Mass treatment with single-dose azithromycin for yaws.

BACKGROUND: 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. METHODS: We performed repeated clinical surveys for active yaws, serologic surveys for latent yaws, and molecular analyses to determine the cause of skin ulcers and identify macrolide-resistant mutations before and 6 and 12 months after mass treatment with azithromycin on a Papua New Guinean island on which yaws was endemic. Primary-outcome indicators were the prevalence of serologically confirmed active infectious yaws in the entire population and the prevalence of latent yaws with high-titer seroreactivity in a subgroup of children 1 to 15 years of age. RESULTS: At baseline, 13,302 of 16,092 residents (82.7%) received one oral dose of azithromycin. The prevalence of active infectious yaws was reduced from 2.4% before mass treatment to 0.3% at 12 months (difference, 2.1 percentage points; P<0.001). The prevalence of high-titer latent yaws among children was reduced from 18.3% to 6.5% (difference, 11.8 percentage points; P<0.001) with a near-absence of high-titer seroreactivity in children 1 to 5 years of age. Adverse events identified within 1 week after administration of the medication occurred in approximately 17% of the participants, included nausea, diarrhea, and vomiting, and were mild in severity. No evidence of emergence of resistance to macrolides against Treponema pallidum subspecies pertenue was seen. CONCLUSIONS: The prevalence of active and latent yaws infection fell rapidly and substantially 12 months after high-coverage mass treatment with azithromycin, with the reduction perhaps aided by subsequent activities to identify and treat new cases of yaws. Our results support the WHO strategy for the eradication of yaws. (Funded by Newcrest Mining and International SOS; YESA-13 ClinicalTrials.gov number, NCT01955252.).

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

BACKGROUND: Yaws--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. METHODS: We did an open-label, non-inferiority, randomised trial at Lihir Medical Centre, Papua New Guinea, between Sept 1, 2010, and Feb 1, 2011. Children aged 6 months to 15 years with a serologically confirmed diagnosis of yaws were randomly allocated, by a computer-generated randomisation sequence, to receive either one 30 mg/kg oral dose of azithromycin or an intramuscular injection of 50,000 units per kg benzathine benzylpenicillin. Investigators were masked to group assignment. The primary endpoint was treatment efficacy, with cure rate defined serologically as a decrease in rapid plasma reagin titre of at least two dilutions by 6 months after treatment, and, in participants with primary ulcers, also by epithelialisation of lesions within 2 weeks. Non-inferiority was shown if the upper limit of the two-sided 95% CI for the difference in rates was lower than 10%. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01382004. FINDINGS: We allocated 124 patients to the azithromycin group and 126 to the benzathine benzylpenicillin group. In the per-protocol analysis, after 6 months of follow-up, 106 (96%) of 110 patients in the azithromycin group were cured, compared with 105 (93%) of 113 in the benzathine benzylpenicillin group (treatment difference -3·4%; 95% CI -9·3 to 2·4), thus meeting prespecified criteria for non-inferiority. The number of drug-related adverse events (all mild or moderate) was similar in both treatment groups (ten [8%] in the azithromycin group vs eight [7%] in the benzathine benzylpenicillin group). INTERPRETATION: A single oral dose of azithromycin is non-inferior to benzathine benzylpenicillin and avoids the need for injection equipment and medically trained personnel. A change to the simpler azithromycin treatment regimen could enable yaws elimination through mass drug administration programmes. FUNDING: International SOS and Newcrest Mining.

Osteoperiostitis in early yaws: case series and literature review.

We describe the clinical and radiological manifestations and outcome after treatment of 7 children who received a diagnosis of early yaws osteoperiostitis. Osteoperiostitis occurred some weeks after the primary infection, and the most common finding was hypertrophic periostitis of long bones. All treated patients had excellent responses to benzyl-penicillin therapy.

Outcome predictors in treatment of yaws.

To estimate failure rates after treatment with benzathine penicillin and to identify determinants of failure that affected outcomes for yaws, we conducted a cohort study of 138 patients; treatment failed in 24 (17.4%). Having low initial titers on Venereal Disease Research Laboratory test and living in a village where yaws baseline incidence was high were associated with increased likelihood of treatment failure.

Hyperendemic dengue transmission and identification of a locally evolved DENV-3 lineage, Papua New Guinea 2007-2010.

BACKGROUND: Dengue is endemic in the Western Pacific and Oceania and the region reports more than 200,000 cases annually. Outbreaks of dengue and severe dengue occur regularly and movement of virus throughout the region has been reported. Disease surveillance systems, however, in many areas are not fully established and dengue incidence is underreported. Dengue epidemiology is likely least understood in Papua New Guinea (PNG), where the prototype DENV-2 strain New Guinea C was first isolated by Sabin in 1944 but where routine surveillance is not undertaken and little incidence and prevalence data is available. METHODOLOGY/PRINCIPAL FINDINGS: Serum samples from individuals with recent acute febrile illness or with non-febrile conditions collected between 2007-2010 were tested for anti-DENV neutralizing antibody. Responses were predominantly multitypic and seroprevalence increased with age, a pattern indicative of endemic dengue. DENV-1, DENV-2 and DENV-3 genomes were detected by RT-PCR within a nine-month period and in several instances, two serotypes were identified in individuals sampled within a period of 10 days. Phylogenetic analysis of whole genome sequences identified a DENV-3 Genotype 1 lineage which had evolved on the northern coast of PNG which was likely exported to the western Pacific five years later, in addition to a DENV-2 Cosmopolitan Genotype lineage which had previously circulated in the region. CONCLUSIONS/SIGNIFICANCE: We show that dengue is hyperendemic in PNG and identify an endemic, locally evolved lineage of DENV-3 that was associated with an outbreak of severe dengue in Pacific countries in subsequent years, although severe disease was not identified in PNG. Additional studies need to be undertaken to understand dengue epidemiology and burden of disease in PNG.

Control of chronic Strongyloides stercoralis infection in an endemic community may be possible by pharmacological means alone: Results of a three-year cohort study.

OBJECTIVES: To assess the effect of treatment with ivermectin on the prevalence of S. stercoralis infection in an Australian Aboriginal population over a three year period, and to assess the validity of using a lower ELISA cut-off in diagnosis. METHODS: A three-year cohort study of 259 adult Australian Aboriginals living in a remote community in northern Australia. S stercoralis infection was diagnosed using commercial ELISA testing, and employed a lower threshold for treatment than that recommended. Follow up was conducted at 6 months and 3 years following ivermectin treatment. FINDINGS: Treatment with ivermectin was highly effective and resulted in a sustained fall in the prevalence of infection in the study group (Initial prevalence 35.3%, 3 year prevalence 5.8%, McNemar's chi2 = 56.5, p<0.001). Results of treatment suggested use of a lower ELISA threshold for treatment was valid in this setting. Follow up identified a small group of subjects with persistently positive ELISA serology despite repeated treatment. INTERPRETATION: Control of S. stercoralis infection in this cohort appears to be feasible using pharmacological treatment alone.

The relationship between treatment for Strongyloides stercoralis infection and type 2 diabetes mellitus in an Australian Aboriginal population: A three-year cohort study.

AIM: To determine the effect of treatment for Strongyloides stercoralis infection on type 2 diabetes mellitus in an Australian Aboriginal population. METHODS: A three-year cohort study of 259 Aboriginal adults living in northern Australia. Subjects were tested for S. stercoralis infection, diabetic status and HbA1c at recruitment. 92 subjects were ELISA positive for S. stercoralis and 91 were treated with two doses of ivermectin 0.2mg/kg. Serological cure was assessed after 6months and those who remained positive were retreated. All subjects then underwent the same testing at 3years follow up. RESULTS: Follow up was successful in 80% of subjects. Eight new cases of T2DM were recorded, 7 in the treatment group and 1 in the non-treatment group (Unadjusted RR 7.71, CI 0.98-60.48, p=0.052. Adjusted RR 5.45, CI 075-35.92, p=0.093). In addition, worsening glycemic control (T2DM or newly diagnosed glucose intolerance) was recorded in 13 cases (10 treatment group, 3 non treatment. Adjusted RR 3.74, CI 1.06-13.20, p=0.04). There was a significant improvement in glycemic control in the patients with pre-existing T2DM when treated for S. stercoralis compared to the non-treatment group (Diff. -1.03, p=0.009). CONCLUSION: This study demonstrated a differential effect of treatment for S. stercoralis on glucose metabolism in patients with and without T2DM. It showed a significant effect on the development of T2DM and glucose intolerance in those without T2DM, while improving glycemic control in subjects with pre-existing T2DM. Although numbers in this study are small, it suggests that larger studies may be of interest.

Strongyloides stercoralis, Eosinophilia, and Type 2 Diabetes Mellitus: The Predictive Value of Eosinophilia in the Diagnosis of S stercoralis Infection in an Endemic Community.

Background. This study examines the predictive value of eosinophilia for Strongyloides stercoralis infection, as measured by enzyme-linked immunosorbent assay (ELISA) testing, in an endemic community. In remote communities, eosinophilia is frequently used as a proxy test for the presence of helminth infections. Past studies of eosinophilia and Strongyloides infection have been conducted in specific groups such as immigrants and refugees, or in subpopulations of nonendemic communities, rather than in endemic communities. Methods. We conducted a cross-sectional study of the relationship between eosinophilia and Strongyloides ELISA serology, as part of a study into the relationship between S stercoralis infection and type 2 diabetes mellitus (T2DM) in an Indigenous community in northern Australia. Results. Two hundred thirty-nine adults had their eosinophil count and S stercoralis ELISA serology measured in 2012 and 2013, along with other biometric and metabolic data. Eosinophilia was found to have a relatively poor sensitivity (60.9%), specificity (71.1%), positive predictive value (54.6%), and negative predictive value (76.1%) for S stercoralis ELISA positivity in this group. However, there was a more constant relationship between eosinophilia and S Stercoralis ELISA positivity in patients with T2DM (negative predictive value 87.5%). Conclusion. This study suggests that the presence or absence of eosinophilia is not an adequate proxy test for S stercoralis infection in a community where the infection is prevalent, and that the association between eosinophilia and S stercoralis ELISA positivity is more constant in patients with T2DM.

Type 2 Diabetes Mellitus Is Associated with Strongyloides stercoralis Treatment Failure in Australian Aboriginals.

OBJECTIVE: To explore the efficacy of ivermectin in the treatment of serologically diagnosed cases of Strongyloides stercoralis (S. stercoralis) infection in an Aboriginal community and to describe factors that may influence the outcome of treatment. METHODS: Longitudinal study of a group of 92 individuals with serologically diagnosed S. stercoralis treated with ivermectin and followed up over a period of approximately 6 months. Main outcomes were serological titers pre and post treatment, diabetic status, and duration of follow up. FINDINGS: Treatment success was achieved in 62% to 79% of cases dependent on the methods employed for the diagnosis of infection and assessment of treatment outcome. Type 2 Diabetes Mellitus (T2DM) was found to be significantly associated with treatment failure in this group for two of the three methods employed. INTERPRETATION: Ivermectin has been confirmed as an effective treatment for S stercoralis infection in this setting. T2DM appears to be an independent risk factor for treatment failure in this population, and plausible mechanisms to explain this observation are presented.

Does Strongyloides stercoralis infection protect against type 2 diabetes in humans? Evidence from Australian Aboriginal adults.

OBJECTIVE: To explore the relationship between infection with Strongyloides stercoralis and the likelihood of having type 2 diabetes mellitus (T2DM). METHODS: Cross-sectional survey of 259 Aboriginal adults living in a remote community in northern Australia during 2013. Prior infection with S. stercoralis was determined by ELISA testing on serum. Main outcomes were eosinophil count, T2DM diagnosis, HbA1c, BMI, fasting lipids, Hb, blood pressure. FINDINGS: Ninety two participants (36%) had prior infection with S. stercoralis and 131 (51%) had T2DM. Those with previous S. stercoralis infection (ELISA titre ≥0.3) were 61% less likely to have a diagnosis of T2DM than those uninfected, adjusted for age, triglycerides, blood pressure and BMI using propensity score (adjusted OR=0.39, 0.23-0.67, P=0.001). INTERPRETATION: In this remote community where prevalence of both S. stercoralis and T2DM is very high, infection with S. stercoralis appears to be associated with a significantly reduced risk of T2DM in adults. A plausible immunological mechanism has been identified in animal models. If confirmed, this result may have practical implications for the prevention of T2DM and associated metabolic disorders in humans. This finding should be explored further with larger longitudinal studies in transitional populations where the risk of both conditions is high. FUNDING: No external funding was required for this study.

Mycetoma caused by Nocardia yamanashiensis, Papua New Guinea.

We report the first documented case of a mycetoma caused by Nocardia yamanashiensis after the initial description of this species. The 16S-rRNA gene sequence analysis was used to identify the novel species, which showed a similarity of 99.9% to the gene sequence of the type strain. The case showed both clinical non-response and reduced susceptibility in vitro to amoxicillin plus clavulanate, and it was treated successfully with trimethoprim-sulfamethoxazole and doxycycline. Given antibiotic resistance concerns, we suggest that antimicrobial susceptibility testing should be done for the majority of Nocardia species without well-established resistance patterns.

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

A global resurgence of yaws in developing countries highlights the need for reliable diagnostic criteria for this neglected infection. We conducted a clinical and serologic survey of 233 children less than 15 years of age who had clinically suspected yaws. A total of 138 (59%) cases were confirmed serologically, and 10 of 12 primary stage cases showed positive results for Treponema pallidum by a polymerase chain reaction assay that has not yet been validated for identification of yaws. A high proportion of cases (46%) were in the secondary stage; 92% of them had osteoarticular involvement, and only 24% had a Venereal Disease Research Laboratory titer greater than 1:32.

The impact of a filariasis control program on Lihir Island, Papua New Guinea.

BACKGROUND: Annual mass drug administration (MDA) over five years is the WHO's recommended strategy to eliminate lymphatic filariasis (LF). Some experts, however, consider that longer periods of treatment might be necessary in certain high prevalence and transmission environments based upon past unsuccessful field experience and modelling. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate predictors of success in a LF control program we conducted an ecological study during a pre-existing MDA program. We studied 27 villages in Lihir Island, Papua New Guinea, from two areas with different infection rates before MDA. We undertook surveys to collect information on variables potentially having an influence on the outcome of the program, including epidemiological (baseline prevalence of infection, immigration rate), entomological (vector density) and operational (treatment coverage, vector control strategies) variables. The success in a village was defined using variables related to the infection (circulating filarial antigenemia prevalence < 1%) and transmission (antigenemia prevalence < 1 in 1000 children born since start of MDA). 8709 people were involved in the MDA program and average coverage rates were around 70%. The overall prevalence of filariasis fell from an initial 17.91% to 3.76% at round 5 (p < 0.001). Viewed on a village by village basis, 12/27 (44%) villages achieved success. In multivariate analysis, low baseline prevalence was the only factor predicting both success in reducing infection rates (OR 19,26; CI 95% 1,12 to 331,82) and success in preventing new infections (OR 27,44; CI 95% 1,05 to 719,6). Low vector density and the use of an optimal vector control strategy were also associated with success in reducing infection rates, but this did not reach statistical significance. CONCLUSIONS/SIGNIFICANCE: Our results provide the data that supports the recommendation that high endemic areas may require longer duration MDA programs, or alternative control strategies.

HMS-related hemolysis after acute attacks of Plasmodium vivax malaria.

Among a cohort of 1,213 cases treated for Plasmodium vivax malaria from an isolated Papua New Guinean population, seven adults with severe and sustained hemolytic anemia after clearance of the peripheral parasitemia were prospectively investigated. All the patients fulfilled the criteria for hyper-reactive malarial splenomegaly and in 2 of 7 cases an IgG warm antibody was identified. Hereditary hemolytic anemia was excluded in 5 of 5 patients. All treated cases improved after an initial high dose of prednisone and antimalarial chemoprophylaxis. The persistence of marked anemia in a patient with splenomegaly after a P. vivax attack should raise the suspicion of hyper-reactive malarial splenomegaly.