. The growth characteristics of NTM have diagnostic, therapeutic, and prognostic implications. The rate of growth can provide useful preliminary information within a specific clinical context, in that growth within 2–3 weeks is much more likely to indicate an NTM than M. tuberculosis. When NTM do grow from cultures, colonization should be distinguished from active disease in order to optimize the risk and benefit of prolonged treatment with multiple medications. According to the recommendations of the American Thoracic Society and the Infectious Diseases Society of America, significant clinical manifestations and/or sputum radiographic evidence of progressive disease consistent with NTM infection as well as either reproducible sputum culture results or a single positive culture are required for the diagnosis of NTM pulmonary disease. Isolation of NTM from blood or from an infected-appearing extrapulmonary site, such as soft tissue or bone, is usually indicative of disseminated or local NTM infection (Chap. 204). Treatment of NTM disease is prolonged and requires multiple medications. Side effects of the regimens employed are common, and intermittent therapy is often used to mitigate these adverse events. Treatment regimens depend on the NTM species, the extent or type of disease, and—to some degree—drug susceptibility test results. The nodular bronchiectatic form of MAC infection is generally treated three times per week, whereas fibrocavitary or disseminated MAC infection is treated daily.
THERAPEUTIC CONSIDERATIONS FOR SPECIFIC NTM
M. avium Complex Among the NTM, MAC organisms most commonly cause human disease. In immunocompetent hosts, MAC species are most often found in conjunction with underlying significant lung disease, such as chronic obstructive pulmonary disease or bronchiectasis. For patients with nodular or bronchiectatic MAC lung disease, an initial regimen consisting of clarithromycin or azithromycin, rifampin or rifabutin, and ethambutol is given three times per week. Routine initial testing for macrolide resistance is recommended, as is testing at 6 months with a failing regimen (i.e., with cultures persistently positive for NTM).
In immunocompromised individuals, disseminated MAC infection is generally treated with clarithromycin, ethambutol, and rifabutin. Azithromycin may be substituted in patients unable to tolerate clarithromycin. Amikacin and fluoroquinolones are often used in salvage regimens. Treatment for disseminated MAC infection in AIDS patients may be lifelong in the absence of immune reconstitution. At least 12 months of MAC therapy and 6 months of effective immune reconstitution may be adequate.
M. kansasii M. kansasii is the second most common NTM causing human disease. It is also the second most common cause of NTM pulmonary disease in the United States, where it is most often reported in the southeastern region. M. kansasii infection can be treated with isoniazid, rifampin, and ethambutol; therapy continues for 12 months after culture conversion. Rifampin-resistant M. kansasii has been treated with clarithromycin, trimethoprim-sulfamethoxazole, and streptomycin.
Rapidly Growing Mycobacteria Rapidly growing mycobacteria causing human disease include Mycobacterium abscessus, Mycobacterium fortuitum, and Mycobacterium chelonae. Treatment of these mycobacteria is complex and should be undertaken with input from experienced clinicians. Testing for macrolide resistance is recommended. However, in rapidly growing mycobacteria, an inducible erm gene may confer in vivo macrolide resistance to isolates that are susceptible in vitro.
M. marinum M. marinum is an NTM found in salt water and freshwater, including swimming pools and fish tanks. It is a cause of localized soft-tissue infections, which may require surgical management. Combination regimens include clarithromycin and either ethambutol or rifampin. Other agents with activity against M. marinum include doxycycline, minocycline, and trimethoprim-sulfamethoxazole.
DRUGS FOR THE TREATMENT OF NTM
Clarithromycin is a macrolide antibiotic with broad activity against many gram-positive and gram-negative bacteria as well as NTM. This drug is active against MAC organisms and many other NTM species, inhibiting protein synthesis by binding to the 50S mycobacterial ribosomal subunit. NTM resistance to macrolides is probably caused by overexpression of the gene ermB, with consequent methylation of the binding site. Clarithromycin is well absorbed orally and distributes well to tissues. It is cleared both hepatically and renally; the dosage should be reduced in renal insufficiency. Clarithromycin is a substrate for and inhibits cytochrome 3A4 and should not be administered with cisapride, pimozide, or terfenadine because cardiac arrhythmias may occur. Numerous drugs interact with clarithromycin through the CYP3A4 metabolic pathway. Rifampin lowers clarithromycin levels; conversely, rifampin levels are increased by clarithromycin. However, the clinical relevance of this interaction does not appear to be great.
For patients with nodular/bronchiectatic MAC infection, the dosage of clarithromycin is 500 mg, given morning and evening three times a week. For the treatment of fibrocavitary or severe nodular/bronchiectatic MAC infection, a dose of 500–1000 mg is given daily. Disseminated MAC infection is treated with 1000 mg daily. Clarithromycin is used in combination regimens that typically include ethambutol and a rifamycin in order to avoid the development of macrolide resistance. Adverse effects include frequent gastrointestinal intolerance, hepatotoxicity, headache, rash, and rare instances of hypoglycemia. Clarithromycin is contraindicated during pregnancy because of its teratogenicity in animal models.
Azithromycin Azithromycin is a derivative of erythromycin. Although technically an azalide and not a macrolide, it works similarly to macrolides, inhibiting protein synthesis through binding to the 50S ribosomal subunit. Resistance to azithromycin is almost always associated with complete cross-resistance to clarithromycin. Azithromycin is well absorbed orally, with good tissue penetration and a prolonged half-life (~48 h). The usual dosage for treatment of MAC infection is 250 mg/d or 500 mg three times per week. Azithromycin is used in combination with other agents to avoid the development of resistance. For prophylaxis against disseminated MAC infection in immunocompromised individuals, a dose of 1200 mg once per week is given. Because azithromycin is not metabolized by cytochrome P450, it interacts with few drugs. Adjustment of the dosage on the basis of renal function is not necessary.
Cefoxitin Cefoxitin is a second-generation parenteral cephalosporin with activity against rapidly growing NTM, particularly M. abscessus, M. marinum, and M. chelonae. Its mechanism of action against NTM is unknown but may involve inactivation of cell wall synthesis enzymes. High doses are used for treatment of NTM: 200 mg/kg IV three or four times per day, with a maximal daily dose of 12 g. The half-life of cefoxitin is ~1 h, with primarily renal clearance that requires adjustment in renal insufficiency. Adverse effects are uncommon but include gastrointestinal manifestations, rash, eosinophilia, fever, and neutropenia.
Treatment of mycobacterial infections requires multiple-drug regimens that often exert significant side effects with the potential to limit tolerability. The prolonged duration of treatment has vastly improved results over those obtained in past decades, but drugs and regimens that will shorten treatment duration and limit adverse drug effects and interactions are needed.
Syphilis, a chronic systemic infection caused by Treponema pallidum subspecies pallidum, is usually sexually transmitted and is characterized by episodes of active disease interrupted by periods of latency. After an incubation period averaging 2–6 weeks, a primary lesion appears—often associated with regional lymphadenopathy—that resolves without treatment. The secondary stage, associated with generalized mucocutaneous lesions and generalized lymphadenopathy, is followed by a latent period of subclinical infection lasting years or decades. Central nervous system (CNS) involvement may occur early in infection and may be symptomatic or asymptomatic. In the preantibiotic era, about one-third of patients with untreated cases developed the tertiary stage, characterized by progressive destructive mucocutaneous, musculoskeletal, or parenchymal lesions; aortitis; or late CNS manifestations.
The Spirochaetales include four genera that are pathogenic for humans and for a variety of other animals: Leptospira species, which cause leptospirosis (Chap. 208); Borrelia species, which cause relapsing fever and Lyme disease (Chaps. 209 and 210); Brachyspira species, which cause intestinal infections; and Treponema species, which cause the diseases known collectively as treponematoses (see also Chap. 207e). The Treponema species include T. pallidum subspecies pallidum, which causes venereal syphilis; T. pallidum subspecies pertenue, which causes yaws; T. pallidum subspecies endemicum, which causes endemic syphilis or bejel; and T. carateum, which causes pinta. Until recently, the subspecies were distinguished primarily by the clinical syndromes they produce. Researchers have now identified molecular signatures that can differentiate the three subspecies of T. pallidum by culture-independent methods based on polymerase chain reaction (PCR), but other sequence signatures cross subspecies boundaries in certain strains. Other Treponema species found in the human mouth, genital mucosa, and gastrointestinal tract have been associated with disease (e.g., periodontitis), but their role as primary etiologic agents is unclear.
T. pallidum subspecies pallidum (referred to hereafter as T. pallidum), a thin spiral organism, has a cell body surrounded by a trilaminar cytoplasmic membrane, a delicate peptidoglycan layer providing some structural rigidity, and a lipid-rich outer membrane containing relatively few integral membrane proteins. Endoflagella wind around the cell body in the periplasmic space and are responsible for motility.
T. pallidum cannot be cultured in vitro, and little was known about its metabolism until the genome was sequenced in 1998. This spirochete possesses severely limited metabolic capabilities, lacking the genes required for de novo synthesis of most amino acids, nucleotides, and lipids. In addition, T. pallidum lacks genes encoding the enzymes of the Krebs cycle and oxidative phosphorylation. The organism contains numerous compensatory genes predicted to encode transporters of amino acids, carbohydrates, and lipids. In addition, genome analyses and other studies have revealed the existence of a 12-member gene family (tpr) that bears similarities to variable outer-membrane antigens of other spirochetes. One member, TprK, has discrete variable (V) regions that undergo antigenic variation during infection, providing a mechanism for immune evasion.
The only known natural host for T. pallidum is the human. T. pallidum can infect many mammals, but only humans, higher apes, and a few laboratory animals regularly develop syphilitic lesions. Rabbits are used to propagate virulent strains of T. pallidum and serve as the animal model that best reflects human disease and immunopathology.
TRANSMISSION AND EPIDEMIOLOGY
Nearly all cases of syphilis are acquired by sexual contact with infectious lesions (i.e., the chancre, mucous patch, skin rash, or condylomata lata; see Fig. 25e-20). Less common modes of transmission include nonsexual personal contact, infection in utero, blood transfusion, and organ transplantation.
SYPHILIS IN THE UNITED STATES
With the advent of penicillin therapy, the total number of cases of syphilis reported annually in the United States declined significantly to a low of 31,575 cases in 2000—a 95% decrease from 1943—with <6000 reported cases of infectious primary and secondary syphilis (the latter being a better indicator of disease activity than total syphilis cases). Since 2000, the number of cases of primary and secondary syphilis has more than doubled, with more than 14,000 cases reported in 2012 (Fig. 206-1). Approximately 70% of these cases were in men who have sex with men (MSM), 20–70% of whom are co-infected with HIV (depending on geographic location). The number of primary and secondary cases among women in the United States increased from 2004 to 2008 but has since been declining in conjunction with a decline in congenital syphilis. Surveillance of the number of new cases of primary and secondary syphilis has revealed multiple 7- to 10-year cycles, which may be attributed to herd immunity in at-risk populations, changing sexual behaviors, and changes in control efforts.
FIGURE 206-1 Primary and secondary syphilis in the United States, 1990–2012, by sex (A) and by race or ethnicity (B). (Data from the Centers for Disease Control and Prevention.)
The populations at highest risk for acquiring syphilis have changed over time, with outbreaks among MSM in the pre-HIV era of the late 1970s and early 1980s as well as at present. It is speculated that recent increases in syphilis and other sexually transmitted infections in MSM may be due to unprotected sex between persons who are HIV concordant and to disinhibition caused by highly effective antiretroviral therapies. The syphilis epidemic that peaked in 1990 predominantly affected African-American heterosexual men and women and occurred largely in urban areas, where infectious syphilis was correlated with the exchange of sex for crack cocaine. The rate of primary and secondary syphilis among African Americans nearly doubled between 2003 and 2009, remains higher than rates for other racial/ethnic groups, but has since declined somewhat (Fig. 206-1).
The incidence of congenital syphilis roughly parallels that of infectious syphilis in women. In 2011, 360 cases in infants <1 year of age were reported, for a decline of 20% since 2008. The case definition for congenital syphilis was broadened in 1989 and now includes all live or stillborn infants delivered to women with untreated or inadequately treated syphilis.
One-third to one-half of individuals named as sexual contacts of persons with infectious syphilis become infected. Many have already developed manifestations of syphilis when they are first seen, and ∼30% of asymptomatic contacts examined within 30 days of exposure actually have incubating infection and will later develop infectious syphilis if not treated. Thus, identification and treatment of all recently exposed sexual contacts continue to be important aspects of syphilis control.
Syphilis remains a significant health problem globally; the number of new infections is estimated at 11 million per year. The regions that are most affected include sub-Saharan Africa, South America, China, and Southeast Asia. During the past decade, the incidence rate in China has increased by approximately eightfold, and higher rates of infectious syphilis have been reported among MSM in many European countries. Worldwide, there are estimated to be 1.4 million cases of syphilis among pregnant women, with 500,000 adverse pregnancy outcomes annually (e.g., stillbirth, neonatal and early fetal death, prematurity/low birth weight, and infection in newborns). Congenital syphilis rates in China are ∼150 cases per 100,000 live births.
NATURAL COURSE AND PATHOGENESIS OF UNTREATED SYPHILIS
T. pallidum rapidly penetrates intact mucous membranes or microscopic abrasions in skin and, within a few hours, enters the lymphatics and blood to produce systemic infection and metastatic foci long before the appearance of a primary lesion. Blood from a patient with incubating or early syphilis is infectious. The generation time of T. pallidum during early active disease in vivo is estimated to be ∼30 h, and the incubation period of syphilis is inversely proportional to the number of organisms inoculated. The 50% infectious dose for intradermal inoculation in humans has been calculated to be 57 organisms, and the treponeme concentration generally reaches 107/g of tissue before a clinical lesion appears. The median incubation period in humans (∼21 days) suggests an average inoculum of 500–1000 infectious organisms for naturally acquired disease; the incubation period rarely exceeds 6 weeks.
The primary lesion appears at the site of inoculation, usually persists for 4–6 weeks, and then heals spontaneously. Histopathologic examination shows perivascular infiltration, chiefly by CD4+ and CD8+ T lymphocytes, plasma cells, and macrophages, with capillary endothelial proliferation and subsequent obliteration of small blood vessels. The cellular infiltration displays a TH1-type cytokine profile consistent with the activation of macrophages. Phagocytosis of opsonized organisms by activated macrophages ultimately causes their destruction, resulting in spontaneous resolution of the chancre.
The generalized parenchymal, constitutional, and mucocutaneous manifestations of secondary syphilis usually appear ∼6–8 weeks after the chancre heals, although primary and secondary manifestations may overlap. In contrast, some patients may enter the latent stage without ever recognizing secondary lesions. The histopathologic features of secondary maculopapular skin lesions include hyperkeratosis of the epidermis, capillary proliferation with endothelial swelling in the superficial dermis, dermal papillae with transmigration of polymorphonuclear leukocytes, and—in the deeper dermis—perivascular infiltration by CD8+ T lymphocytes, CD4+ T lymphocytes, macrophages, and plasma cells. Treponemes are found in many tissues, including the aqueous humor of the eye and the cerebrospinal fluid (CSF). T. pallidum invades the CNS during the first weeks or months of infection, and CSF abnormalities are detected in as many as 40% of patients during the secondary stage. Clinical hepatitis and immune complex–induced glomerulonephritis are relatively rare but recognized manifestations of secondary syphilis; liver function tests may yield abnormal results in up to one-quarter of patients with early syphilis. Generalized nontender lymphadenopathy is noted in 85% of patients with secondary syphilis. The paradoxical appearance of secondary manifestations despite high titers of antibody (including immobilizing antibody) to T. pallidum may result from immune evasion due to antigenic variation or changes in expression of surface antigens. Secondary lesions generally subside within 2–6 weeks, and the infection enters the latent stage, which is detectable only by serologic testing. In the preantibiotic era, up to 25% of untreated patients experienced at least one generalized or localized mucocutaneous relapse, usually during the first year. Therefore, identification and examination of sexual contacts are most important for patients with syphilis of <1 year’s duration.
As stated earlier, about one-third of patients with untreated latent syphilis developed clinically apparent tertiary disease in the preantibiotic era, when the most common types of tertiary disease were the gumma (a usually benign granulomatous lesion); cardiovascular syphilis (usually involving the vasa vasorum of the ascending aorta and resulting in aneurysm); and late symptomatic neurosyphilis (tabes dorsalis and paresis). In Western countries today, specific treatment for early and latent syphilis and coincidental therapy (i.e., therapy with antibiotics that are given for other conditions but are active against treponemes) have nearly eliminated tertiary syphilis. Asymptomatic CNS involvement, however, is still demonstrable in up to 40% of persons with early syphilis and 25% of patients with late latent syphilis, and cases of general paresis and tabes dorsalis are being reported from China. The factors that contribute to the development and progression of tertiary disease are unknown.
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.
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.
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.
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-field-positive 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 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.
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. Involvement of the hair follicles may result in patchy alopecia of the scalp hair, eyebrows, or beard in up to 5% of cases.
FIGURE 206-3 Secondary syphilis. Left: Maculopapular truncal eruption. Middle: Papules on the palms. Right: Papules on the soles. (Courtesy of Jill McKenzie and Christina Marra.)
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.
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 often but not always associated with other CSF abnormalities.
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 of the secondary stage resolve spontaneously, usually within 1–6 months.
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 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.
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.
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 demonstrated 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 rabbits 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 abnormalities, but organisms can be recovered from patients with otherwise normal CSF. Although the prognostic implications of these findings in early syphilis are uncertain, it may be appropriate to conclude that even patients with 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 recent studies, neurosyphilis was associated with a rapid plasma reagin (RPR) titer of ≥1:32, regardless of clinical stage or HIV infection status.
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.
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.
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 light. Optic atrophy also occurs frequently in association with tabes.
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.
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.
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.
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 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
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 congenital infections, including rubella, cytomegalovirus or herpes simplex virus infection, and toxoplasmosis, as well as from erythroblastosis fetalis.
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.
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.
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.
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.
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 discussed (see “Evaluation for Neurosyphilis,” below), the RPR titer may be useful in determining which patients will benefit from CSF examination.
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 treatment and cannot differentiate past from current T. pallidum infection. Figure 206-4 provides a suggested algorithm for management of such cases.
FIGURE 206-4 Algorithm for interpretation of results from syphilis enzyme immunoassays (EIAs) used for screening. FTA-ABS, fluorescent 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.)
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.
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.
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 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 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.
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 utility of measuring CXCL13 in CSF to distinguish between neurosyphilis and HIV-related CSF abnormalities has been demonstrated.
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 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.
INDICATIONS FOR CEREBROSPINAL FLUID EXAMINATION IN ADULTS WITH ALL STAGES OF SYPHILIS
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
Additional Indications in HIV-Infected Persons
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.
Evaluation of HIV-Infected Patients for Syphilis Because persons at highest risk for syphilis are also at increased risk for HIV infection, these 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.
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 studies. Serologic testing after treatment is important for all patients with syphilis, particularly for those also infected with HIV.
TREATMENT OF ACQUIRED SYPHILIS
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 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 must be ensured.
RECOMMENDATIONS FOR THE TREATMENT OF SYPHILISa
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 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.
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.
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.
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 neurosyphilis.
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.
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.
EVALUATION AND MANAGEMENT OF CONGENITAL SYPHILIS
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.
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.
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 Jarisch-Herxheimer reaction occurs in ∼50% of patients with primary syphilis, 90% of those with secondary syphilis, and a lower proportion of persons with later-stage disease. Defervescence takes place within 12–24 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 required for this mild transient reaction.
FOLLOW-UP EVALUATION OF RESPONSES TO THERAPY
Efficacy of treatment should be assessed by clinical evaluation and monitoring of the quantitative VDRL or RPR titer for a fourfold decline (e.g., from 1:32 to 1:8). Patients with primary or secondary syphilis should be examined 6 and 12 months after treatment and persons with latent or late syphilis at 6, 12, and 24 months. More frequent clinical and serologic examination (3, 6, 9, 12, and 24 months) is recommended for patients concurrently infected with HIV, regardless of the stage of syphilis.
After successful treatment of seropositive first-episode primary or secondary syphilis, the VDRL or RPR titer progressively declines, becoming negative by 12 months in 40–75% of seropositive primary cases and in 20–40% of secondary cases. Patients with HIV infection or a history of prior syphilis are less likely to become nonreactive in the VDRL or RPR test. Rates of decline of serologic titers appear to be slower, and serologically defined treatment failures more common, among HIV-infected patients than among those without HIV co-infection; however, effective antiretroviral therapy may reduce these differences. Re-treatment should be considered if serologic responses are not adequate or if clinical signs persist or recur. Because 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 titer increase within 14 days after treatment; however, this early elevation does not significantly affect the serologic outcome at 6 months after treatment. Patients treated for late latent syphilis frequently have low initial VDRL or RPR 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. Because treponemal tests may remain reactive despite treatment for seropositive syphilis, these tests are not useful in following the response to therapy.
The activity of neurosyphilis (symptomatic or asymptomatic) correlates best with CSF pleocytosis, and this measure provides the most sensitive index of response to treatment. Repeat CSF examinations should be performed every 6 months until the cell count is normal. An elevated CSF cell count falls to normal in 3–12 months in adequately treated HIV-uninfected patients. The persistence of mild pleocytosis in HIV-infected patients may be due to the presence of HIV in CSF; this scenario may be difficult to distinguish from treatment failure. Elevated levels of CSF protein fall more slowly, and the CSF VDRL titer declines gradually over several years. In patients treated for neurosyphilis, a fourfold reduction in serum RPR titer has been positively correlated with normalization of CSF abnormalities; this correlation is stronger in HIV-uninfected patients and in HIV-infected patients receiving effective antiretroviral therapy.
IMMUNITY TO SYPHILIS
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 correlations between molecular type and clinical manifestations are being examined.
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 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.
FIGURE 207e-1 Geographic distribution of endemic treponematoses. (Courtesy of the World Health Organization; updated from www.who.int/yaws/epidemiology/Map_yaws_90s.jpg.)
COMPARISON OF THE TREPONEMES AND ASSOCIATE DISEASES
In a World Health Organization (WHO)–sponsored mass eradication campaign from 1952 to 1969, more than 160 million 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, 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 are thought to persist in Haiti and other Caribbean islands, Peru, Colombia, Ecuador, Brazil, Guyana, and Surinam, although recent data are lacking. Pinta is limited to Central America and northern South America, where it is found rarely and only in very remote villages. 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 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 clade that contains the human isolates, but uncertainty remains about the importance of the nonhuman primate reservoir for human infection.
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.
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 medical personnel in endemic regions, the delay of many years between infection 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.
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 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.
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].)
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.
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 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 white and giving the skin a mottled appearance. White achromic lesions are characteristic of the late stage.
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.
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 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 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.