Treponematosis, also known as treponemiasis, traditionally refers to the group of nonvenereal diseases (including endemic syphilis [nonvenereal syphilis]) caused by Treponema species that are morphologically and serologically identical to each other and to Treponema pallidum subspecies pallidum, the cause of venereal syphilis. DNA from T pallidum subspecies pallidum is at least 99% homologous to that of T pallidum subspecies pertenue and T pallidum subspecies endemicum.[1] However, they differ in terms of clinical manifestations.
Treponema species typically associated with nonvenereal disease are transmitted among children living in tropical, subtropical, or warm arid climates, chiefly by direct contact. In humans, the pathogenic treponemes include T pallidum pallidum (syphilis), Treponema pallidum pertenue (yaws), Treponema pallidum endemicum (bejel or endemic syphilis), and Treponema carateum (pinta).[2, 3] Recently, T pallidum endemicum (bejel) has been found in men who have sex with men in Japan, although transmission is believed to occur nonsexually.[4]
Transmission of yaws and bejel typically occurs in children. Transmission typically occurs via direct skin-to-skin contact of lesions, which are infectious. Bejel is also transmitted skin to skin but can also be transmitted mouth to mouth and on fomites (eg, via shared eating utensils or cups). Pinta is also transmitted by skin-to-skin contact and is more common in older children or teenagers.
Treponemes usually invade traumatized cutaneous or mucosal surfaces that come in contact with a draining open sore of the index case. A primary cutaneous lesion appears at the site of inoculation following an incubation period of a few weeks. Treponema may be spread from this site either topically (by scratching) or hematogenously. These lesions often heal spontaneously. Treponematosis can remain latent or it may recur.
The secondary stage of any of these diseases follows the dissemination of the treponemes. It may begin while the primary lesion is still present or after a variable latent period. It may also resolve spontaneously, recur, or persist. The long-term effects of these infections include multiple cutaneous lesions and destruction of bones or cartilage.
Although treponematosis does not occur in the United States, imported cases have been documented. It may be found in children immigrating from areas of endemicity, and the US Centers for Disease Control and Prevention (CDC) has recommended screening of all refugee children from endemic regions with a nontreponemal test at initial health screening.[5]
International
In 1997, the World Health Organization (WHO) estimated that 460,000 new cases of endemic treponematosis occurred worldwide. Currently, more than 2.5 million people may be infected. Currently, it is difficult to estimate disease burden owing to sporadic reporting and lack of data, which are reviewed in Global Health Observatory (GHO) data.[6]
Endemic syphilis (bejel) (T pallidum endemicum) is typically spread among children, most commonly in the Middle East and the southern regions of the Sahara Desert. In Europe, cases have been diagnosed in children who have moved from endemic areas. In one study, 12% of children younger than 5 years in Niger were seropositive.[7] High rates of seropositivity are also observed in Mali, Burkina Faso, and Senegal. Pinta (T carateum), which occurs in the Caribbean and in Central and South America, is more common in young adults.
Yaws (T pallidum pertenue) occurs mainly in equatorial regions and can be found in South America, Central America, the Caribbean, Africa, and Southeast Asia. It is associated with high humidity and rainfall. Fifty years ago, the WHO recognized that endemic treponematoses—yaws in particular—were a major cause of disfigurement and disability and a significant economic burden in poor countries.
In Haiti and the Dominican Republic, a pilot project was initiated to eradicate the disease with mass applications of penicillin. This project was so successful that it was extended to 46 other countries. Overall, the incidence of yaws was reduced to isolated foci of endemicity. As public health priorities changed and support for the eradication programs lapsed, the disease saw a resurgence in the 1970s and 1980s. The introduction of mass treatment has been necessary in some areas. In a WHO survey in 2012,[8] the status of yaws was unknown in many of the countries where it had previously been known to be endemic.
Now that an oral treatment has been recommended for first-line therapy, a new eradication campaign is underway by the WHO.[9]
Mortality/Morbidity
Untreated treponematosis may cause disfiguring cutaneous lesions and deformities of bone, cartilage (particularly the nose), and skin, potentially leading to significant disfigurement, pain, and disability. Affected children can become socially ostracized and often miss school. Thickening and cracking of the soles may make walking difficult. Treponematosis can extract a significant economic toll on already-disadvantaged populations. Fortunately, with penicillin or azithromycin therapy, cure rates of 95-97% are possible.
Race
Treponematosis has no reported racial predilection in terms of frequency or severity.
Sex
Treponematosis has no reported sexual predilection in terms of frequency or severity.
Age
Although individuals of any age can acquire treponematosis, endemic syphilis and yaws are more common in children younger than 10 years, whereas pinta is more common in young adults. Yaws most often infects children and peaks in those aged 2-10 years. Of new cases, 75% arise in children younger than 15 years. Congenital infections with the endemic treponemes are unusual because most primary infections occur in children. Primary treponematosis during pregnancy is rare.
For excellent patient education resources, visit eMedicineHealth's Sexual Health Center. Also, see eMedicineHealth's patient education article Syphilis.
The primary lesions are painless, white, mucinous ulcers within the oral cavity, where they may be overlooked.
Secondary lesions may be in the mouth or widely disseminated. The secondary lesions may be papules, macules, or various other rashes.
The organism may infect the periosteal space, which leads to bone deformities.
Late in the disease course, a condition known as gangosa (destruction of nasopharyngeal cartilage) may occur.
Ocular manifestations include uveitis, optic atrophy, and chorioretinitis.[10]
Pinta (T carateum)
Pinta, which occurs in the Caribbean and Central and South America, is more common in young adults. It is favored by an arid rather than humid climate. Over the past 2 decades, the incidence of pinta has been reduced to only several hundred reported cases annually.
The primary lesions appear 1-3 weeks after inoculation as slowly enlarging copper-colored papules, which may become hyperkeratotic and blue. Smaller satellite lesions may be observed and may coalesce with the larger ones. The lymph draining this area may be swollen. Lesions may persist for years and may heal, leaving hypopigmentation.
Secondary lesions may develop within 3-12 months as small papules, which are often located at the site of primary lesions. The lesions may be numerous and are called pintids. They are initially red but can become pigmented and appear blue over time. Lesions may later become depigmented to varying degrees, leading to a mottled appearance. Later manifestations are limited to cutaneous involvement. The deeper tissues or viscera are not involved.
Yaws (T pallidum pertenue)
The primary lesion occurs 2 weeks to 6 months after inoculation. It begins as a papule that typically becomes a large papilloma. This may persist for several months and then may resolve spontaneously, often with scarring. During this stage, the treponeme may disseminate via the bloodstream or the lymphatics or topically through excoriation by the individual.
Secondary disease can involve multiple cutaneous lesions, including macules, papules, nodules, hyperkeratoses, and ulcerations. Lymphadenitis with swollen and tender lymph nodes may occur proximal to lesions. Periosteal infection and destruction of cartilage occur later in the course of the disease. See the image below.
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Nigerian boy with ulcerative skin lesions characteristic of yaws. Courtesy of the CDC/Dr. Lyle Conrad.
The initial lesions characteristically resolve spontaneously by 6 months but then recur after a latent period. Relapses often occur for up to 5 years, after which they diminish in severity and frequency.
Approximately 10 -40% of patients with untreated yaws develop late disease, including periosteal lesions that damage bone.
Deformities are also observed, including saber shins caused by chronic periosteal infection of the tibia and gangosa, as well as destruction of the cartilage in the nose.
Other late-stage manifestations include hyperkeratoses of the palms and soles, which may fissure, predisposing to painful secondary bacterial infections, and gummas of the skull, sternum tibia, and other bones.[11]
Direct contact with lesions, or in the case of endemic syphilis, fomites, spreads treponematoses.
Endemic syphilis (bejel) (T pallidum endemicum): The organism can be indirectly transmitted onto objects and by direct contact with lesions. Much of the transmission is thought to be from mouth-to-mouth contact or from shared eating utensils or drinking cups.
Yaws is transmitted by direct exposure to skin lesions that shed the treponemes.
Treponematosis should be suspected in persons with appropriate clinical findings (eg, chronic skin or bone lesions) who live in or are from endemic areas. As with other treponeme diseases, confirmation of the diagnosis depends on dark-field examination, if available, or serologic testing. The epidemiologic setting is vital because the nonvenereal treponemes cannot be distinguished from T pallidum pallidum (the cause of venereal syphilis) with laboratory studies.
Tests for endemic treponematosis are the same as for syphilis. Because treponemes cannot be easily and readily cultured, use other laboratory methods of identifying infection. The current tests for syphilis fall into the following 3 categories: direct microscopic identification when lesions are present, nontreponemal tests used for screening, and treponemal tests used for confirmation.
Direct microscopy
Direct microscopic identification of treponemes from lesion fluids by either dark-field microscopy or direct fluorescent antibody should be the initial step in diagnosing a treponemal infection. This is most helpful during the primary stage of infection because treponemal antibodies do not usually appear until 1-4 weeks after the lesion has formed. See the image below.
View Image
Photomicrograph (540X) of Treponema carateum obtained from an early pinta lesion. Courtesy of the CDC.
A negative dark-field finding does not exclude the diagnosis of treponematosis because the organisms may be too few if the lesion is in the healing stage or if the infection has been altered by treatment.
Nontreponemal tests
These include the nontreponemal rapid plasma reagin (RPR) test and the Venereal Disease Research Laboratory (VDRL) test. These tests usually become positive within 2-4 weeks of the appearance of the primary lesion. They can be used as tests of cure because they usually become negative after treatment.
RPR is inexpensive and rapid and is convenient for screening large numbers of sera specimens.
The standard nontreponemal test is the VDRL slide test, in which serum is tested for its ability to flocculate a suspension of cardiolipin-cholesterol-lecithin antigen. This test is based on the observation that antibodies elicited against treponemal surface antigens cross-react with cardiolipin.
Treponemal tests
The confirmatory treponemal tests are the fluorescent treponemal antibody absorption (FTA-ABS) test, T pallidum hemagglutination assay (TPHA), and T pallidum particle agglutination assay (TPPA). These tests use T pallidum organisms as the antigen. The patient's serum is first absorbed to remove any naturally occurring cross-reacting antibody; it is then reacted with the organism.
Because of the nonstandardized, qualitative, and subjective nature of these tests, their principal use is to confirm any positive VDRL or RPR test result.
Other tests
New rapid point-of-care tests are currently being evaluated.
Currently, none of the available tests can reliably distinguish between the organisms that cause syphilis from other endemic treponematoses.
Imaging studies are generally not used in the diagnosis or treatment of endemic treponematosis, although changes to bone periosteum and cartilage may be observed on radiography in late-stage yaws or endemic syphilis.
Dark-field microscopy of material from cutaneous lesions often yields treponemes. However, this technique may not be available in endemic areas, and pathologic diagnosis is not considered necessary. In yaws and pinta, granulomatous inflammation resembles that of syphilis. Endarteritis is a feature of late yaws lesions.
Treatment of treponematosis is based on single-dose antibiotic therapy with benzathine penicillin or azithromycin.
Treponemes are highly sensitive to azithromycin and penicillin, which are the drugs of choice.
The WHO revised policies for treating yaws in 2012. One oral dose of azithromycin (30 mg/kg, not to exceed 2 g) is now recommended as equivalent to benzathine benzylpenicillin. Because of the ease of administration and low cost, it is now considered the drug of first choice.[12]
Yaws, pinta, and endemic syphilis may also be treated with benzathine penicillin G. Children younger than 10 years should receive 600,000 U intramuscularly, and children older than 10 years should receive 1.2 million U intramuscularly.
Alternatives are appropriate only if azithromycin or benzathine penicillins cannot be used. Tetracycline (25 mg/kg/d for 10-14 d) and chloramphenicol (25 mg/kg/d for 10-14 d) have been used successfully, as has a 10-day course of doxycycline. Other penicillins, cephalosporins, and macrolides are probably active against the treponemes; however, quinolones, aminoglycosides, and sulfa antibiotics are ineffective.
Treatment failures with penicillin have been reported,[13] but reinfection could not be ruled out.
Other important measures from the perspective of the individual patient and for public health include avoiding contact with others with cutaneous lesions and careful follow-up care to identify and to re-treat initial treatment failures.
With antibiotic treatment, the primary and secondary lesions usually resolve. Bone involvement can be a late complication of untreated yaws. Rarely, it can cause malformation of the long bones (eg, tibia), subcutaneous nodules, and ulcers in the palate and nose.
In 2012, the WHO developed a strategy for eradicating yaws, involving treatment of all eligible at-risk members of the community with one dose of oral azithromycin. Intramuscular penicillin G is substituted in patients in whom azithromycin is contraindicated. Active surveillance at 6-month intervals was then performed, especially in children, who represent the major reservoir of active infection. In one area of the community, the prevalence of yaws decreased from 2.4% before therapy to 0.3% a year after.[14] This approach is being scaled up in many affected areas.
By extrapolation from the treatment of syphilis, follow-up testing with a nontreponemal test, usually RPR, can be performed 6 and 12 months posttreatment and should show a 4-fold decrease in titer levels by 12 months in most patients.
Conscientious follow-up care to detect treatment failures and reinfection is recommended. Treatment failures or reinfections should be treated again. If azithromycin was initially used, penicillin should be considered.[15] Resistance to penicillin is considered unlikely, but resistance to azithromycin in syphilis has been described.
Clinical Context:
Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected.
Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. This drug is used to treat mild-to-moderate microbial infections.
Clinical Context:
Interferes with synthesis of cell wall mucopeptides during active multiplication, which results in bactericidal activity. Combination of 1 M penicillin and 2 M ammonium base. Repository form providing tissue depot from which the drug is absorbed over days. Must be administered IM and provides detectable serum levels for 15-30 d.
Clinical Context:
Treats gram-positive and gram-negative organisms as well as mycoplasmal, chlamydial, and rickettsial infections. Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s).
Clinical Context:
Binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gram-negative and gram-positive bacteria. Well-absorbed from GI tract and metabolized in the liver, where it is inactivated by conjugation with glucuronic acid and then excreted by the kidneys.
Treponemes are highly sensitive to azithromycin and penicillin, which remain the drugs of choice. Yaws, pinta, and endemic syphilis are treated with azithromycin or penicillin G benzathine. Alternatives are appropriate only if penicillin cannot be used. Tetracyclines or chloramphenicol have been used. Treatment failures with penicillin have been reported, but reinfection could not be ruled out.
Steven M Fine, MD, PhD, Associate Professor, Department of Internal Medicine, Division of Infectious Diseases, University of Rochester School of Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Lynn S Fine, PhD, MPH, Manager of Clinical Microbiology Laboratory, ACM Medical Laboratories; Adjunct Professor, Department of Biology, St John Fisher College and Nazareth College
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance
Disclosure: Nothing to disclose.
Chief Editor
John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance
Disclosure: Nothing to disclose.
Additional Contributors
Jeffrey M Zaks, MD, Clinical Associate Professor of Medicine, Wayne State University School of Medicine; Vice President, Medical Affairs, Chief Medical Officer, Department of Internal Medicine, Providence Hospital
Centers for Disease Control and Prevention. Notice to readers: Recommendations regarding screening of refugee children for treponemal infection. MMWR Morb Mortal Wkly Rep. 2005. 54(37):933-4.
Global Health Observatory Data (Endemic treponematoses). World Health Organization. Available at https://www.who.int/gho/neglected_diseases/treponematoses/en/. October 16, 2019;
World Health Organization. Yaws, Fact sheet no. 316, Updated February 2014. World Health Organization. Available at http://www.who.int/mediacentre/factsheets/fs316/en/. Accessed: June 4, 2014.
Ahmed SS and Winslow DL. Endemic Treponematoses. J. Bennett, R. Dolin, M. Blaser. Principles and Practice of Infectious Diseases. 9th. Philadelphia, PA: Elsevier; 2019. 2: 2893-2897.
Oriol Mitjà, Kingsley Asiedu, David Mabey. Published OnlineSeminar. Yaws February 13, 2013http://dx.doi.org/10.1016/S0140-6736(12)62130-8.
Perine PL, Hopkins DR, Niemel PLA. Handbook of Endemic Treponematoses: Yaws, Endemic Syphilis, and Pinta. WHO Publications Centre, USA: World Health Organization; 1984.
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