CHAPTER 79: ENDEMIC TREPONEMATOSES

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. 78). 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. 79-1). 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 79-1.

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 79-1. 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. 79-2A). 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. 79-2B), 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.

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. 79-2C) 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. 79-2D), 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. 78) 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.

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.