John LN, Beiras CG, Houinei W, Medappa M, Sabok M, Kolmau R, et al. Trial of Three Rounds of Mass Azithromycin Administration for Yaws Eradication. New England Journal of Medicine. 2022;386(1):47--56. [ DOI | ePrint ]

Treponema pallidum subspecies pertenue causes yaws. Strategies to better control, eliminate, and eradicate yaws are needed. In an open-label, cluster-randomized, community-based trial conducted in a yaws-endemic area of Papua New Guinea, we randomly assigned 38 wards (i.e., clusters) to receive one round of mass administration of azithromycin followed by two rounds of target treatment of active cases (control group) or three rounds of mass administration of azithromycin (experimental group); round 1 was administered at baseline, round 2 at 6 months, and round 3 at 12 months. The coprimary end points were the prevalence of active cases of yaws, confirmed by polymerase-chain-reaction assay, in the entire trial population and the prevalence of latent yaws, confirmed by serologic testing, in a subgroup of asymptomatic children 1 to 15 years of age; prevalences were measured at 18 months, and the between-group differences were calculated.

John LN, Gonzalez-Beiras C, Vall-Mayans M, Kolmau R, Houinei W, Wangi J, et al. Safety of mass drug coadministration with ivermectin, diethylcarbamazine, albendazole, and azithromycin for the integrated treatment of neglected tropical diseases: a cluster randomized community trial. The Lancet Regional Health -- Western Pacific. 2021. [ DOI | ePrint ]

Neglected tropical diseases control programmes run separately. For settings with more than one endemic disease, combined mass drug administration (MDA) has potential practical advantages compared with separate programmes but needs confirmation of safety. We assessed the safety of combined MDA for multiple neglected tropical diseases using ivermectin, diethylcarbamazine, albendazole (IDA) and azithromycin (AZI).

Grant JC, González-Beiras C, Amick KM, Fortney KR, Gangaiah D, Humphreys TL, et al. Multiple Class I and Class II Haemophilus ducreyi Strains Cause Cutaneous Ulcers in Children on an Endemic Island. Clinical Infectious Diseases. 2018;67(11):1768--1774. [ DOI | ePrint ]

Together with Treponema pallidum subspecies pertenue, Haemophilus ducreyi is a major cause of exudative cutaneous ulcers (CUs) in children. For H. ducreyi, both class I and class II strains, asymptomatic colonization, and environmental reservoirs have been found in endemic regions, but the epidemiology of this infection is unknown.Based on published whole-genome sequences of H. ducreyi CU strains, a single-locus typing system was developed and applied to H. ducreyi–positive CU samples obtained prior to, 1 year after, and 2 years after the initiation of a mass drug administration campaign to eradicate CU on Lihir Island in Papua New Guinea. DNA from the CU samples was amplified with class I and class II dsrA-specific primers and sequenced; the samples were classified into dsrA types, which were geospatially mapped. Selection pressure analysis was performed on the dsrA sequences.Thirty-seven samples contained class I sequences, 27 contained class II sequences, and 13 contained both. There were 5 class I and 4 class II types circulating on the island; 3 types accounted for approximately 87
% of the strains. The composition and geospatial distribution of the types varied little over time and there was no evidence of selection pressure.Multiple strains of H. ducreyi cause CU on an endemic island and coinfections are common. In contrast to recent findings with T. pallidum pertenue, strain composition is not affected by antibiotic pressure, consistent with environmental reservoirs of H. ducreyi. Such reservoirs must be addressed to achieve eradication of H. ducreyi.

Marks M, Mitjà O, Bottomley C, Kwakye C, Houinei W, Bauri M, et al. Comparative efficacy of low-dose versus standard-dose azithromycin for patients with yaws: a randomised non-inferiority trial in Ghana and Papua New Guinea. The Lancet Global Health. 2018;6(4):e401--e410. [ DOI | ePrint ]

A dose of 30 mg/kg of azithromycin is recommended for treatment of yaws, a disease targeted for global eradication. Treatment with 20 mg/kg of azithromycin is recommended for the elimination of trachoma as a public health problem. In some settings, these diseases are co-endemic. We aimed to determine the efficacy of 20 mg/kg of azithromycin compared with 30 mg/kg azithromycin for the treatment of active and latent yaws.

Mitjà O, Godornes C, Houinei W, Kapa A, Paru R, Abel H, et al. Re-emergence of yaws after single mass azithromycin treatment followed by targeted treatment: a longitudinal study. The Lancet. 2018;391(10130):1599--1607. [ DOI | ePrint ]

Yaws is a substantial cause of chronic disfiguring ulcers in children in at least 14 countries in the tropics. WHO's newly adopted strategy for yaws eradication uses a single round of mass azithromycin treatment followed by targeted treatment programmes, and data from pilot studies have shown a short-term significant reduction of yaws. We assessed the long-term efficacy of the WHO strategy for yaws eradication.

Houinei W, Godornes C, Kapa A, Knauf S, Mooring EQ, González-Beiras C, et al. Haemophilus ducreyi DNA is detectable on the skin of asymptomatic children, flies and fomites in villages of Papua New Guinea. PLOS Neglected Tropical Diseases. 2017;11(5):1--10. [ DOI | ePrint ]

Author summary Children in rural communities of tropical countries often suffer skin ulcers that are caused by the bacteria Haemophilus ducreyi–causative agent of chancroid- and Treponema pallidum subsp. pertenue -causative agent of yaws-. The currently recommended strategy for yaws eradication is one round of mass drug administration (MDA) with azithromycin. We attempted to find reasons for the limited impact of yaws MDA on the prevalence of H. ducreyi leg ulcers by examining potential sources of infection in healthy carriers, flies, and bed linen. H. ducreyi DNA was found in skin swabs from 20% of asymptomatic children, in 9/10 flies, and 3/6 bed sheets from the houses of children with ulcers. While H. ducreyi DNA has been detected in the genital tract of asymptomatic women without genital ulcers, this is the first report of such detection on the skin of asymptomatic individuals. Importantly, skin cultures obtained from two asymptomatic children yielded viable H. ducreyi, confirming colonization and a potential reservoir of infection. If confirmed to contain viable bacteria, flies and fomites may also contribute to the continued presence of this infection after mass treatment with azithromycin. Our findings provide evidence that persistence of H. ducreyi ulcers after antibiotic MDA is due to the ubiquity of the organism in the environment. Improved hygiene and additional strategies such as repeated rounds of MDA could be able to control such a reservoir.

González-Beiras C, Kapa A, Vall-Mayans M, Paru R, Gavilán S, Houinei W, et al. Single-Dose Azithromycin for the Treatment of Haemophilus ducreyi Skin Ulcers in Papua New Guinea. Clinical Infectious Diseases. 2017;65(12):2085--2090. [ DOI | ePrint ]

Haemophilus ducreyi (HD) and Treponema pallidum subspecies pertenue (TP) are major causative agents of cutaneous ulcer (CU) in the tropics. Azithromycin is recommended to treat sexually transmitted HD infections and has good in vitro activity against HD strains from both genital and skin ulcers. We investigated the efficacy of oral single-dose azithromycin on HD-CU.We conducted a community-based cohort study in Lihir Island, Papua New Guinea, from October 2014 through May 2016. Consenting patients with skin ulcers
>1 cm in diameter were eligible for this study and had collected a lesional swab for polymerase chain reaction (PCR). All participants were treated with single-dose azithromycin (30 mg/kg) and were followed up for assessment of clinical resolution. We retrospectively classified patients according to PCR results into HD, TP, and PCR-negative groups. The primary endpoint was healing rates of HD-CU at 14 days after treatment.We obtained full outcome data from 246 patients; 131 (53.3
%) were HD PCR positive, 37 (15.0
%) were TP positive, and 78 (31.7
%) were negative for all tests. Healing rates were 88.5
% (95
% confidence interval [CI], .82–.93) in the HD group, 78.4
% [95
% CI, .63–.89] in the TP group, and 74.4
% (95
% CI, .64–.83) in the PCR-negative group. If we included the participants with improved ulcers, the healing rates increased to 94.7
%, 97.3
%, and 89.7
% respectively. HD cases classified as not healed all converted to HD-negative PCR.Based upon clinical resolution and PCR conversion to HD negative, a single oral dose of azithromycin is efficacious for the treatment of HD-CU. These results have implications for the treatment of individual patients and for the use of antibiotics in public health strategies to control CU in the tropics.

Mitjà O, González-Beiras C, Godornes C, Kolmau R, Houinei W, Abel H, et al. Effectiveness of single-dose azithromycin to treat latent yaws: a longitudinal comparative cohort study. The Lancet Global Health. 2017;5(12):e1268--e1274. [ DOI | ePrint ]

Treatment of latent yaws is a crucial component of the WHO yaws eradication strategy to prevent relapse and the resulting transmission to uninfected children. We assessed the effectiveness of single-dose azithromycin to treat patients with latent yaws.

González-Beiras C, Marks M, Chen Y C, Roberts S, Mitjà O. Epidemiology of Haemophilus ducreyi Infections. Emerging Infectious Diseases. 2016;22(1):1--8. [ DOI | ePrint ]

The global epidemiology of Haemophilus ducreyi infections is poorly documented because of difficulties in confirming microbiological diagnoses. We evaluated published data on the proportion of genital and nongenital skin ulcers caused by H. ducreyi before and after introduction of syndromic management for genital ulcer disease (GUD). Before 2000, the proportion of GUD caused by H. ducreyi ranged from 0.0% to 69.0% (35 studies in 25 countries). After 2000, the proportion ranged from 0.0% to 15.0% (14 studies in 13 countries). In contrast, H. ducreyi has been recently identified as a causative agent of skin ulcers in children in the tropical regions; proportions ranged from 9.0% to 60.0% (6 studies in 4 countries). We conclude that, although there has been a sustained reduction in the proportion of GUD caused by H. ducreyi, this bacterium is increasingly recognized as a major cause of nongenital cutaneous ulcers.

Mitjà O, Marks M, Konan DJP, Ayelo G, Gonzalez-Beiras C, Boua B, et al. Global epidemiology of yaws: a systematic review. The Lancet Global Health. 2015;3(6):e324--e331. [ DOI | ePrint ]

To achieve yaws eradication, the use of the new WHO strategy of initial mass treatment with azithromycin and surveillance twice a year needs to be extended everywhere the disease occurs. However, the geographic scope of the disease is unknown. We aimed to synthesise published and unpublished work to update the reported number of people with yaws at national and subnational levels and to estimate at-risk populations.

Marks M, Mitjà O, Vestergaard LS, Pillay A, Knauf S, Chen CY, et al. Challenges and key research questions for yaws eradication. The Lancet Infectious Diseases. 2015;15(10):1220--1225. [ DOI | ePrint ]

Yaws is endemic in west Africa, southeast Asia, and the Pacific region. To eradicate yaws by 2020, WHO has launched a campaign of mass treatment with azithromycin. Progress has been made towards achievement of this ambitious goal, including the validation of point-of-care and molecular diagnostic tests and piloting of the strategy in several countries, including Ghana, Vanuatu, and Papua New Guinea. Gaps in knowledge need to be addressed to allow refinement of the eradication strategy. Studies exploring determinants of the spatial distribution of yaws are needed to help with the completion of baseline mapping. The finding that Haemophilus ducreyi causes lesions similar to yaws is particularly important and further work is needed to assess the effect of azithromycin on these lesions. The integration of diagnostic tests into different stages of the eradication campaign needs investigation. Finally, studies must be done to inform the optimum mass-treatment strategy for sustainable interruption of transmission.

Mitjà O, Houinei W, Moses P, Kapa A, Paru R, Hays R, et al. Mass Treatment with Single-Dose Azithromycin for Yaws. New England Journal of Medicine. 2015;372(8):703--710. [ DOI | ePrint ]

Mass treatment with azithromycin is a central component of the new World Health Organization (WHO) strategy to eradicate yaws. Empirical data on the effectiveness of the strategy are required as a prerequisite for worldwide implementation of the plan.

Ayove T, Houniei W, Wangnapi R, Bieb SV, Kazadi W, Luke LN, et al. Sensitivity and specificity of a rapid point-of-care test for active yaws: a comparative study. The Lancet Global Health. 2014;2(7):e415--e421. [ DOI | ePrint ]

To eradicate yaws, national control programmes use the Morges strategy (initial mass treatment and biannual resurveys). The resurvey component is designed to actively detect and treat remaining yaws cases and is initiated on the basis of laboratory-supported reactive non-treponemal serology (using the rapid plasma reagin [RPR] test). Unfortunately, the RPR test is available rarely in yaws-endemic areas. We sought to assess a new point-of-care assay?the Dual Path Platform (DPP) syphilis assay, which is based on simultaneous detection of antibodies to treponemal and non-treponemal antigens?for guiding use of antibiotics for yaws eradication. A secondary goal was to ascertain at what timepoint the DPP assay line reverted to negative after treatment.

Mitjà O, Lukehart SA, Pokowas G, Moses P, Kapa A, Godornes C, et al. Haemophilus ducreyi as a cause of skin ulcers in children from a yaws-endemic area of Papua New Guinea: a prospective cohort study. The Lancet Global Health. 2014;2(4):e235--e241. [ DOI | ePrint ]

Skin infections with ulceration are a major health problem in countries of the south Pacific region. Yaws, caused by Treponema pallidum subspecies pertenue and diagnosed by the presence of skin ulcers and a reactive syphilis serology, is one major cause, but this infection can be confused clinically with ulcers due to other causative agents. We investigated T pallidum pertenue and another bacterium known to cause skin infections in the Pacific islands Haemophilus ducreyi as causes of skin ulceration in a yaws-endemic region. Additionally, we identified specific signs and symptoms associated with these causative agents of cutaneous ulcers and compared these findings with laboratory-based diagnoses.

Mitjà O, Asiedu K, Mabey D. Yaws. The Lancet. 2013;381(9868):763--773. [ DOI | ePrint ]

Yaws is an infectious disease caused by Treponema pallidum pertenue?a bacterium that closely resembles the causative agent of syphilis?and is spread by skin-to-skin contact in humid tropical regions. Yaws causes disfiguring, and sometimes painful lesions of the skin and bones. As with syphilis, clinical manifestations can be divided into three stages; however, unlike syphilis, mother-to-child transmission does not occur. A major campaign to eradicate yaws in the 1950s and 1960s, by mass treatment of affected communities with longacting, injectable penicillin, reduced the number of cases by 95% worldwide, but yaws has reappeared in recent years in Africa, Asia, and the western Pacific. In 2012, one oral dose of azithromycin was shown to be as effective as intramuscular penicillin in the treatment of the disease, and WHO launched a new initiative to eradicate yaws by 2020.

Mitjà O, Hays R, Ipai A, Penias M, Paru R, Fagaho D, et al. Single-dose azithromycin versus benzathine benzylpenicillin for treatment of yaws in children in Papua New Guinea: an open-label, non-inferiority, randomised trial. The Lancet. 2012;379(9813):342--347. [ DOI | ePrint ]

Yaws is an endemic treponematosis and, as such, a neglected tropical disease?is re-emerging in children in rural, tropical areas. Oral azithromycin is effective for syphilis. We assessed the efficacy of azithromycin compared with intramuscular long-acting penicillin to treat patients with yaws.