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Yaws, bejel, and pinta

Yaws, bejel, and pinta
Authors:
Oriol Mitjà, MD, PhD, DTMH
David Mabey, BM, BCh, DM, FRCP
Section Editors:
Edward T Ryan, MD, DTMH
Ted Rosen, MD
Deputy Editors:
Elinor L Baron, MD, DTMH
Abena O Ofori, MD
Literature review current through: Jan 2024.
This topic last updated: Jan 12, 2022.

INTRODUCTION — The endemic treponematoses include yaws (Treponema pallidum subsp pertenue), bejel (T. pallidum subsp endemicum), and pinta (Treponema carateum) [1]. These are bacterial infections caused by organisms that are morphologically and serologically indistinguishable from Treponema pallidum subsp pallidum, which is the causative organism of venereal syphilis [2,3]. They may be differentiated by clinical manifestations, geographic distribution, and molecular diagnostic testing [4,5].

Yaws and bejel affect skin and bones; pinta affects the skin only. Other terms for yaws include buba, bouba, framboesia, parangi, paru, and pian [6,7]. Other terms for bejel include endemic syphilis, dichuchwa, sklerjevo, belesh, bishel, firjal, and loath. Other terms for pinta include enfermedad azul, carate, cute, and mal de pinto.

EPIDEMIOLOGY

Historic perspective — Between 1952 and 1964, the number of endemic treponematoses cases was reduced from an estimated 50 million to 2.5 million as a result of mass treatment campaigns led by the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) in 46 countries. In some regions, disease was eliminated; bejel was eliminated in Bosnia [8], and yaws was eliminated in Malaysia and Brazil [9,10].

Endemic treponematoses began to reemerge in the late 1970s. Efforts to eradicate yaws were renewed in 1978 by the WHO; however, endemic treponematoses have not been prioritized in many regions, and surveillance and reporting have been sporadic; one exception is the WHO South Asia region, which kept yaws on its agenda [11].

Geographic distribution — The nonvenereal treponematoses are endemic in rural areas among communities living in overcrowded conditions with poor hygiene (figure 1). Imported cases of yaws from Ghana and Congo have been reported in the United States and the Netherlands [12,13]. In addition, cases of bejel imported from Pakistan, Mali, and the Republic of Senegal have been reported in France [14,15] and Canada [16]. There is also evidence of genital ulcer cases allegedly caused by T. p. endemicum (on the basis of genetic findings) that were transmitted in Cuba and Japan via sexual contact [17,18].

Yaws is the most prevalent nonvenereal treponematosis. It is endemic mainly in warm, humid equatorial regions of Africa, Southeast Asia, and the Pacific (table 1) [19-33]. Between 2007 and 2016, between 76,000 and 86,000 new cases annually were reported to the WHO from 13 countries known to be endemic for yaws [34]. Between 2017 and 2019, two additional countries reported confirmed yaws cases (Liberia and Philippines). In 2020, 87,877 cases were reported: the majority from Papua New Guinea (81,369 in 2020). Other countries reporting yaws in West Africa and the Pacific Region are Ghana (4695 cases in 2020), Cameroon (1713 in 2019), Cote d'Ivoire (564 cases in 2020), Togo (291 in 2020), the Democratic Republic of the Congo (45 in 2020), the Solomon Islands (13,047 in 2019), Vanuatu (823 in 2020), and Indonesia (81 in 2020). India reported elimination of yaws in 2006 [35], and the WHO officially declared India free of yaws in May 2016. Elimination of yaws has also been reported in Ecuador, although this has not yet been certified by the WHO [32]; additional data on yaws in the Americas are limited. Of the 96 countries known to have been endemic in the 1950s, 76 need to be reassessed by the WHO to determine whether transmission has been interrupted.

Bejel occurs mainly in the arid areas of the Sahel (southern border of the Sahara desert), including Senegal [36], Burkina Faso [37], Mali [38], and Niger [39,40]. In these areas, high rates of seropositivity (10 to 20 percent of children under 15 years) have been reported. Bejel has also been described among the nomadic people of the Arabian Peninsula (Saudi Arabia, Iraq, and Syria) [41,42]. There was a report of three cases of bejel in Turkey in 1995 (where the disease was considered to be eliminated) [43], as well as one case report from Iran in 2012 and one from Pakistan in 2013 [15,44].

Data on the distribution of pinta are limited; there is the perception that the disease has sustained a marked decline over the past century. Pinta might remain endemic in remote regions of Mexico (states of Oaxaca, Guerrero, Michoacan, and Chiapas) [45,46] and Central and South America (among Indian tribes in the Amazon region of Brazil [47], Colombia [48], Venezuela [49], and Peru [50]). A survey in Panama in the 1980s noted evidence of active or inactive pinta among 20 percent of the population [51].

Transmission — Yaws and bejel usually occur in children; 65 to 75 percent of new cases arise in individuals between 1 and 15 years (peak between 5 and 10 years), the infection is uncommon in children less than 1 year of age [52-54]. The age range for pinta is 15 to 50 years (median 30 to 34 years) [55].

Data on the incubation period of endemic treponematoses are limited; the range is 9 to 90 days (mean 21 days) [56,57]. Infected individuals may develop immunity to reinfection, which may be strain specific [58,59].

Yaws is transmitted by direct skin-to-skin, nonsexual contact with infectious lesions. Because T. p. pertenue is temperature and humidity dependent, the incidence of skin lesions is higher in the wet season; high humidity promotes exuberant growth of papillomata and survival of treponemes in serous exudates [52]. Transmission may be facilitated by a breach in the skin of the recipient, such as a scratch or insect bite [60]. Cases of yaws are often seen in temporal clusters within neighboring households or communities as transmission occurs between children in the community, schools, and other public places [61]. Yaws is generally transmitted during childhood, and infectious lesions usually resolve before sexual maturity; sexual transmission might be possible but is not frequently described.

Bejel is transmitted by direct skin-to-skin or mouth-to-mouth contact and by indirect contact through sharing of communal eating or drinking utensils [8,62]. Initial lesions are often in or around the mouth; infection can be spread by older children kissing younger siblings. In addition, bejel has been detected in primary genital lesions and may be transmitted sexually [15,17,62].

Pinta is transmitted by direct skin-to-skin contact. Inoculation of fluid from a pinta lesion can reproduce skin lesions in previously uninfected individuals [63]. Transmission is thought to occur frequently within families; in the absence of infection among adults in a household, the likelihood of infection among children is extremely low [63].

Indirect transmission of endemic treponematoses by nonbiting flies has been suggested on the basis that Musca spp could transmit yaws to monkeys in the laboratory [57,60,63]. Molecular studies have demonstrated that wild-caught flies from a yaws-endemic setting harbor T. pallidum DNA but could not demonstrate that fly-associated bacteria were viable and present in sufficient numbers for transmission [64,65].

MICROBIOLOGY — The causative organisms of endemic treponematoses include Treponema pallidum subsp pertenue (yaws), T. pallidum subsp endemicum (bejel), and T. carateum (pinta). T. pallidum belongs to a family of gram-negative spiral-shaped bacteria, the Spirochaetaceae, and has a length ranging from 10 to 15 microns and a diameter of 0.2 microns, making it invisible to light microscopy except under dark field illumination [66,67]. Electron microscope studies have shown that there are not significant differences in morphology or structure between T. pallidum subspecies or with T. carateum [66-68].

The organisms are easily killed by drying, elevated temperature, and exposure to oxygen. They multiply slowly (once every 30 to 33 hours) [69] and cannot survive outside the mammalian host [69]. Since T. pallidum species could not be grown in culture, testing for antibiotic resistance had been performed only by indirect molecular methods, experimental infection of animals, or polymerase chain reaction (PCR) detection of mutations to antibiotic target sites [70]. A novel cell culture-based cultivation system able to support long-term in vitro propagation of T. p. pallidum was described in 2018 [71], which has allowed investigators to perform in vitro susceptibility studies.

One in vitro assay to assess the effect of antibiotics on treponemal protein synthesis (as measured by the incorporation of radiolabeled 35S-methionine) demonstrated sensitivity of T. p. pallidum and T. p. pertenue to penicillin, chloramphenicol, tetracycline, and erythromycin [72], and lack of sensitivity to streptomycin (up to 500 mcg/mL), rifampin (up to 100 mcg/mL), or quinolones (up to 10 mcg/mL) [72,73].

In the culture-based cultivation system, growth was inhibited with penicillin G at concentrations ≥0.003 mg/mL (0.06 units/mL), cefixime ≥0.03 mcg/mL, linezolid ≥0.5 mcg/mL, and dalbavancin ≥0.1 mcg/mL. The same study showed no treponemicidal activity for moxifloxacin (up to 2 mcg/mL), clofazimine (up to 2 mcg/mL), isoniazid (up to 0.5 mcg/mL), or pyrazinamide (up to 64 mcg/mL) [74,75].

In animal models, penicillin, cephalosporins, monobactams, macrolides, and linezolid have shown curative results [74,76]; tests on experimentally infected patients showed that benzylpenicillin levels >0.03 units/mL of serum maintained for at least seven days were treponemicidal [77]. In contrast, ofloxacin, moxifloxacin, and clofazimine could not cure the infection in the animal model [74,78].

Azithromycin resistance has been described in yaws [79]. Macrolide resistance in T. pallidum is associated with alteration of the target site due to a mutation of the 23S ribosomal RNA gene and was previously reported in patients with syphilis [80-82]. Detection of a mutation causing macrolide resistance in 23S rRNA genes of T. p. pertenue has been observed in five patients who presented with treatment failure in a mass azithromycin treatment trial [79]. A real-time PCR assay for detection of mutations has been developed, enabling molecular surveillance for detection of macrolide resistance in T. p. pertenue [83,84].

PATHOPHYSIOLOGY

Virulence — Treponemes penetrate the human host through the skin, move through epithelial cells via tight junctions, and attach to fibronectin-coated surfaces on the extracellular matrix of host cells [85]. In the hamster model, the rate of appearance and resolution of cutaneous lesions varies with the size of the inoculum, and the minimum infective dose has been estimated to be 103 to 104 bacteria [86,87]. Clinical lesions appear when a concentration of approximately 107 organisms per mg of tissue is reached.

After invasion, the organisms appear in lymph nodes within minutes and disseminate widely within hours, reaching and surviving in distal skin and mucosal sites to enhance opportunities for subsequent transmission [87]. Treponemes are extracellular pathogens that exhibit characteristic corkscrew motility due to endoflagella [88], with rapid rotation about the longitudinal axis, and are able to swim efficiently in a gel-like environment such as connective tissue [89]. This virulence factor plays a role in the widespread dissemination of treponemal infections and the establishment of chronic disease [90].

In the face of a hostile host environment and a strong specific immune response (including macrophage phagocytosis due to opsonization) [87,91], the bacterium utilizes several survival mechanisms. T. pallidum may stimulate trafficking of T cells out of the peripheral blood circulation [92,93]. The organism may also exploit its low metabolic rate in order to maintain infection with very few viable cells, avoiding the stimulation of an immune response [58]. Antigenic variation in candidate outer membrane protein antigenic targets (eg, TprK) may be important in immune evasion and persistence of infection [94].

Immunology — New skin lesions are rarely found in adults, suggesting that immunity to reinfection can develop in humans. Studies in the experimental model designed to identify resistance to infection and immunologic correlates of resistance suggest that acquired resistance to the yaws bacteria can develop in untreated animals and persist after treatment [95].

Genetics — Whole-genome analysis for several pathogenic treponemes has been performed, and several genetic differences between T. p. pallidum, T. p. pertenue, and T. p. endemicum have been identified. The overall sequence identity between genomes of the three subspecies is 99.8 percent [5,96], but the regions of sequence divergence are used for the molecular detection and discrimination of syphilis and yaws strains, which is not possible with other tests [4,13,97-103].

Laboratory isolates from patients with syphilis and yaws genetically cluster according to subspecies classification, and there is a robust correlation between clinical presentation and genetics. However, because data for bejel strains are limited, it is uncertain whether genetic tests can accurately differentiate T. p. endemicum.

HISTOPATHOLOGY — Yaws and bejel affect skin and bones; pinta is unique in that it affects the skin only. The skin pathology in endemic treponematoses is largely similar to that of venereal syphilis.

Early yaws lesions consist of epidermal hyperplasia and papillomatosis, often with focal spongiosis and intraepidermal collections of neutrophils. In contrast with syphilis, skin biopsies from yaws patients show numerous plasma cells in the dermis but few T and B cells [104], and vascular changes are less marked [105,106]. The treponemes are found mostly in extracellular clusters in the upper regions of the proliferative epidermis, unlike subspecies pallidum, which primarily localizes in the dermis and dermal-epidermal junction (picture 1) [67,107]. These differences are relative, so they cannot be used to differentiate yaws from venereal syphilis.

The histopathology of bejel closely resembles that of venereal syphilis. The inflammatory infiltrate is mainly perivascular and is composed of lymphocytes and plasma cells. Granulomas consisting of epithelioid cells and multinuclear giant cells may be present [108].

In pinta, there is no ulcer formation comparable with that in yaws [106]. In the early lesion, there is loss of melanin in basal cells and liquefaction degeneration. A superficial and perivascular mixed infiltrate primarily composed of lymphocytes and plasma cells develops in the dermis [109]. In the late stage, there is epidermal atrophy and many melanophages are present in the dermis [108]. Absence of treponemes and inflammatory cells in the achromic lesions are typical findings [110].

YAWS

Clinical manifestations — Yaws consists of primary, secondary, and tertiary phases [111]. Most patients present in childhood with a primary cutaneous lesion on the lower extremity; some develop arthralgias due to joint involvement. The cutaneous lesions begin as a painless papule and, if left untreated, progress over weeks to months into an ulcerating nodule; bony involvement can occur as a late complication. The clinical manifestations are summarized in the table (table 2). Issues related to transmission and incubation period are described above. (See 'Transmission' above.)

The primary lesion ("mother yaw") appears at the site of initial infection [111]. It is usually a localized papule that may develop into a typically large yellow nodule (2 to 5 cm in diameter, often called papilloma) that ulcerates (picture 2). The lesion is not painful but may be pruritic. Ulcers characteristically have a red base consisting of granulation tissue, and the edges are commonly indurated and elevated (picture 3) [6]. The primary lesion is most commonly found on the legs and ankles (65 to 85 percent of cases) [112,113] but can also occur on the buttocks, arms, hands, or face. It usually spontaneously heals after three to six months, regressing into a hyperpigmented pitted scar [114]. Sometimes the primary lesion is present at the onset of the secondary stage [56].

Secondary lesions are the result of lymphatic and hematogenous spread of organisms; they appear a few weeks to two years after the primary lesion. Secondary skin lesions consist of a solitary papillomatous nodule or ulcer resembling the primary lesion or an eruption of multiple smaller excrescences that cover a region of the body (picture 4) [115]. Multiple scaly patches or plaques with discoid or irregular shapes also may develop (picture 5).

Arthralgia occurs commonly in the setting of secondary yaws; in one study including 233 children in Papua New Guinea with suspected yaws, up to 75 percent presented with arthralgia [113].

Other manifestations of secondary yaws include palmar and plantar papilloma or hyperkeratotic plaques (which may be so painful that the affected individual favors weight bearing on the side of the foot, producing a characteristic crab-like gait) (picture 6) [115], and nocturnal bone pain due to osteoperiostitis of the proximal phalanges of the fingers (dactylitis) (picture 7) or long bones (forearm, tibia, or fibula) (picture 8). Yaws is a polyostotic disorder; the mean number of affected bones is three. Involvement of the hands and feet is common [116].

In general, primary and secondary lesions are reversible with treatment. If untreated, the manifestations spontaneously regress due to host's immune response against the pathogen, and a stage of latency begins. Latent yaws is characterized by absence of physical signs but persistence of serological evidence of the infection. Relapse of symptomatic infection can occur and is most common in the first 1 to 2 years after the initial exposure but may occur for up to 5 to 10 years.

Tertiary yaws is not common; it occurs in approximately 10 percent of untreated patients and consists of late lesions that develop after five or more years of infection [52]. This stage is characterized by gummatous lesions of skin, bones, and overlying tissues. Manifestations include:

●Malformation of long bones (eg, anterior bowing of the tibia) (picture 9)

●Juxta-articular subcutaneous nodules

●Hyperostosis of the nasal processes of the maxillae ("goundou")

●Ulceration of the palate and nasopharynx (rhinopharyngitis mutilans) with secondary infection resulting in foul-smelling discharge ("gangosa")

Yaws can spread systemically via the lymphatics or hematogenously. Yaws has been associated with neurologic and ophthalmologic abnormalities, but there is no definitive evidence of a causal relationship [117-120]. An association between tertiary yaws and cardiovascular disease has been postulated; among 3645 autopsies performed in Ghana between 1921 and 1953, aortitis was the most common cardiovascular disease (and the incidence of syphilis was relatively low) [121].

Yaws is not known to cause congenital infection; this may be because most new infections occur in children rather than in women of child-bearing age.

Diagnosis — Diagnosis of endemic treponematoses requires correlation of clinical manifestations, epidemiology, and demographic characteristics with serologic testing, if available (table 1 and table 2).

Clinical approach — The diagnosis of yaws should be suspected based on clinical manifestations (cutaneous papule on lower extremity that may develop into an ulcerating nodule, as well as joint and bone involvement in secondary disease; most commonly occurs in children) and the geographic distribution (tropics).

The diagnosis of yaws may be definitively established by serology, polymerase chain reaction (PCR) or via direct visualization of the organism in a clinical specimen [4,5]. Serologic testing is the mainstay of diagnosis due to complexities of direct visualization techniques and lack of access to molecular techniques in endemic countries.

In the absence of access to serology, empiric therapy for patients with suspected infection based on clinical grounds is reasonable.

Diagnostic tools

Serologic tests — The serological tests used to diagnose endemic treponematoses are the same as those used to diagnose syphilis; the tests cannot differentiate between endemic treponematoses and syphilis [122]. Serologic testing requires detection of two distinct antibodies: one against a treponemal antigen and one against a nontreponemal antigen. (See "Syphilis: Screening and diagnostic testing".)

Nontreponemal tests — Nontreponemal agglutination tests (rapid plasma reagin [RPR] or Venereal Disease Research Laboratory [VDRL]) are positive in untreated patients and can be used as a test of cure since the quantitative titers fall following treatment. The RPR can be read with the naked eye, whereas the VDRL requires a microscope. Two automated RPR assays have been cleared by the US Food and Drug Administration. The nontreponemal tests may give rise to false positives in patients with other conditions, including malaria, leprosy, and rheumatologic diseases [123]. They are often performed on serial dilutions of serum to give a quantitative titer, defined as the highest dilution that yields a positive result.

Nontreponemal tests become positive within two to four weeks after appearance of the primary lesion [124]. Nontreponemal tests yield false-negative results in about 10 percent of patients with early infections (eg, window period). In the setting of clinical suspicion for yaws and a negative RPR result, we favor repeat testing with a nontreponemal test within two to four weeks or, if available, we use PCR for identification of the organism.

There is a negative correlation between the duration of yaws infection and the nontreponemal titer; in end-stage disease, nontreponemal tests may be nonreactive. Large serologic cohort surveys of yaws have reported an association between low nontreponemal titers (<1:32) and secondary stage infection (70 to 83 percent) [61,124,125].

Treponemal tests — Treponemal tests (Treponema pallidum hemagglutination assay [TPHA], Treponema pallidum particle agglutination assay [TPPA], the fluorescent treponemal antibody absorption [FTA-Abs], Treponemal enzyme immunoassay, and Treponemal chemiluminescent immunoassay) are more specific than nontreponemal tests [126,127]. These assays cannot distinguish between current (untreated) and previously treated infection and remain positive even after successful treatment.

Rapid point-of-care testing — There are more than 20 commercially available point-of-care tests that detect treponemal antibodies. These can be performed outside a laboratory setting with minimal training and do not require refrigeration [2,128-131].

The Dual Path Platform (DPP) assay is a rapid point-of-care test that detects both treponemal and nontreponemal antibodies; it has high accuracy for diagnostic confirmation of yaws (in clinical settings) as well as for community surveillance [130,131]. In one meta-analysis including more than 1600 patients with suspected yaws, there was good concordance with standard tests for samples with RPR ≥1:16 (sensitivity 97 percent compared with the treponemal test and 96 percent compared with the nontreponemal test). However, concordance was relatively poor with low titer RPR <1:16 (sensitivity 73 percent compared with the treponemal test and 59 percent compared with the nontreponemal test) [132].

Polymerase chain reaction — PCR for detection of T. pallidum DNA is performed on swabs from ulcer or lesion exudate; PCR on whole blood is not recommended due to low sensitivity. Samples should initially be screened with a pan treponemal PCR (for example, targeting 47-kDa or polA DNA sequences) and then proceed to subspecies-level identification if necessary. Several PCR assays to distinguish nonvenereal T. pallidum subspecies have been developed using targets for T. p. pertenue and T. p. endemicum DNA regions encompassing unique genetic signatures [97-102]. Tests are highly reliable to identify T. p. pertenue, but it is uncertain whether they can reliably identify T. p. endemicum. Specimens that test positive on the screening assay should also be tested for evidence of azithromycin resistance with an assay targeting the 23s RNA gene.

PCR can be a useful method for diagnosis in early-stage infection (prior to the development of detectable antibodies) and for differentiation of active yaws from other conditions such as chancroid. In seropositive patients presenting with an ulcer, active yaws is defined as ulcers positive for T. p. pertenue PCR and latent yaws is defined as ulcers negative for T. p. pertenue PCR.

PCR tests are not suitable for screening asymptomatic individuals [133] and are unlikely to be available outside research laboratories [134,135].

Radiographic imaging — Radiographic imaging may be helpful to evaluate bony involvement in patients with yaws.

In secondary yaws, radiography demonstrates periostitis (picture 8). The lesions tend to be most common in the long bones of the forearms, hands, legs, and feet, but almost any bone may be involved. Periostitis is frequently bilateral and may be asymmetric. The earliest bony change is a focal osteoporosis of the bone, which rapidly becomes a localized lytic area in the cortex and medulla with no sequestra. An associated lamellar periosteal reaction is characteristic and is more marked in the area immediately overlying the foci of bone destruction (this is the phase of "osteoperiostitis").

In tertiary yaws, the predominant radiographic feature is marked cortical thickening, which causes an increased diameter of the bone and narrowing or partial obliteration of the medullary cavity. Deformity of the bones, particularly bowing, is a characteristic finding in advanced treponemal infections (image 1).

Differential diagnosis — The differential diagnosis for yaws includes (table 3):

●Venereal syphilis – Manifestations of syphilis that overlap with endemic treponematoses include cutaneous manifestations and bone involvement. Syphilis has been associated with congenital infection and involvement of the central nervous system; these manifestations have not been associated definitively with endemic treponematoses [1]. The serologic tests for endemic treponematoses are the same as those used for syphilis; the conditions are distinguished based on clinical manifestations, epidemiology, and demographic characteristics. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV" and "Syphilis: Screening and diagnostic testing".)

●Chancroid – Chancroid presents with one or more painful skin ulcers caused by infection with Haemophilus ducreyi [136]. The diagnosis is challenging because testing for H. ducreyi is not routinely available; most providers rely on clinical criteria to make a diagnosis (picture 10). (See "Chancroid".)

●Tropical ulcer – Tropical ulcer occurs as a result of a necrotic reaction induced by anaerobic bacteria. It occurs as a result of exposure to vegetation and/or dampness; malnutrition may also play a role. It typically presents with margins that are not undermined (as is typical of Buruli ulcer) and not raised (as is typical for cutaneous leishmaniasis) (picture 11).

●Streptococcus pyogenes − S. pyogenes has also been found to be a frequent causal agent of cutaneous ulcer in the tropics [137].

●Cutaneous diphtheria – Cutaneous diphtheria presents with chronic, nonhealing sores or shallow ulcers with a dirty gray membrane caused by infection with nontoxigenic strains of Corynebacterium diphtheriae. The diagnosis is made by culturing the organism from a skin lesion. (See "Clinical manifestations, diagnosis, and treatment of diphtheria".)

●Cutaneous leishmaniasis – Cutaneous leishmaniasis is a parasitic infection transmitted by the bite of a sandfly; it presents with cutaneous lesions on exposed areas of the skin. The lesion begins as a pink-colored papule that enlarges and develops into a nodule or plaque-like lesion (often with central softening), leading to a painless ulceration with an indurated border. Definitive diagnosis requires demonstration of the parasite in a clinical specimen by histology, culture, or molecular analysis via PCR. (See "Cutaneous leishmaniasis: Clinical manifestations and diagnosis".)

●Pyoderma gangrenosum (PG) – PG is an uncommon neutrophilic dermatosis that presents with a rapidly developing, painful purulent ulcer with a violaceous and undermined border. More than half of patients have associated systemic disease (such as inflammatory bowel disease or hematologic disorder). The clinical and histologic findings of PG are nonspecific, so it is a diagnosis of exclusion. (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis".)

Treatment

General approach — For treatment of nonpregnant individuals with high clinical suspicion for yaws (ie, skin ulcer with indurated edges or presence of yellow papules or nodules) or positive RPR test, we favor treatment with either azithromycin (30 mg/kg single dose; maximum dose 2 g) or injectable penicillin G benzathine (<10 years of age: 1.2 million units single dose; ≥10 years of age: 2.4 million units single dose) [19]. Penicillin has the longest track record of efficacy but requires an injection; azithromycin may be administered orally, but some resistance has been described. Other agents with activity include erythromycin, doxycycline, and tetracycline.

For treatment of pregnant or breastfeeding women with high clinical suspicion for yaws, we favor treatment with injectable penicillin G benzathine (2.4 million units single dose) because the safety of benzathine penicillin in this group is better established than the safety of azithromycin. In addition, if the diagnosis of yaws cannot be established definitively, it may represent syphilis (which warrants treatment with penicillin).

In addition, contacts of patients with yaws (individuals who live with or come into frequent contact with an infectious case) should receive empiric treatment. For the purpose of yaws eradication, contacts include household members, schoolmates in the same class, and close playmates.

Individuals with latent yaws (positive serologic testing but no physical signs following spontaneous healing of skin lesion[s], or positive serologic testing and presence of a T. p. pertenue PCR-negative lesion) warrant treatment (with the same regimen as for treatment of active disease) to prevent relapse and progression of yaws to the destructive tertiary stage.

A dry dressing is useful for keeping skin lesions clean and protected from trauma. Arthralgia and bone pain usually improve within 24 to 72 hours after starting antibiotic therapy; if needed, discomfort may be managed with nonopioid analgesics (eg, acetaminophen).

Preferred antimicrobial agents

Penicillin G benzathine — Long-acting penicillin (single intramuscular dose) was demonstrated to be effective against endemic treponematoses in 1948 and has been the mainstay of treatment for yaws, bejel, and pinta [138,139]. We favor high-dose (<10 years of age: 1.2 million units single dose; ≥10 years of age: 2.4 million units single dose) as in treatment of syphilis, even though the dosing recommended by the WHO is lower (<10 years of age: 600,000 units single dose; ≥10 years of age: 1.2 million units single dose) [3].

Among adults with yaws in Haiti, cure rates associated penicillin doses of 1.2 million and 2.4 million units were 91 and 94 percent, respectively [140]. In one study of yaws treatment in Thailand, the average number of RPR titer dilution reductions at 12 months with the two regimens were 2.5 and 3.5 dilutions, respectively (eg, a reduction from 64 to 8 is recorded as a change in value of 3 dilutions) [125].

Oral penicillin V is rarely used due to inadequate serum levels that require long treatment schedules with frequent dosing.

There are a few reports of possible penicillin failure for treatment of yaws in Papua New Guinea [141] and in Ecuador [32], although these findings could not be proven microbiologically. The distinction between reinfection and resistance is difficult; development of penicillin resistance is unlikely since it would require a multistep mutation or acquisition of new genetic information [31].

Azithromycin — Azithromycin (30 mg/kg single dose; maximum dose 2 g) was noninferior to intramuscular penicillin G benzathine for treatment of yaws in a randomized trial including 250 children in Papua New Guinea [142]. Efficacy of azithromycin for patients with primary-stage and secondary-stage disease (including polyarthralgia or bone pain and swelling) was 91 and 100 percent, respectively. Similar findings were reported in a randomized trial including 500 patients with primary yaws skin lesions in Ghana [143].

Azithromycin has also been shown to be effective among individuals with latent yaws. In one study including 165 patients with latent yaws, the efficacy of azithromycin was 88 percent (based on decline in serological titer at 24 months after treatment) [144].

Azithromycin resistance has been described in yaws. (See 'Microbiology' above.)

Alternative antimicrobial agents — Alternative agents for treatment of endemic treponematoses in nonpregnant adults include doxycycline (100 mg orally twice daily for 15 days) or tetracycline (500 mg orally four times a day for 15 days) [134,145,146]. Erythromycin (8 to 10 mg/kg orally four times a day for 15 days) has been used for penicillin-allergic children <12 years and pregnant women [147].

These regimens are based on clinical efficacy observed in small case series. Adverse effects and frequent dosing for these second-line antibiotics can result in poor compliance and, therefore, higher rates of treatment failure.

Follow up — Skin lesions of yaws become noninfectious within 24 hours of treatment. In most cases, complete healing of primary and secondary lesions is observed within two to four weeks following treatment [142,148].

Patients should undergo follow-up nontreponemal testing at 6 and 12 months after treatment. In general, a fourfold reduction in RPR or VDRL titer (for example, decline from 1:16 to 1:4) occurs within 12 months after treatment in approximately 95 percent of cases [61,148-150]. RPR reversion to negative at 12 months occurs in 20 to 40 percent of patients. Those who present with early infection and low initial titer are more likely to have RPR reversion to negative. In some cases, the RPR or VDRL may persist at low titer (below 1:8); such patients are considered to be serofast.

The treponemal tests (ie, TPHA, TPPA, and FTA-Abs) remain positive for life.

Treatment failure — Forms of treatment failure include clinical failure and serologic failure.

Clinical treatment failure should be suspected in the setting of early-stage yaws lesions that have not healed within four weeks following initiation of antimicrobial therapy or in the setting of a repeated episode of yaws lesion(s) within one year. In such cases, patients treated initially with azithromycin should be retreated with penicillin G benzathine, and patients treated initially with penicillin G benzathine should be treated with a repeat course of penicillin G benzathine (given absence of resistance to penicillin). If feasible, clinical samples should be collected for laboratory confirmation of yaws by PCR and detection of mutations that confer antimicrobial resistance [151]. In addition, alternative conditions should be considered (table 3).

Serologic treatment failure is defined as ≥4-fold increase in the RPR titer (for example, change from 1:16 to 1:64) or titer persistently ≥1:64 over 12 months. In addition, some experts also consider individuals with a less than twofold decrease in RPR over 12 months to have treatment failure.

Patients who do not have an appropriate decline in serologic titer should be retreated; patients treated initially with azithromycin should be retreated with penicillin G benzathine, and patients treated initially with penicillin G benzathine should be treated with repeat course of penicillin G benzathine.

Most serologically defined treatment failures are thought to be caused by reinfection following treatment or slow decline in nontreponemal test titer rather than relapse or antibiotic resistance. Penicillin is favored for retreatment; some cases of macrolide resistance have been reported [79]. In addition, it is important to ensure that all household and community contacts are treated to decrease the risk of reinfection [61].

Eradication

●Rationale for mass treatment – Yaws is a potentially eradicable disease; the diagnosis and treatment are relatively straightforward and it is not known to have a significant animal reservoir [148].

In the early eradication programs (beginning in the 1950s), reactivation of infectious skin lesions highlighted the importance of subclinical or latent cases as a source of reinfection. It was estimated that there could be as many as six latent cases for every clinically apparent case, and treatment of active cases only had little impact on the prevalence of yaws one year later [152,153]. Subsequently, treatment of the entire population (rather than just active cases) in a Nigerian eradication campaign resulted in a rapid reduction in prevalence within 6 to 12 months [154].

●Approach  

•Antibiotic selection – The approach to yaws eradication consists of mass treatment with oral azithromycin (30 mg/kg, maximum 2 g) administered to the entire population (aiming for coverage of at least 90 percent) in areas known to harbor yaws [19,135,155-158]. No serious adverse events have been observed following a single dose of azithromycin; the incidence of mild adverse events (gastrointestinal symptoms) ranges from 10 and 15 percent [155,156].

Penicillin G benzathine may be used as an alternative for individuals who cannot be treated with azithromycin or for mass treatment in places where azithromycin is not available.

•Frequency of administration – In highly endemic areas, a single round of mass treatment may be insufficient to achieve yaws eradication; three rounds of mass treatment may be warranted [79,159].

Data from longitudinal studies include:

-In a study including more than 16,000 individuals in Papua New Guinea, a single mass azithromycin treatment followed by targeted treatment reduced the prevalence of active yaws from 1.8 to 0.1 percent at 18 months; however, infection began to re-emerge after 24 months, with a significant increase in prevalence to 0.4 percent at 42 months [79].

-In a study including more than 56,000 individuals in Papua New Guinea, greater reduction in prevalence was achieved with three rounds rather than one round of mass azithromycin treatment [159]. Clusters were randomly assigned to either one round of mass azithromycin followed by two rounds of targeted treatment for active cases (control group), or three rounds of mass azithromycin at 0, 6, and 12 months (experimental group). At 18 months, the prevalence of active yaws decreased from 0.46 to 0.16 percent in the control group and from 0.43 to 0.04 percent in the experimental group (adjusted relative risk [ARR] 4.08); the prevalence of latent yaws was 6.54 and 3.28 percent, respectively (ARR 2.03). Further evaluation for antimicrobial resistance and reemergence of infection is needed.

•Surveillance – Mass treatment should be followed by repeat surveys at four weeks and every six months thereafter to detect and treat remaining cases. Clinical monitoring at four weeks after mass treatment should identify any individuals with presumed treatment failure who warrant resistance testing and further treatment. In the interval between surveys, infected individuals and their close contacts must be treated [155].

•Criteria for success – Criteria to determine whether a mass treatment intervention has been successful in interrupting yaws transmission include [19]:

-Clinical criteria – The absence of any report of a new, serologically confirmed indigenous case over three successive years

-Molecular criteria – The absence of molecular positivity (ie, T. p. pertenue PCR is negative) in the lesion of any serologically confirmed case during a three-year surveillance period

-Serologic criteria – There is evidence of continuous negative serologic tests in samples of asymptomatic children between 1 and 5 years of age as measured by community serosurveys

●Integration with management for other conditions – For settings with more than one skin neglected tropical disease, we favor (and the WHO encourages) integrated active case detection to identify multiple conditions in a single visit [160,161]. As an example, for settings in which yaws and lymphatic filariasis (both amenable to mass treatment) are both endemic, we favor combined mass treatment to reduce costs and simplify logistics:

•A study performed in Papua New Guinea including more than 15,000 participants demonstrated feasibility and safety of combining the regimen for treatment of filariasis outside sub-Saharan Africa (ivermectin, diethylcarbamazine, and albendazole) with the regimen for yaws (azithromycin) [162].

•A study performed in Mali assessed the safety of integrated treatment of filariasis in Africa (ivermectin and albendazole) with the trachoma regimen (azithromycin) [163].

●Additional benefits of mass treatment - In addition to its benefit for yaws eradication, mass azithromycin administration has been associated with a reduction in childhood mortality in sub-Saharan Africa. This is discussed further separately. (See "Trachoma", section on 'Wider impact of mass treatment'.)

BEJEL

Clinical manifestations — Most patients with bejel present in childhood with one or more lesions involving the oral mucosa and pain involving the long bones of the lower extremities; left untreated, destructive lesions of the nose and palate may develop. The clinical manifestations are summarized in the table (table 2). Issues related to transmission and incubation period are described above. (See 'Transmission' above.)

The primary lesions of bejel are seldom seen because of their small size and location within the oral and oropharyngeal mucosa (picture 12) [3].

The most common secondary-stage manifestations include mucous patches (ie, shallow, painless ulcers in the oropharynx and on the lips) and bone pain due to periostitis (particularly of the long bones of the leg) [54]. Other common manifestations include hoarseness related to laryngitis, cutaneous involvement that favors warm and moist areas of the body and manifests as split papules or angular stomatitis at the labial commissures or condyloma lata in intertriginous areas [40].

Later, the patient may enter the latent phase, which may be prolonged; after this, some patients develop juxta-articular nodules and late destructive lesions, especially of the nose, nasal septum nasopharynx, and soft palate, which are similar to those seen in yaws [164,165].

Bejel can spread systemically via the lymphatics or hematogenously. Bejel has been associated with neurologic and ophthalmologic abnormalities, but there is no definitive evidence of a causal relationship [117-120].

Bejel is not known to cause congenital infection; this may be because most new infections occur in children rather than in women of childbearing age.

Bejel can present as genital ulcer disease in adults that is clinically indistinguishable from venereal syphilis as revealed by genetic tests. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV".)

Diagnosis — Diagnosis of endemic treponematoses requires correlation of clinical manifestations, epidemiology, and demographic characteristics with serologic testing, if available (table 1 and table 2).

The diagnosis of bejel should be suspected based on clinical manifestations (shallow, painless ulcers in the oropharynx and on the lips, and bone pain associated with periostitis frequently involving the long bones of the leg; most commonly occurs in children) and the geographic distribution (deserts of Africa and Saudi Arabia).

The diagnosis of bejel may be definitively established by serology, polymerase chain reaction (PCR), or via direct visualization of the organism in a clinical specimen [4,5]. Serologic testing is the mainstay of diagnosis due to complexities of direct visualization techniques and lack of access to molecular techniques in endemic countries. Laboratory tools for diagnosis of bejel are the same as those for diagnosis of yaws. (See 'Diagnostic tools' above.)

Radiographic imaging may be helpful to evaluate bony involvement in patients with bejel. The predominant radiographic feature in bejel is marked cortical thickening, which causes an increased diameter of the bone and narrowing or partial obliteration of the medullary cavity. Deformity of the bones, particularly bowing, is a characteristic finding in advanced treponemal infections (image 1).

The differential diagnosis for bejel is summarized in the table (table 3).

Treatment — We favor injectable penicillin G benzathine for treatment of bejel (<10 years of age, 1.2 million units single dose; ≥10 years of age, 2.4 million units single dose). In addition, contacts of patients with bejel (individuals who live with or come into frequent contact with an infectious case) should receive empiric treatment with penicillin G benzathine.

This approach is extrapolated from the approach to treatment of yaws, the endemic treponemal infection for which the approach to treatment is best studied. Given the similarity in the pathophysiology between bejel and yaws, azithromycin is an acceptable alternative regimen for treatment of bejel [111]. (See 'Preferred antimicrobial agents' above.).

A dry dressing is useful for keeping skin lesions clean and protected from trauma. Arthralgia and bone pain usually improve within 24 to 72 hours after starting antibiotic therapy; if needed, discomfort may be managed with nonopioid analgesics (eg, acetaminophen).

Skin lesions of bejel become noninfectious within 24 hours of treatment. In most cases, complete healing of primary and secondary lesions is observed within two to four weeks following treatment [142,148].

Patients with early bejel lesions that have not healed or improved within four weeks following initiation of antimicrobial therapy should be retreated in the same way as patients with yaws treatment failure. (See 'Treatment failure' above.)

Patients should undergo follow-up nontreponemal testing at 6 and 12 months after treatment as described above for yaws. Patients who do not have an appropriate decline in serologic titer should be retreated with penicillin G benzathine. (See 'Follow up' above.)

PINTA

Clinical manifestations — Most patients with pinta present in adulthood with itchy papules and/or plaques on the lower extremities. The clinical manifestations are summarized in the table (table 2). Issues related to transmission and incubation period are described above. (See 'Transmission' above.)

Pinta is confined to the skin and is the mildest of the treponematoses. The primary lesion is an itchy, red, scaly papule or a plaque that expands to >10 cm but does not ulcerate (picture 13). This sentinel lesion is most commonly found on the exposed lower extremities and is teeming with treponemes [166]. Satellite lesions and regional lymphadenopathy are common.

The secondary stage develops several months later in other areas with the appearance of pintids, which are similar to the initial lesions and are also pruritic [167]. They undergo a variety of color changes from red to copper colored, gray, and bluish-black [139,167]. The secondary lesions remain active and infectious for years, leading to extensive depigmentation resembling vitiligo.

The late lesions are characterized by varying degrees of hypochromia, discoloration, atrophy, and achromia (picture 14A-B) [138].

Diagnosis — Diagnosis of endemic treponematoses requires correlation of clinical manifestations, epidemiology, and demographic characteristics with serologic testing, if available (table 1 and table 2).

The diagnosis of pinta should be suspected based on clinical manifestations (initial lesion is an itchy, red, scaly papule or a plaque that expands to >10 cm but does not ulcerate; most commonly occurs in adults) and geographic distribution (Central and South America).

The diagnosis of pinta may be definitively established by serology or via direct visualization of the organism in a clinical specimen [4,5]. Polymerase chain reaction (PCR) to detect the agent of pinta has not been developed because no laboratory strain of this pathogen is available. T. carateum is the least characterized of the agents of the human treponematoses.

The differential diagnosis for pinta is summarized in the table (table 3).

Treatment — We favor injectable penicillin G benzathine for treatment of pinta (<10 years of age: 1.2 million units single dose; ≥10 years of age: 2.4 million units single dose). In addition, contacts of patients with pinta (individuals who live with or come into frequent contact with an infectious case) should receive empiric treatment with penicillin G benzathine.

This approach is extrapolated from the approach to treatment of yaws, the endemic treponemal infection for which the approach to treatment is best studied. Given the similarity in the pathophysiology between pinta and yaws, azithromycin is an acceptable alternative regimen for treatment of pinta [111].

Skin lesions of pinta heal within 6 to 12 months after treatment [139]. Administration of antibiotic treatment during early infection usually results in cure; administration of antibiotic treatment in the setting of advanced infection does not typically reverse skin changes [138].

Patients with early pinta lesions that have not improved within four weeks following initiation of antimicrobial therapy should be retreated in the same way as patients with yaws treatment failure. (See 'Treatment failure' above.)

Patients should undergo follow-up nontreponemal testing at 6 and 12 months after treatment as described above for yaws. Patients who do not have an appropriate decline in serologic titer should be retreated with penicillin G benzathine. (See 'Follow up' above.)

SUMMARY AND RECOMMENDATIONS

●The endemic treponematoses include yaws (Treponema pallidum subsp pertenue), bejel (T. pallidum subsp endemicum), and pinta (Treponema carateum). These are chronic bacterial infections caused by organisms that are morphologically and serologically indistinguishable from Treponema pallidum subsp pallidum, which is the causative organism of venereal syphilis. They can be differentiated by clinical manifestations and by genetic differences. (See 'Introduction' above.)

●The nonvenereal treponematoses are endemic in rural areas among communities living in overcrowded conditions with poor hygiene. Yaws is the most prevalent nonvenereal treponematosis; it is endemic mainly in warm, humid equatorial regions of Africa, South East Asia, and the Pacific. Bejel occurs mainly in the arid areas of the Sahel (southern border of the Sahara desert) and the Arabian peninsula region. Pinta is endemic in remote regions of Central and South America. (See 'Geographic distribution' above.)

●Yaws usually occurs in children and affects skin and bones; it is transmitted by direct skin-to-skin, nonsexual contact with infectious lesions. Bejel usually occurs in children and affects skin and bones; it is transmitted by direct skin-to-skin or mouth-to-mouth contact and by indirect contact through infected communal eating or drinking utensils. Pinta occurs in adolescents and adults and affects skin only; it is transmitted by direct skin-to-skin, nonsexual contact with infectious lesions. (See 'Transmission' above.)

●Clinical manifestations of yaws, bejel and pinta are summarized in the table (table 2). Endemic treponematoses can be confused with a number of conditions common in the tropics; the differential diagnosis is summarized in the table (table 3). (See 'Differential diagnosis' above.)

●The diagnosis of yaws, bejel, or pinta is established via serology. The serologic tests are the same as those used to diagnose syphilis. Existing serologic tests cannot differentiate between endemic treponematoses and syphilis; if more specific assays (such as polymerase chain reaction) are not available, diagnosis requires use of serologic tests together with clinical manifestations and epidemiologic and demographic characteristics. In the absence of access to serology, empiric therapy for patients with suspected infection based on clinical grounds is reasonable. (See 'Diagnostic tools' above.)

●Nontreponemal agglutination tests (rapid plasma reagin [RPR] or Venereal Disease Research Laboratory [VDRL]) are positive in untreated patients and can also be used as a test of cure since the quantitative titer declines after successful treatment. Nontreponemal tests become positive within two to four weeks after appearance of the primary lesion. (See 'Nontreponemal tests' above.)

●The approach to treatment of yaws is as follows (see 'General approach' above):

•For treatment of nonpregnant individuals with symptomatic yaws, we recommend either injectable penicillin G benzathine or oral azithromycin over other regimens or no treatment (Grade 1B). Penicillin has longest track record of efficacy but requires an injection; azithromycin may be administered orally, but some resistance has been described. (See 'Penicillin G benzathine' above and 'Azithromycin' above.)

•For treatment of pregnant or breastfeeding women with symptomatic yaws, we suggest treatment with injectable penicillin G benzathine (Grade 2C).

•For treatment of individuals with latent yaws, we suggest treatment with either oral azithromycin or injectable penicillin G benzathine over other regimens or no treatment (Grade 2C).

•For treatment of contacts of patients with yaws, we suggest treatment with either oral azithromycin or injectable penicillin G benzathine over other regimens or no treatment (Grade 2C).

●For treatment of individuals with bejel or pinta, we suggest injectable penicillin G benzathine over oral azithromycin (Grade 2C). For treatment of contacts of patients with bejel or pinta, we suggest treatment with injectable penicillin G benzathine over oral azithromycin or no treatment (Grade 2C). Contacts should receive empiric treatment. (See 'Treatment' above and 'Treatment' above.)

●Yaws and bejel lesions become noninfectious within 24 hours of treatment, and, in most cases, complete healing of the primary and secondary lesions is observed within two to four weeks. Skin lesions of pinta heal more slowly after treatment (within 6 to 12 months). Patients should undergo repeat nontreponemal testing at 6 and 12 months after treatment; in most cases, titers decline fourfold within less than one year. (See 'Follow up' above.)

●Yaws is a potentially eradicable disease since the diagnosis and treatment are relatively straightforward and it is not known to have a significant animal reservoir. The eradication approach consists of administering oral azithromycin to entire populations in endemic areas; injectable penicillin G benzathine may be used as an alternative agent. Most communities require more than one round of mass treatment to interrupt transmission, followed by repeat surveys at four weeks and every six month thereafter to detect and treat remaining cases and their contacts. (See 'Eradication' above.)

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Topic 87120 Version 26.0

References

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9 : Yaws in Malaysia.

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11 : ["Is a shot alone enough?": concepts of health, hygiene, and nutrition and the Program to Eradicate Yaws in Brazil, 1956-1961].

12 : Early yaws, imported in The Netherlands.

13 : Laboratory-confirmed case of yaws in a 10-year-old boy from the Republic of the Congo.

14 : [Bejel: an unusual cause of stomatitis in the child].

15 : Treponema pallidum 11qj Subtype May Correspond to a Treponema pallidum Subsp. Endemicum Strain.

16 : Local transmission of imported endemic syphilis, Canada, 2011.

17 : Bejel in Cuba: molecular identification of Treponema pallidum subsp. endemicum in patients diagnosed with venereal syphilis.

18 : Bejel, a Nonvenereal Treponematosis, among Men Who Have Sex with Men, Japan.

19 : Eradication of yaws--the Morges strategy.

20 : Yaws in the Western pacific region: a review of the literature.

21 : The prevalence of common skin infections in four districts in Timor-Leste: a cross sectional survey.

22 : Yaws in the periurban settlements of Port Moresby, Papua New Guinea.

23 : Yaws in the periurban settlements of Port Moresby, Papua New Guinea.

24 : [Campaign to eradicate yaws on Santo Island, Vanuatu in 2001].

25 : Resurgence of yaws in Tanna, Vanuatu: time for a new approach?

26 : Yaws in Polynesia's Wallis and Futuna Islands: a seroprevalence survey.

27 : Surveillance and control of resurgent yaws in the African region.

28 : Clinical outcome of skin yaws lesions after treatment with benzathinebenzylpenicillin in a pygmy population in Lobaye, Central African Republic.

29 : Prevalence study of yaws in the Democratic Republic of Congo using the lot quality assurance sampling method.

30 : [Yaws in Côte d'lvoire: health problem forgotten and neglected].

31 : [Resurgence of endemic yaws in Togo. Cause and eradication approach].

32 : Community participation eliminates yaws in Ecuador.

33 : Efficacy of a targeted, oral penicillin-based yaws control program among children living in rural South America.

34 : Global epidemiology of yaws: a systematic review.

35 : Eradication of yaws in India.

36 : The endemic treponematoses: not yet eradicated.

37 : [A clinical and serologic survey of bejel in north Burkina Faso].

38 : [Serological and clinical studies of endemic treponematosis in the Republic of Mali].

39 : [Serologic studies of non-venereal treponematoses in infants in Niamey, Niger].

40 : [Aspects of endemic syphilis among the Tuaregs of Niger].

41 : Endemic nonvenereal treponematosis (bejel) in Saudi Arabia.

42 : Endemic non-venereal syphilis (bejel) in Saudi Arabia.

43 : Bejel in Malatya, Turkey.

44 : A case of endemic syphilis, Iran.

45 : Endemic treponematoses

46 : The clinical appearance of pinta mimics secondary syphilis: another trap of treponematosis?

47 : [Immunology of tertiary pinta].

48 : Pinta, yaws, and venereal syphilis in Colombia.

49 : El carate o mal de pinto en la etnia Yaruro del estado Apure

50 : Nonvenereal treponematoses: yaws, endemic syphilis, and pinta.

51 : Specificity of antibodies from patients with pinta for antigens of Treponema pallidum subspecies pallidum.

52 : Extent and nature of the yaws problem in Africa.

53 : Endemic treponematosis (balash or bejel) in Saudi Arabia.

54 : Clinical aspects of bejel.

55 : An epidemiological study of pinta in Mexico

56 : Framboesia: History of its Introduction into India; with Personal Observations of over 200 Initial Lesions.

57 : Experimental Investigations on Framboesia Tropica (Yaws).

58 : Experimental Investigations on Framboesia Tropica (Yaws).

59 : Experimental Investigations on Framboesia Tropica (Yaws).

60 : MECHANICAL TRANSMISSION OF TRYPANOSOMIASIS, LEISHMANIASIS, AND YAWS THROUGH THE AGENCY OF NON-BITING HAEMATOPHAGOUS FLIES: (PRELIMINARY NOTE ON EXPERIMENTS).

61 : Outcome predictors in treatment of yaws.

62 : Syphilis as a Contagious Disease of Children

63 : La nocion del contagio y la idea del vector en el mal de pinto.

64 : Isolation of Treponema DNA from Necrophagous Flies in a Natural Ecosystem.

65 : Haemophilus ducreyi DNA is detectable on the skin of asymptomatic children, flies and fomites in villages of Papua New Guinea.

66 : Treponema pertenue under the electron microscope.

67 : Ultrastructural aspects of infection with Treponema pallidum subspecies pertenue (Pariaman strain).

68 : Electronmicrography of treponemas from cases of yaws, pinta, and the so-called Cuban form of pinta.

69 : The minimal infectious inoculum of Spirochaeta pallida (Nichols strain) and a consideration of its rate of multiplication in vivo.

70 : Global challenge of antibiotic-resistant Treponema pallidum.

71 : Long-Term In Vitro Culture of the Syphilis Spirochete Treponema pallidum subsp. pallidum.

72 : In vitro assay to demonstrate high-level erythromycin resistance of a clinical isolate of Treponema pallidum.

73 : Potential for development of antibiotic resistance in pathogenic treponemes.

74 : Efficacy of linezolid on Treponema pallidum, the syphilis agent: A preclinical study.

75 : Efficacy of linezolid on Treponema pallidum, the syphilis agent: A preclinical study.

76 : Clarithromycin therapy of experimental Treponema pallidum infections in hamsters.

77 : Time-dosage relation in penicillin therapy with special reference to yaws. I. Laboratory basis for effective therapy.

78 : Effect of ofloxacin on Treponema pallidum in incubating experimental syphilis.

79 : Re-emergence of yaws after single mass azithromycin treatment followed by targeted treatment: a longitudinal study.

80 : Macrolide resistance conferred by base substitutions in 23S rRNA.

81 : A point mutation associated with bacterial macrolide resistance is present in both 23S rRNA genes of an erythromycin-resistant Treponema pallidum clinical isolate.

82 : Macrolide treatment failure in a case of secondary syphilis: a novel A2059G mutation in the 23S rRNA gene of Treponema pallidum subsp. pallidum.

83 : Macrolide resistance in Treponema pallidum in the United States and Ireland.

84 : Antibiotic selection may contribute to increases in macrolide-resistant Treponema pallidum.

85 : Comparison of major protein antigens and protein profiles of Treponema pallidum and Treponema pertenue.

86 : Use of CB hamsters in the study of Treponema pertenue.

87 : Phagocytosis of Treponema pallidum pertenue by hamster macrophages on membrane filters.

88 : Phagocytosis of Treponema pallidum pertenue by hamster macrophages on membrane filters.

89 : Genetics of motility and chemotaxis of a fascinating group of bacteria: the spirochetes.

90 : Biological basis for syphilis.

91 : The effect of C3 depletion on resistance of hamsters to infection with the yaws spirochete.

92 : Mitogenic responses of hamsters infected with Treponema pertenue Lack of correlation with passive transfer of resistance.

93 : Characterization of lymphocyte responsiveness in early experimental syphilis. I. In vitro response to mitogens and Treponema pallidum antigens.

94 : Comparative investigation of the genomic regions involved in antigenic variation of the TprK antigen among treponemal species, subspecies, and strains.

95 : Passive transfer of resistance to frambesial infection in hamsters.

96 : Whole genome sequences of three Treponema pallidum ssp. pertenue strains: yaws and syphilis treponemes differ in less than 0.2% of the genome sequence.

97 : The flanking region sequences of the 15-kDa lipoprotein gene differentiate pathogenic treponemes.

98 : Sequence conservation of glycerophosphodiester phosphodiesterase among Treponema pallidum strains.

99 : Opsonic potential, protective capacity, and sequence conservation of the Treponema pallidum subspecies pallidum Tp92.

100 : Multiple alleles of Treponema pallidum repeat gene D in Treponema pallidum isolates.

101 : Molecular characterization and analysis of a gene encoding the acidic repeat protein (Arp) of Treponema pallidum.

102 : The sequence of the acidic repeat protein (arp) gene differentiates venereal from nonvenereal Treponema pallidum subspecies, and the gene has evolved under strong positive selection in the subspecies that causes syphilis.

103 : Whole genome sequence of Treponema pallidum ssp. pallidum, strain Mexico A, suggests recombination between yaws and syphilis strains.

104 : The localisation of treponemes and characterisation of the inflammatory infiltrate in skin biopsies from patients with primary or secondary syphilis, or early infectious yaws.

105 : Early yaws: a light microscopic study.

106 : Comparative studies on the histo-pathology of syphilis, yaws, and pinta.

107 : Ultrastructure of cells of Treponema pertenue obtained from experimentally infected hamsters.

108 : Ultrastructure of cells of Treponema pertenue obtained from experimentally infected hamsters.

109 : Ultrastructure of cells of Treponema pertenue obtained from experimentally infected hamsters.

110 : [Histopathological aspects of tertiary pinta].

111 : Yaws.

112 : Studies on a focus of yaws in the Santiago Basin, province of Esmeraldas, Ecuador.

113 : Challenges in recognition and diagnosis of yaws in children in Papua New Guinea.

114 : Leg ulcers caused by yaws and endemic syphilis.

115 : Yaws revisited.

116 : Osteoperiostitis in early yaws: case series and literature review.

117 : Neuro-ophthalmological study of late yaws and pinta. II. The Caracas project.

118 : Occurrence of congenital, cardiovascular, visceral, neurologic, and neuro-ophthalmologic complications in late yaws: a theme for future research.

119 : Ocular manifestations of endemic syphilis (bejel).

120 : Nervous manifestations of Bejel

121 : Cardiovascular disease as a cause of death in the Gold Coast African.

122 : Comparison of cardiolipin and treponemal tests in the serodiagnosis of yaws.

123 : The rapid plasma reagin (circle) card test in biological false positive and leprosy sera.

124 : Serological study of yaws in Java.

125 : Serological studies of yaws in Thailand.

126 : Treponema pallidum haemagglutination test for yaws. Comparison with the TPI and FTA-ABS tests.

127 : Evaluation of immunoglobulin G enzyme immunoassay for serodiagnosis of yaws.

128 : A multi-centre evaluation of nine rapid, point-of-care syphilis tests using archived sera.

129 : Are Treponema pallidum specific rapid and point-of-care tests for syphilis accurate enough for screening in resource limited settings? Evidence from a meta-analysis.

130 : Sensitivity and specificity of a rapid point-of-care test for active yaws: a comparative study.

131 : Evaluation of a rapid diagnostic test for yaws infection in a community surveillance setting.

132 : Metaanalysis of the Performance of a Combined Treponemal and Nontreponemal Rapid Diagnostic Test for Syphilis and Yaws.

133 : Failure of PCR to Detect Treponema pallidum ssp. pertenue DNA in Blood in Latent Yaws.

134 : Aureomycin in the treatment of yaws.

135 : Molecular differentiation of Treponema pallidum subspecies in skin ulceration clinically suspected as yaws in Vanuatu using real-time multiplex PCR and serological methods.

136 : Haemophilus ducreyi as a cause of skin ulcers in children from a yaws-endemic area of Papua New Guinea: a prospective cohort study.

137 : Streptococcus pyogenes Is Associated with Idiopathic Cutaneous Ulcers in Children on a Yaws-Endemic Island.

138 : Tertiary pinta: case reports and overview.

139 : El Carate en Venezuela: Estudio de la enfermedad en el medio natural y resultado de los ensayos de inoculacion experimental

140 : Time-dosage relation in penicillin therapy with special reference to yaws. II. Clinical basis for effective therapy.

141 : Failure of penicillin treatment of yaws on Karkar Island, Papua New Guinea.

142 : Single-dose azithromycin versus benzathine benzylpenicillin for treatment of yaws in children in Papua New Guinea: an open-label, non-inferiority, randomised trial.

143 : A Single Dose Oral Azithromycin versus Intramuscular Benzathine Penicillin for the Treatment of Yaws-A Randomized Non Inferiority Trial in Ghana.

144 : Effectiveness of single-dose azithromycin to treat latent yaws: a longitudinal comparative cohort study.

145 : Aureomycin in the treatment of yaws and tropical ulcer in Africa

146 : The modern treatment of frambesia (yaws)

147 : ORAL PROPIONYL ERYTHROMYCIN IN TREATING EARLY SYPHILIS.

148 : Treatment of yaws in the Haitian peasant.

149 : Serological study of yaws in Java.

150 : [Evolutive serological responses in patients with buba].

151 : [Evolutive serological responses in patients with buba].

152 : [Evolutive serological responses in patients with buba].

153 : Some important aspects of yaws eradication.

154 : Yaws eradication campaign in Nsukka Division, Eastern Nigeria.

155 : Mass treatment with single-dose azithromycin for yaws.

156 : Antibiotics for trachoma.

157 : A cross-sectional study of 'yaws' in districts of Ghana which have previously undertaken azithromycin mass drug administration for trachoma control.

158 : Prevalence of Active and Latent Yaws in the Solomon Islands 18 Months after Azithromycin Mass Drug Administration for Trachoma.

159 : Trial of Three Rounds of Mass Azithromycin Administration for Yaws Eradication.

160 : Integrated Control and Management of Neglected Tropical Skin Diseases.

161 : Integrated Control and Management of Neglected Tropical Skin Diseases.

162 : Safety of mass drug coadministration with ivermectin, diethylcarbamazine, albendazole, and azithromycin for the integrated treatment of neglected tropical diseases: a cluster randomized community trial.

163 : A cluster randomized study of the safety of integrated treatment of trachoma and lymphatic filariasis in children and adults in Sikasso, Mali.

164 : Late mutilating bejel in the nomadic Bedouins of Kuwait.

165 : Mutilating bejel.

166 : La lesion inicial del mal de Pinta

167 : [Not Available].

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