Safety of mass drug coadministration with ivermectin, diethylcarbamazine, albendazole, and azithromycin for the integrated treatment of neglected tropical diseases: a cluster randomized community trial.

INTRODUCTION: 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). METHODS: We conducted an open-label, cluster-randomized trial involving individuals living in 34 wards (smaller administrative division) in two study sites, Namatanai District and Lihir Island, Papua New Guinea. We randomly assigned wards to the combined treatment arm (which received a single dose of the triple combination IDA and a single dose of AZI at the same visit) or the control arm (which received IDA separately followed by AZI separately one week after). All participants underwent safety assessments one day after drug administration. Methodology for collecting the adverse events (AEs) was a general question (in Namatanai) and individual questions about specific AEs (in Lihir). The primary endpoint was the prevalence of AEs. Safety of combined treatment was taken to be non-inferior to that of IDA if the upper limit of the two-sided CI for the difference in rates was equal or lower than 5%. FINDINGS: The study enrolled 15,656 participants. Of those enrolled, 7,281 (46.3%) received the combined regimen and 8,375 (53.3%) received standard treatment with IDA for lymphatic filariasis between Nov 1, 2018, and Apr 15, 2019. Of the individuals in the control group, 4,228 (50.5%) attended a second visit one week apart to receive AZI for yaws. In Namatanai, the proportion of AEs was similar in the combined group (0.8%) compared to the IDA group (1.3%, difference 0.5% [95CI -2.5% to 1.4%]) or the AZI group (3.6%, d -2.8% [95CI -8.6% to 2.8%]). In Lihir, the proportion of AEs was higher in the combined group (23.0%) compared to the IDA group (12.2%, d 10.8% [95% CI 1.5% to 20.2%]) or the AZI group (11.1%, d 11.9% [95% CI 2.7% to 21.1%]).We observed 21 (0.3%) grade-2 AEs in the combined treatment group, 33 (0.4%) in the IDA separately group, and 18 (0.2%) in the AZI separately group. No participants required treatment for any AE. We observed no deaths, serious AEs, or AEs of special interest. INTERPRETATION: In the largest trial so far involving coadministration of regimens based on IDA and AZI, the combination was safe and feasible in a population of more than 15,000 people. Combined MDA based on these two regimens opens up new potential for the control of neglected tropical diseases in the Western Pacific region

Yaws re-emergence and bacterial drug resistance selection after mass administration of azithromycin: a genomic epidemiology investigation.

BACKGROUND: In a longitudinal study assessing the WHO strategy for yaws eradication using mass azithromycin treatment, we observed resurgence of yaws cases with dominance of a single JG8 sequence type and emergence of azithromycin-resistant Treponema pallidum subspecies pertenue (T p pertenue). Here, we analyse genomic changes in the bacterial population using samples collected during the study. METHODS: We did whole bacterial genome sequencing directly on DNA extracted from 37 skin lesion swabs collected from patients on Lihir Island, Papua New Guinea, between April 1, 2013, and Nov 1, 2016. We produced phylogenies and correlated these with spatiotemporal information to investigate the source of new cases and the emergence of five macrolide-resistant cases. We used deep amplicon sequencing of surveillance samples to assess the presence of minority macrolide-resistant populations. FINDINGS: We recovered 20 whole T p pertenue genomes, and phylogenetic analysis showed that the re-emerging JG8 sequence type was composed of three bacterial sublineages characterised by distinct spatiotemporal patterns. Of five patients with resistant T p pertenue, all epidemiologically linked, we recovered genomes from three and found no variants. Deep sequencing showed that before treatment, the index patient had fixed macrolide-sensitive T p pertenue, whereas the post-treatment sample had a fixed resistant genotype, as did three of four contact cases. INTERPRETATION: In this study, re-emergence of yaws cases was polyphyletic, indicating multiple epidemiological sources. However, given the genomic and epidemiological linkage of resistant cases and the rarity of resistance alleles in the general population, azithromycin resistance is likely to have evolved only once in this study, followed by onward dissemination. FUNDING: Wellcome and Provincial Deputation of Barcelona

Prospective individual patient data meta-analysis of two randomized trials on convalescent plasma for COVID-19 outpatients

Data on convalescent plasma (CP) treatment in COVID-19 outpatients are scarce. We aimed to assess whether CP administered during the first week of symptoms reduced the disease progression or risk of hospitalization of outpatients. Two multicenter, double-blind randomized trials (NCT04621123, NCT04589949) were merged with data pooling starting when = 50 years and symptomatic for <= 7days were included. The intervention consisted of 200-300mL of CP with a predefined minimum level of antibodies. Primary endpoints were a 5-point disease severity scale and a composite of hospitalization or death by 28 days. Amongst the 797 patients included, 390 received CP and 392 placebo; they had a median age of 58 years, 1 comorbidity, 5 days symptoms and 93% had negative IgG antibody-test. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The odds ratio (OR) of CP for improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311); OR for hospitalization or death was 0.919 (CI 0.592-1.416). CP effect on hospital admission or death was largest in patients with <= 5 days of symptoms (OR 0.658, 95%CI 0.394-1.085). CP did not decrease the time to full symptom resolution

Global epidemiology of yaws: a systematic review.

BACKGROUND: 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. METHODS: We searched PubMed and WHO databases to identify published data for prevalence of active and latent yaws from Jan 1, 1990, to Dec 31, 2014. We also searched for ongoing or recently completed unpublished studies from the WHO yaws surveillance network. We estimated yaws prevalence (and 95% CIs). We collected yaws incidence data from official national surveillance programmes at the first administrative level from Jan 1, 2010, to Dec 31, 2013, and we used total population data at the second administrative level to estimate the size of at-risk populations. FINDINGS: We identified 103 records, of which 23 published articles describing 27 studies and four unpublished studies met the inclusion criteria. Prevalence of active disease ranged from 0·31% to 14·54% in yaws-endemic areas, and prevalence of latent yaws ranged from 2·45% to 31·05%. During 2010-13, 256 343 yaws cases were reported to WHO from 13 endemic countries, all of which are low-income and middle-income countries. 215 308 (84%) of 256 343 cases reported to WHO were from three countries-Papua New Guinea, Solomon Islands, and Ghana. We estimated that, in 2012, over 89 million people were living in yaws-endemic districts. INTERPRETATION: Papua New Guinea, Solomon Islands, and Ghana should be the focus of initial efforts at implementing the WHO yaws eradication strategy. Community-based mapping and active surveillance must accompany the implementation of yaws eradication activities. FUNDING: None

Haemophilus ducreyi DNA is detectable on the skin of asymptomatic children, flies and fomites in villages of Papua New Guinea

BACKGROUND: Haemophilus ducreyi and Treponema pallidum subsp. pertenue are major causes of leg ulcers in children in Africa and the Pacific Region. We investigated the presence of DNA (PCR positivity) from these bacteria on asymptomatic people, flies, and household linens in an endemic setting. METHODOLOGY/PRINCIPAL FINDINGS: We performed a cross-sectional study in rural villages of Lihir Island, Papua New Guinea during a yaws elimination campaign. Participants were asymptomatic subjects recruited from households with cases of leg ulcers, and from households without cases of leg ulcers. We rubbed swabs on the intact skin of the leg of asymptomatic individuals, and collected flies and swabs of environmental surfaces. All specimens were tested by PCR for H. ducreyi and T. p. pertenue DNA. Of 78 asymptomatic participants that had an adequate specimen for DNA detection, H. ducreyi-PCR positivity was identified in 16 (21%) and T. p. pertenue-PCR positivity in 1 (1%). In subgroup analyses, H. ducreyi-PCR positivity did not differ in participants exposed or not exposed to a case of H. ducreyi ulcer in the household (24% vs 18%; p = 0.76). Of 17 cultures obtained from asymptomatic participants, 2 (12%) yielded a definitive diagnosis of H. ducreyi, proving skin colonization. Of 10 flies tested, 9 (90%) had H. ducreyi DNA and 5 (50%) had T. p. pertenue DNA. Of 6 bed sheets sampled, 2 (33%) had H. ducreyi DNA and 1 (17%) had T. p. pertenue DNA. CONCLUSIONS/SIGNIFICANCE: This is the first time that H. ducreyi DNA and colonization has been demonstrated on the skin of asymptomatic children and that H. ducreyi DNA and T. p. pertenue DNA has been identified in flies and on fomites. The ubiquity of H. ducreyi in the environment is a contributing factor to the spread of the organism

Global epidemiology of yaws: a systematic review

Background: 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. Methods: We searched PubMed and WHO databases to identify published data for prevalence of active and latent yaws from Jan 1, 1990, to Dec 31, 2014. We also searched for ongoing or recently completed unpublished studies from the WHO yaws surveillance network. We estimated yaws prevalence (and 95% CIs). We collected yaws incidence data from official national surveillance programmes at the first administrative level from Jan 1, 2010, to Dec 31, 2013, and we used total population data at the second administrative level to estimate the size of at-risk populations. Findings: We identified 103 records, of which 23 published articles describing 27 studies and four unpublished studies met the inclusion criteria. Prevalence of active disease ranged from 0·31% to 14·54% in yaws-endemic areas, and prevalence of latent yaws ranged from 2·45% to 31·05%. During 2010–13, 256 343 yaws cases were reported to WHO from 13 endemic countries, all of which are low-income and middle-income countries. 215 308 (84%) of 256 343 cases reported to WHO were from three countries—Papua New Guinea, Solomon Islands, and Ghana. We estimated that, in 2012, over 89 million people were living in yaws-endemic districts. Interpretation: Papua New Guinea, Solomon Islands, and Ghana should be the focus of initial efforts at implementing the WHO yaws eradication strategy. Community-based mapping and active surveillance must accompany the implementation of yaws eradication activities. Funding: None

Subcutaneous anti-COVID-19 hyperimmune immunoglobulin for prevention of disease in asymptomatic individuals with SARS-CoV-2 infection: a double-blind, placebo-controlled, randomised clinical trialResearch in context

Summary: Background: Anti-COVID-19 hyperimmune immunoglobulin (hIG) can provide standardized and controlled antibody content. Data from controlled clinical trials using hIG for the prevention or treatment of COVID-19 outpatients have not been reported. We assessed the safety and efficacy of subcutaneous anti-COVID-19 hyperimmune immunoglobulin 20% (C19-IG20%) compared to placebo in preventing development of symptomatic COVID-19 in asymptomatic individuals with SARS-CoV-2 infection. Methods: We did a multicentre, randomized, double-blind, placebo-controlled trial, in asymptomatic unvaccinated adults (≥18 years of age) with confirmed SARS-CoV-2 infection within 5 days between April 28 and December 27, 2021. Participants were randomly assigned (1:1:1) to receive a blinded subcutaneous infusion of 10 mL with 1 g or 2 g of C19-IG20%, or an equivalent volume of saline as placebo. The primary endpoint was the proportion of participants who remained asymptomatic through day 14 after infusion. Secondary endpoints included the proportion of individuals who required oxygen supplementation, any medically attended visit, hospitalisation, or ICU, and viral load reduction and viral clearance in nasopharyngeal swabs. Safety was assessed as the proportion of patients with adverse events. The trial was terminated early due to a lack of potential benefit in the target population in a planned interim analysis conducted in December 2021. ClinicalTrials.gov registry: NCT04847141. Findings: 461 individuals (mean age 39.6 years [SD 12.8]) were randomized and received the intervention within a mean of 3.1 (SD 1.27) days from a positive SARS-CoV-2 test. In the prespecified modified intention-to-treat analysis that included only participants who received a subcutaneous infusion, the primary outcome occurred in 59.9% (91/152) of participants receiving 1 g C19-IG20%, 64.7% (99/153) receiving 2 g, and 63.5% (99/156) receiving placebo (difference in proportions 1 g C19-IG20% vs. placebo, −3.6%; 95% CI -14.6% to 7.3%, p = 0.53; 2 g C19-IG20% vs placebo, 1.1%; −9.6% to 11.9%, p = 0.85). None of the secondary clinical efficacy endpoints or virological endpoints were significantly different between study groups. Adverse event rate was similar between groups, and no severe or life-threatening adverse events related to investigational product infusion were reported. Interpretation: Our findings suggested that administration of subcutaneous human hyperimmune immunoglobulin C19-IG20% to asymptomatic individuals with SARS-CoV-2 infection was safe but did not prevent development of symptomatic COVID-19. Funding: Grifols