Treponema pallidum pertenue, Treponema pallidum endemicum and Treponema carateum (Yaws, Bejel, Pinta)
Authors: Oriol Mitjà MD, PhD
Microbiology
The endemic treponematoses include yaws (Treponema pallidum subsp. pertenue), bejel (T. pallidum subsp. endemicum), and pinta (T. carateum). Unlike syphilis, which is caused by the almost identical T. pallidum subsp. pallidum, the endemic treponematoses are not sexually transmitted. Treponemes are gram-negative spirochetes which cannot be cultured in vitro. They divide slowly (every 30 hours), have a characteristic corkscrew like motility, and can move through gel-like environments such as connective tissue. They are rapidly killed by drying, oxygen exposure or heating, and cannot survive outside the mammalian host (24). The four pathogenic treponemes are morphologically and serologically indistinguishable, and share at least 99% DNA sequence homology. Whole-genome sequencing has demonstrated that the genome of T. pallidum pertenue differs by only 0.2% from that of T. pallidum (7). The phylogenetic relationship between different sub-species of treponemes is not clear, as very few isolates of the non-venereal subspecies are available (Table 1).
Epidemiology
From a global perspective, the nonvenereal treponematoses constitute a significant cause of morbidity in many developing countries. In the 1950s and 1960s, mass screening and treatment campaigns designed to eradicate these diseases were led by the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF). The number of endemic treponematoses cases was reduced from an estimated 50 million in 1952 to 2.5 million in 1964 (3,5). Nonetheless, poverty, overcrowding, poor hygiene, lack of local surveillance, and absence of funding for ongoing control measures all contributed to a resurgence of endemic treponematoses, particularly yaws (11,35). The frequency and ease of international air travel may facilitate migration of infected persons into nonendemic geographic areas (12).
Yaws
Yaws is most commonly seen in children 5 to 15 years of age and it is transmitted by direct skin-to-skin contact with infectious lesions. Transmission may be facilitated by a breach in the skin of the recipient, such a scratch or insect bite. Yaws occurs primarily in rural settings in hot and humid environments. The disease is now thought to be endemic in at least twelve countries in West Africa, South-East Asia and the Pacific (27). There are a further 76 countries that previously reported yaws, throughout Africa, the Americas, Asia and the Pacific, for which adequate up to date surveillance data are not currently available. Most yaws cases are concentrated in just three countries: from 2008 – 2014 Ghana, Papua New Guinea and the Solomon Islands reported more than 15,000 cases annually each. In another eight countries transmission occurs in focal communities. Both India and Ecuador have reported eliminating yaws in recent years. Yaws goes under many local names, including frambesia tropica (German), pian (French), buba (Spanish), bouba (African dialects), and parangi and paru (Malay).
Bejel
Bejel predominantly occurs in children less than 15 years of age and it is acquired by direct skin-to-skin or mouth-to-mouth contact, and by indirect contact through contaminated drinking vessels and pipes. Bejel occurs primarily in dry, arid areas. It is seen in nomads in Saudi Arabia and in the immediate sub-Saharan region of Africa (Sahel) (8). Bejel was once common in Eastern Europe, but it is now extremely rare in this area (37). Bejel is known most commonly as endemic syphilis, but is also called njovera or dichuchwa in Africa and belesh, bishel, firjal and loath in the Middle East.
Pinta
Pinta is seen in early to late adulthood. Prolonged close personal contact is required for transmission and it is thought to occur frequently within families. Pinta occurs in hot humid rural areas. Data on the prevalence of pinta are limited and there is the perception that the disease had sustained decline over the past century. Pinta might remain endemic in Central and South America and Mexico. Countries with historically high prevalence include Columbia, Peru, Ecuador, Venezuela, and Brazil (18). Occurrence of pinta outside the Americas is controversial. The word pinta means "spot" or "mark" in Spanish; synonyms for this disease include carate, cute, enfermedad azul (18). In the Central American countries of Nicaragua and Guatemala, afflicted individuals are called morados, which means "the blue ones".
Clinical Manifestations
Like syphilis, these diseases undergo sequential clinical stages following inoculation.
Yaws
Yaws is a chronic disease of the skin and bone (Figure 1).
Primary Lesions: After 9 to 90 days, the initial lesion (‘mother yaw’) manifests as one or more non tender papules. The initial papule increases in diameter (3-5 cm) to become a large nodule that can ulcerate. Nodules and ulcers have a characteristic granular surface and often exude a yellow discharge that may dry to form a crust. The primary lesion is most commonly found on the legs and ankles (65 to 85% of cases), but may be on the buttocks, arms, hands, and face. It usually heals after 3–6 months, regressing into a pitted scar with dark margins.
Secondary Lesions: Secondary lesions, which are the result of lymphatic and haematogenous spread of organisms, appear from a few weeks to 2 years after the primary lesion. Secondary skin lesions consist of multiple smaller excrescences, often resembling the initial papule. A generalized eruption may cover a region of the body or the whole body. Hyperkeratotic plaques may form on the palms and soles, and be responsible for a characteristic ‘crablike’ gait. Early osteoperiostitis of the proximal phalanges of the fingers (dactylitis) or of long bones (i.e. forearm, tibia or fibula) may result in nocturnal bone pain and swelling (24).
Tertiary Lesions: Following resolution of the secondary lesions, latency begins with only serologic evidence of the infection remaining. In less than 10% of patients, late destructive lesions of skin, bone, and cartilage develop (4). Neurologic and ophthalmologic complications may occur but appear to be rare (18).
Bejel
Bejel is a chronic debilitating disease and is characterized by an early secondary stage of disease, variable period of latency and late destructive lesions.
Primary Lesions: Primary lesions are rare, and if present often go undetected as a small papule or erosion on the oropharyngeal mucosa.
Secondary Lesions: Widespread oropharyngeal erosions similar to the "mucous patches" of secondary syphilis soon develop. It may be accompanied by a disseminated papulosquamous skin eruption. Generalized lymphadenopathy and periostitis (especially of the long bones of the leg) may occur.
Tertiary Lesions: Late bejel is characterized by painful osseous lesions; ulcerations of the soft palate, larynx, and nasopharynx; and destructive lesions of the nose and nasal septum. Ocular complications, especially uveitis, are possible in late bejel (34).
Pinta
Pinta is unique among the nonvenereal treponematoses in having only skin lesions.
Primary Lesions: Primary lesions manifest as coalescing scaly papules and plaques that expand to more than 10 cm but do not ulcerate.
Secondary Lesions: Secondary lesions occur 3-12 months after the initial lesions. The lesions appears as a small scaly papule and occur in the same sites as the primary lesions. These secondary lesions and occasionally the primary lesions develop variable dyschromia: slate- blue, violaceous, brown, gray, or black. Ultimately, pinta may manifest as complete achromia, resembling vitiligo. Cutaneous atrophy, characterized by wrinkling of the skin, may also be seen (4).
Laboratory Diagnosis
Yaws, Bejel and Pinta are diagnosed presumptively from the typical clinical presentation of patients living in known endemic areas. Laboratory tests are required to confirm them as a treponemal disease and include darkfield examination of early lesions, serological tests and PCR tests. Treponema can be demonstrated in exudates from early lesions by darkfield examination, and they can also be found in biopsy specimens processed with silver or immunoperoxidase stains. Yaws, Bejel and Pinta elicit the same positive serologic tests (e.g., RPR, VDRL, FTA-abs, MHA- TP) as syphilis. A combined point-of-care test – the Dual Path Platform (DPP) syphilis assay - which detects both treponemal and nontreponemal antibodies has been evaluated for the diagnosis of yaws and has shown high accuracy (6). PCR tests that have been commonly adopted for the diagnosis of venereal syphilis are equally efficacious in detecting T. pallidum pertenue DNA in lesional swabs. Sequencing of genetic signatures specific for each of the agents of human treponematoses can be used to distinguish between subspecies of T. pallidum, but this is only available at research laboratories (12,28).
Pathogenesis
The clinical manifestations of infection results from the immune response of the host to the bacteria. The treponemes elicit cellular proliferation and a plasma cell, lymphocyte and macrophage infiltration. Their favorite location is in the intercellular spaces of the epidermis. In yaws the blood vessels show limited or no endothelial proliferation, while this is common in bejel. T. pallidum pertenue and T. pallidum endemicun damage the skin and bone, while T. carateum affects only the superficial layers of the skin with loss of melanin and liquefaction degeneration. The late lesions of yaws and bejel are attributed to a hypersensitivity induced mechanism similar to that postulated for the syphilitic gumma.
SUSCEPTIBILITY IN VITRO AND IN VIVO
There is scant in vitro susceptibility laboratory data for the nonvenereal treponematoses because treponemes cannot be cultured. Assays to examine the in vitro susceptibility of T. pallidum subspecies to antimicrobial agents are all laborious and technically challenging.
The most reliable method of assessing in vitro sensitivity consists of measuring active protein synthesis via quantitative incorporation of radiolabeled 35S-methionine while freshly isolated treponemes are incubated with and without test antibiotics (32). Using this methodology, T. pallidum pertenue was found to be sensitive to penicillin, chloramphenicol, tetracycline, and erythromycin at concentrations achievable in the serum of patients receiving the drug according to recommended regimens. The same in vitro system demonstrated insensitivity to streptomycin (up to 500 ug/mL and to rifampin (up to 100 ug/mL) (Table 2) (33).
Laboratory in vivo studies with animal models have been consistent with the in vitro susceptibility findings. Tests on experimentally infected animals and infected patients showed that benzylpenicillin levels >0.03 units/mL of serum maintained for at least 7 days were treponemicidal (9). These levels can be achieved either by giving repeated doses of short-acting benzylpenicillin preparations (ie, aqueous benzylpenicillin) or a single intramuscular injection of slowly absorbed, repository benzylpenicillin preparations such as benzathine penicillin. Clarithromycin was shown to be curative in T. p. pertenue infections in animal models with concentrations of the drug in serum similar to those achieved in humans (Table 3) (1). Other macrolides, including roxithromycin and azithromycin were effective against T. pallidum strains (21,22).
ANTIMICROBIAL THERAPY
Drugs of choice
The efficacy of injectable benzathine penicillin (1.2 million units) and oral azithromycin (30mg/Kg) is comparable for treatment of yaws; azithromycin preferred because of the ease of administration (Table 4).
Long acting Penicillin has been the drug of choice for yaws, pinta and bejel for over 50 years. This is based upon clinical trials done many decades ago and often using formulations no longer in use or no longer recommended (penicillin in oil and beeswax; procaine penicillin in oil with aluminum monostearate). Procaine penicillin achieved an 83 to 100% clinical cure for pinta treated in Mexico (17) and over 97% clinical cure rate for yaws treated in Haiti (15).
The WHO recommend regimen consist of benzathine penicillin 1.2 million units for adults and 0.6 million units for children under 10 years of age; the dosing being lower that for syphilis. Benzathine penicillin achieved cure rates of 86 to 100% when used to treat yaws in Thailand (13). Similar cure rates were seen with dosages of 1.2 million units and with 2.4 million units for adults in Haiti (29). Disadvantages of using benzathine penicillin however, include the need for a cold chain, needles and syringes, and trained personnel.
A single oral dose of azithromycin (30mg/Kg, maximum dose 2g) is as effective as benzathine penicillin for treatment of yaws. In a randomized trial conducted in Papua New Guinea clinical and serological cure rates of children treated with azithromycin were 96% (25). Efficacy of azithromycin was 91% for patients with primary stage lesions, and 100% for patients with secondary stage disease, including polyarhralgia or bone pain and swelling (25). Similar findings on efficacy were reported among 500 patients with primary yaws in Ghana. A single 2g dose azithromycin is generally well tolerated; the most commonly observed adverse events in 10-15% of cases are related to the gastrointestinal tract and these are all transient and short lived. Given the similarity in the pathophysiology between yaws and the other endemic treponematoses, azithromycin may also be used for treatment of bejel and pinta.
Alternative therapy
For patients over the age of 8 who are allergic to drugs of choice, oral tetracycline (500mg q6h) or doxycycline (100mg q12h) for 15 days is considered the best substitute. This is based upon small series of yaws patients treated with tetracycline derivatives (aureomycin, terramycin, or oxytetracycline) in Africa (2), Haiti (19,20), and Jamaica (14). These studies, done some 40 years ago and not replicated recently, demonstrated cure rates from 83 to 100%. Tetracyclines are not recommended for pregnant and breastfeeding women and for children under the age of 8 years because of their association with dental staining.
Oral erythromycin (8-10 mg/kg, q6h for 15 days) (31) had been used as an alternative for penicillin allergic children under 8 years, and pregnant women. However, now azithromycin is the preferred macrolide antibiotic for yaws because of the very much improved profile.
Oral penicillin V is rarely used due to inadequate levels in blood, despite one report describing the successful clinical use of oral phenoxymethylpenicillin for 7–10 days (12.5 mg/kg q6h; maximum dose 300 mg q6h) given to children < 14 years with active yaws lesions in rural Guyana (30). Regimens requiring the administration of multiple oral doses over a number of days raise, however, concerns with patient compliance.
Ceftriaxone, a broad-spectrum cephalosporin with a long half-life in serum (7 h), has demonstrated activity against T. pallidum pallidum in a rabbit model (16). The long half-life allows for daily dosing and has been used by some experts as an alternative to penicillin for the treatment of syphilis. However, clinical data for its use to treat yaws are lacking.
ADJUNCTIVE THERAPY
A simple dry dressing is useful for keeping ulcerated lesions clean and protected from trauma. Pain control with non-opioid analgesics (eg, acetaminophen) is usually sufficient for managing mild discomfort related to arthralgias, osteoperiostitis, or palmoplantar keratoses. In general arthralgias and bone pain usually improve within 24 to 72 hours after the start of antibiotic treatment; some patients with more severe pain may require a more aggressive regimen of pain medication.
ENDPOINTS FOR MONITORING THERAPY
Treatment failure, either based on clinical or serological findings, is generally considered to be an indication of re-treatment.
Efficacy of therapy is determined by healing of active skin lesions, healing of mucocutaneous erosions, and relief of bone/joint pain. The depigmented skin seen in late pinta usually does not revert to normal skin color (10). An early stage yaws or bejel lesion that has not healed within four weeks is considered a treatment failure and patients should be switched to an alternative regimen.
Nontreponemal test titers (RPR, VDRL) usually reverts to nonreactive after treatment. However, the longer the patient remains untreated, the more slowly will conversion to seronegativity occur. Treponemal tests (MHA-TP and FTA-abs) remain reactive for life after adequate therapy. Serological treatment failure is defined as >4-fold increase in the RPR titer, titer persistently >1:64, or <4-fold decrease in titer over 12 months. Patients who do not have an appropriate decline in serological titer should be managed with another course of treatment.
VACCINES
Currently there are no vaccines available for the nonvenereal treponematoses.
PREVENTION
Yaws is a potentially eradicable disease since the diagnosis and treatment are relatively straightforward and there is no significant animal reservoir; it was the first disease slated for global eradication by the World Health Organization (WHO) in 1948. The WHO has set a target of 2020 global eradication of yaws. Eradication of yaws will be declared when no cases have been reported over three successive years (35).
The emergence of azithromycin as an effective, single dose oral agent for the treatment of yaws has led to renewed interest in the disease. In 2012 the WHO outlined a new strategy (the Morges strategy) for yaws eradication (Table 5). This strategy is based on community mass treatment with single-dose oral azithromycin, with subsequent clinical case detection to direct further rounds of mass or targeted treatment with azithromycin. The efficacy of this approach was demonstrated in a study of mass treatment performed in rural villages on Lihir Island, Papua New Guinea (26). One year after mass treatment the prevalence of active yaws decreased from 2.4 to 0.3 percent and no evidence of macrolide resistance was observed.
Health education and improvement of social conditions can contribute to halting the spread of the treponematoses. Supportive measures for the eradication of yaws include strengthening access to primary health care, training clinicians to detect and treat patients, general health education, improvement in the standard of living and in personal hygiene, and providing soap, water, and clothing to children.
CONTROVERSIES, CAVEATS OR COMMENTS
Monitoring for treatment failure and resistance to azithromycin is important because there is biological evidence that antibiotic pressure can select for resistant strains in T. pallidum subspecies (23). Macrolide resistance in T. pallidum is associated with alteration of the target site due to a single step mutation of the 23S ribosomal RNA gene. A real-time PCR assay for detection of the above mentioned mutations has been developed that would enable molecular surveillance for rapid identification of macrolide-resistance in T. pallidum pertenue.
Other challenges for eradication will be represented by: 1) incomplete information of the geographic scope of the disease due to inadequate surveillance, 2) the necessity to screen and treat populations difficult to reach, 3) and the possibility that animal reservoirs for human treponemal pathogens may exist.
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Tables
Table 1. Comparative Features of Nonvenereal Treponematoses
| Causative agent | Yaws (T p pertenue) |
Bejel (T p endemicum) |
Pinta (T carateum) |
Syphilis (T p pallidum) |
|---|---|---|---|---|
| Geographical distribution (climate) | Western/Central Africa, Southeast Asia, Pacific Islands (Tropical) |
Deserts of Africa and Saudi Arabia (Hot and dry areas) | Central and South America (Warm, semiarid) |
Worldwide |
| Age group (peak incidence) | Children (5-15) | Children (2-10) | Adults (15-50) | Adults (18-30) |
| Transmission | Skin-to-skin contact | Mouth-to-mouth or Utensils | Skin-to-skin contact | Sexual and Congenital |
| Initial lesion (frequency) | Common | Rare | Common | Common |
| Initial lesion (location) | Lower extremities | Oral mucosa (rarely seen) | Extremities | Genitalia, anal, and oral mucosae |
| Dissemination | Widespread to skin and bone | Limited to intertriginous areas and facial bone | Limited to skin | Widespread and Systemic |
| Late complications without treatment | Destructive lesions of skin and bones (10%) | Destruction of nose/palate | Local skin hypo- acromia | Ulcers (10%), Neurological (10%), Cardiovascular (10-15%) |
| Animal models | Rabbit=hamster | Rabbit=hamster | Primate only | Rabbit>primate> guinea pig>hamster |
| Genome size (kbp) | 1,1139.3 – 1,139.7 | 1,137.7 | ND | 1,138.0 - 1,140.0 |
| Genomic identity with T. pallidum subsp. pallidum (%) | 99.8 | 99.7 | ND | NA |
Table 2. In vitro assay results for drug susceptibility)
Antibiotic and conc. (ug/ml) |
Inhibition of protein synthesis | ||
|---|---|---|---|
| T. pallidum pallidum Nichols strain (%) | T. pallidum pertenue Gauthier strain (%) | ||
| Chloramphenicol | |||
20 |
92.5 |
86.4 |
|
200 |
93.3 |
94.6 |
|
| Tetracycline | |||
4 |
86.9 |
88.8 |
|
40 |
94.5 |
96.3 |
|
| Erythromycin | |||
10 |
86.8 |
83.7 |
|
100 |
89.5 |
86.5 |
|
| Streptomycin | |||
50 |
32.6 |
6.7 |
|
500 |
60.9 |
42.4 |
|
| Rifampicin | |||
10 |
24.8 |
0 |
|
100 |
41.5 |
0.2 |
|
| Penicillin G | |||
0.03 |
51.7 |
29.8 |
|
0.3 |
64.6 |
Not tested |
|
* Extracted from Stamm LV et al, AAC 1988 (33)
Table 3. Burden of T. pallidum pertenue in lymph node tissue on hamsters treated with antibiotics
| Treatment | Dose (per Kg) | Schedule (days) | No. of organisms/lymphnode (105) |
|---|---|---|---|
| Penicillin | 250U | QD x 1 day | 13.5 |
| 2500U | QD x 1 day | 0.8 | |
| 25000U | QD x 1 day | 0.0 | |
| Clarithromycin | 2.5mg | QD x 7days | 0.5 |
| 12.5mg | QD x 7days | 0.0 | |
| 25.0mg | QD x 7days | 0.0 | |
| None | NA | NA | 23.3 |
Table 4. First and second-line drugs, dosage and duration
| Treament | Dosage | Route; duration |
|---|---|---|
| First-line | ||
Azithromycin |
30 mg/kg (maximum dose 2 g) | Oral; single dose |
Benzathine-penicillin |
1.2 million units (adult); 0.6 million unit (children <10 years) | Intramuscular; single dose |
| Second-line | ||
Tetracyclines |
500 mg q6h (adults only) | Oral; 15 days |
Doxycycline |
100 mg q12h (adults only) | Oral; 15 days |
Erythromycin |
8-10 mg/kg q6h | Oral; 15 days |
Phenoxy-methylpenicillin |
7–10 days; 12.5 mg/kg q6h (maximum dose 300 mg q6h) | Oral; 7–10 days; |
Table 5. New WHO Yaws eradication strategy and treatment policies for Yaws based on azithromycin (2012)
| Component | >Recommendations | >|
|---|---|---|
| Initial assessment | >In areas with limited information on yaws:
|
|
| Treatment policies | >First round: | >Total community treatment (TCT): Initially treat the entire endemic village or community (recommended treatment coverage of 100%) | >
| Resurveys and retreatment | >3-6 monthly until clinical 0 case prevalence:
|
|
| Strengthening health and community systems | >
|
|
| Post-zero case surveillance | >
|
|
Figure 1. Yaws primary lesions, ulcer (left) and papilloma (right)
Credit. Oriol Mitja and Kingsley Asiedu
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