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Background Trachoma is a progressive blinding disease initiated by infection of the conjunctiva with Chlamydia trachomatis. Repeated infections are thought to cause chronic inflammation, which drives scarring, leading to in-turning of the eyelids. The relationship between C. trachomatis, clinical inflammation and scarring development in children is not fully understood due to a paucity of longitudinal studies with infection data at frequent follow-up. Methods and findings This longitudinal cohort study took place in northern Tanzania. Children aged 6–10 years at baseline were eligible for inclusion. Participants were visited every three months for four years. Clinical signs and conjunctival swabs for C. trachomatis detection by qPCR were collected at each time-point. Conjunctival photographs from baseline and final time-points were graded and compared side-by-side to determine scarring incidence and progression. Of the 666 children enrolled in the study, outcome data were obtained for 448. Scarring progression was detected in 103/448 (23%) children; 48 (11%) of which had incident scarring and 55 (12%) had progression of existing scarring. Scarring was strongly associated with increasing episodes of trachomatous papillary inflammation (TP). Weaker associations were found between episodes of C. trachomatis infection and follicular trachoma (TF) with scarring progression in unadjusted models, which were absent in multivariable analysis after adjusting for inflammation (multivariable results: C. trachomatis p = 0.44, TF p = 0.25, TP p =, Author summary Trachoma is the leading cause of preventable blindness worldwide and is targeted for elimination as a public health problem by 2020. The natural history of trachoma is not completely understood however. We conducted a four-year longitudinal study in a trachoma-endemic area of northern Tanzania with detailed follow up every three months. In the four-year study period, nearly one quarter of children developed progression of conjunctival scarring, despite three rounds of annual mass drug administration (MDA) for trachoma control. Disease progression was strongly associated with increasing proportion of episodes with conjunctival papillary inflammation (TP), and only weakly associated with Chlamydia trachomatis infection and trachomatous inflammation–follicular (TF). Analysis revealed that associations between infection and TF with scarring progression were mediated through TP, and that other factors causing individual differences in TP were also contributing to scarring progression. These data have significant implications for trachoma control. We hypothesise that in individuals who have previously experienced ocular C. trachomatis infection, TP is the primary driver of scarring progression. The addition of TP to trachoma surveillance programs would provide an indicator for active disease progression in the community and a more accurate guide to the need for future trichiasis interventions.

Background Trachoma, caused by Chlamydia trachomatis, remains the leading infectious cause of blindness worldwide. Persistence and progression of the resulting clinical disease appears to be an immunologically mediated process. Azithromycin, which is distributed at the community level for trachoma control, has immunomodulatory properties. We investigated the impact of one round of oral azithromycin on conjunctival immune responses, C. trachomatis infection and clinical signs three- and six- months post treatment relative to three pre-treatment time-points. Methodology A cohort of children aged 6 to 10 years were recruited from a trachoma endemic region of northern Tanzania and were visited five times in a 12-month period. They were examined for clinical signs of trachoma and conjunctival swabs were collected for laboratory analysis. C. trachomatis infection was detected and the expression of 46 host genes was quantified using quantitative PCR. All community members were offered azithromycin treatment immediately after the six-month timepoint according to international guidelines. Findings The prevalence of C. trachomatis infection and inflammatory disease signs were significantly reduced three- and six- months post-mass drug administration (MDA). C. trachomatis infection was strongly associated with clinical signs at all five time-points. A profound anti-inflammatory effect on conjunctival gene expression was observed 3 months post-MDA, however, gene expression had largely returned to pre-treatment levels of variation by 6 months. This effect was less marked, but still observed, after adjusting for C. trachomatis infection and when the analysis was restricted to individuals who were free from both infection and clinical disease at all five time-points. Interestingly, a modest effect was also observed in individuals who did not receive treatment. Conclusion Conjunctival inflammation is the major clinical risk factor for progressive scarring trachoma, therefore, the reduction in inflammation associated with azithromycin treatment may be beneficial in limiting the development of potentially blinding disease sequelae. Future work should seek to determine whether this effect is mediated directly through inhibition of pro-inflammatory intracellular signalling molecules, through reductions in concurrent, sub-clinical infections, and/or through reduction of infection exposure., Author summary Trachoma, caused by conjunctival infection with Chlamydia trachomatis, remains the leading infectious cause of blindness. Repeated infection during childhood can trigger prolonged inflammation, which is the main risk factor for conjunctival scarring. Azithromycin is distributed globally for trachoma control, however it is also widely reported to have immunomodulatory properties. This report investigated the impact of one round of oral azithromycin for trachoma control on conjunctival immune responses, clinical signs and C. trachomatis infection in Tanzanian children. A large anti-inflammatory effect of azithromycin on conjunctival gene expression was observed 3 months post-treatment, however, gene expression patterns had mostly resumed to pre-treatment levels by 6 months. The effect was evident after adjusting for C. trachomatis infection and when analysis was restricted to uninfected individuals, however it was also observed to a lesser extent in individuals that did not receive treatment. These findings suggest that azithromycin may have a direct immunomodulatory effect on conjunctival gene expression but that it may also reduce inflammation by reducing exposure to C. trachomatis and other infections. This anti-inflammatory effect could have therapeutic potential in limiting the development of disease sequelae, that goes beyond its effect on the clearance of ocular C. trachomatis infection.

Yaws is a disabling bacterial infection found primarily in warm and humid tropical areas. The World Health Organization strategy mandates an initial round of total community treatment (TCT) with single-dose azithromycin followed either by further TCT or active case-finding and treatment of cases and their contacts (the Morges strategy). We sought to investigate the effectiveness of the Morges strategy. We employed a stochastic household model to study the transmission of infection using data collected from a pre-TCT survey conducted in the Solomon Islands. We used this model to assess the proportion of asymptomatic infections that occurred in households without active cases. This analysis indicated that targeted treatment of cases and their household contacts would miss a large fraction of asymptomatic infections (65%–100%). This fraction was actually higher at lower prevalences. Even assuming that all active cases and their households were successfully treated, our analysis demonstrated that at all prevalences present in the data set, up to 90% of (active and asymptomatic) infections would not be treated under household-based contact tracing. Mapping was undertaken as part of the study “Epidemiology of Yaws in the Solomon Islands and the Impact of a Trachoma Control Programme,” in September–October 2013.

Yaws is an important cause of skin disease in tropical countries. Using next-generation sequencing, we tested yaws-like ulcers, which were negative using standard molecular diagnostics. We found primer binding site mutations explaining the negative results of the standard assay., Background Yaws-like chronic ulcers can be caused by Treponema pallidum subspecies pertenue, Haemophilus ducreyi, or other, still-undefined bacteria. To permit accurate evaluation of yaws elimination efforts, programmatic use of molecular diagnostics is required. The accuracy and sensitivity of current tools remain unclear because our understanding of T. pallidum diversity is limited by the low number of sequenced genomes. Methods We tested samples from patients with suspected yaws collected in the Solomon Islands and Ghana. All samples were from patients whose lesions had previously tested negative using the Centers for Disease Control and Prevention (CDC) diagnostic assay in widespread use. However, some of these patients had positive serological assays for yaws on blood. We used direct whole-genome sequencing to identify T. pallidum subsp pertenue strains missed by the current assay. Results From 45 Solomon Islands and 27 Ghanaian samples, 11 were positive for T. pallidum DNA using the species-wide quantitative polymerase chain reaction (PCR) assay, from which we obtained 6 previously undetected T. pallidum subsp pertenue whole-genome sequences. These show that Solomon Islands sequences represent distinct T. pallidum subsp pertenue clades. These isolates were invisible to the CDC diagnostic PCR assay, due to sequence variation in the primer binding site. Conclusions Our data double the number of published T. pallidum subsp pertenue genomes. We show that Solomon Islands strains are undetectable by the PCR used in many studies and by health ministries. This assay is therefore not adequate for the eradication program. Next-generation genome sequence data are essential for these efforts.

Introduction Neurological involvement is one of the most important clinical manifestations of syphilis and neurological disease occurs in both early and late syphilis. The impact of HIV co-infection on clinical neurosyphilis remains unclear. The highest prevalence of both syphilis and HIV is in Africa. Therefore it might be expected that neurosyphilis would be an important and not uncommon manifestation of syphilis in Africa and frequently occur in association with HIV co-infection; yet few data are available on neurosyphilis in Africa. The aim of this study is to review data on neurosyphilis in Africa since the onset of the HIV epidemic. Methods We searched the literature for references on neurosyphilis in Africa for studies published between the 1st of January 1990 and 15th February 2017. We included case reports, case series, and retrospective and prospective cohort and case-control studies. We did not limit inclusion based on the diagnostic criteria used for neurosyphilis. For retrospective and prospective cohorts, we calculated the proportion of study participants who were diagnosed with neurosyphilis according to the individual study criteria. Depending on the study, we assessed the proportion of patients with syphilis found to have neurosyphilis, and the proportion of patients with neurological syndromes who had neurosyphilis. Due to heterogeneity of data no formal pooling of the data or meta-analysis was undertaken. Results Amongst patients presenting with a neurological syndrome, three studies of patients with meningitis were identified; neurosyphilis was consistently reported to cause approximately 3% of all cases. Three studies on stroke reported mixed findings but were limited due to the small number of patients undergoing CSF examination, whilst neurosyphilis continued to be reported as a common cause of dementia in studies from North Africa. Ten studies reported on cases of neurosyphilis amongst patients known to have syphilis. Studies from both North and Southern Africa continue to report cases of late stage syphilis, including tabes dorsalis and neurosyphilis, in association with ocular disease. Discussion This is the first systematic review of the literature on neurosyphilis in Africa since the beginning of the HIV epidemic. Neurosyphilis continues to be reported as a manifestation of both early and late syphilis, but the methodological quality of the majority of the included studies was poor. Future well-designed prospective studies are needed to better delineate the incidence and clinical spectrum of neurosyphilis in Africa and to better define interactions with HIV in this setting., Author summary Involvement of the central nervous system is an important manifestation of syphilis which may be more common in patients co-infected with HIV. As most cases of syphilis and HIV are seen in Africa it might be anticipated that neurosyphilis was common there. We reviewed all published material on neurosyphilis in Africa since 1990. There were few well designed studies of neurosyphilis. A small number of studies suggested that syphilis remains a cause of meningitis in Africa. Our data suggest that neuosyphilis remains an important disease in Africa but better prospective studies are needed to understand its epidemiology.

BACKGROUND Mass drug administration (MDA) with azithromycin is a corner-stone of trachoma control however it may drive the emergence of antimicrobial resistance. In a cluster-randomized trial (Clinical trial gov NCT00792922), we compared the reduction in the prevalence of active trachoma in communities that received three annual rounds of MDA to that in communities that received a single treatment round. We used the framework of this trial to carry out an opportunistic study to investigate if the increased rounds of treatment resulted in increased prevalence of nasopharyngeal carriage of macrolide-resistant Staphylococcus aureus. Three cross-sectional surveys were conducted in two villages receiving three annual rounds of MDA (3 × treatment arm). Surveys were conducted immediately before the third round of MDA (CSS-1) and at one (CSS-2) and six (CSS-3) months after MDA. The final survey also included six villages that had received only one round of MDA 30 months previously (1 × treatment arm). RESULTS In the 3 × treatment arm, a short-term increase in prevalence of S. aureus carriage was seen following MDA from 24.6% at CSS-1 to 38.6% at CSS-2 (p

Background: The Solomon Islands is targeting elimination of malaria by 2030. The dominant vector is the predominantly exophagic, exophilic Anopheles farauti sensu strictu. This biting behaviour limits the efficacy of conventional vector control tools and highlights the need for new strategies. When administered to humans ivermectin has been shown to have a mosquitocidal effect. Mass drug administration (MDA) with ivermectin is an emerging strategy in the control of scabies. In this study we explored any incidental effect of ivermectin MDA conducted for scabies control on mosquitoes. Methods: MDA for scabies was conducted in three villages. We performed human landing catches and measured 5-day mortality amongst Anopheles mosquitoes caught before and after MDA. Cox regression was used to calculate hazard ratios (HR) for mortality between mosquitoes caught before and after MDA. Results: There was a significant increase in 5-day mortality in anopheline mosquitoes caught post-MDA which was highest on the day of MDA itself (HR 4.2 95% CI 1.8 to 10.1, p=0.001) and the following day (HR 4.4 95% CI 1.8 to 10.8, p=0.002) compared to mosquitoes caught before MDA. Conclusions: This study shows a possible mosquitocidal effect of ivermectin MDA conducted for scabies control. Studies with a larger sample size with clinical as well as entomological outcomes should be conducted in this population.