Effectiveness of Trachomatous Trichiasis Case-identification Approaches in Ethiopia.

BACKGROUND: Trachoma control programs use multiple approaches to identify individuals with trachomatous trichiasis (TT). Evidence is limited regarding which approaches are most effective and cost-efficient. METHODS: We evaluated the effectiveness of two TT case-identification approaches in Ethiopia: community mobilization to encourage self-referral for centralized screening and house-to-house screenings conducted by case finders. We compared the number of true cases found per 1000 population and costs associated with case identification under each approach, stratified by villages that received one or multiple screening visits. RESULTS: We conducted screenings in 396 villages. In villages receiving one house-to-house visit, case finders identified 14,229 suspected cases, of whom 10,513 (73.9%) presented for TT confirmation. A median of 17.2% (interquartile range [IQR]: 9.1%-27.8%) of those presenting truly had TT (positive predictive value). In single-visit villages, the community mobilization approach yielded higher rates of confirmed cases than the house-to-house approach (1.5 [IQR: 1.1, 2.6] vs. 1.1 [IQR: 0.5, 1.9] cases per 1000 population), and the median cost of identifying a TT case was less ($5.59 vs. $31.18) using community mobilization than house-to-house. In multiple-visit villages, additional screening visits increased the median rate of confirmed cases to 2.5 per 1000 population in community mobilization villages, but the rate remained unchanged in house-to-house villages. CONCLUSIONS: Community mobilization-based TT case finding had a higher yield than house-to-house, at a substantially lower cost. Future research should examine whether additional tools to aid case finders in their diagnosis increases case-finding efficiency and accuracy and whether TT prevalence and surgical program duration impact case-finding success.

Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa.

BACKGROUND: We hypothesized that mass distribution of a broad-spectrum antibiotic agent to preschool children would reduce mortality in areas of sub-Saharan Africa that are currently far from meeting the Sustainable Development Goals of the United Nations. METHODS: In this cluster-randomized trial, we assigned communities in Malawi, Niger, and Tanzania to four twice-yearly mass distributions of either oral azithromycin (approximately 20 mg per kilogram of body weight) or placebo. Children 1 to 59 months of age were identified in twice-yearly censuses and were offered participation in the trial. Vital status was determined at subsequent censuses. The primary outcome was aggregate all-cause mortality; country-specific rates were assessed in prespecified subgroup analyses. RESULTS: A total of 1533 communities underwent randomization, 190,238 children were identified in the census at baseline, and 323,302 person-years were monitored. The mean (±SD) azithromycin and placebo coverage over the four twice-yearly distributions was 90.4±10.4%. The overall annual mortality rate was 14.6 deaths per 1000 person-years in communities that received azithromycin (9.1 in Malawi, 22.5 in Niger, and 5.4 in Tanzania) and 16.5 deaths per 1000 person-years in communities that received placebo (9.6 in Malawi, 27.5 in Niger, and 5.5 in Tanzania). Mortality was 13.5% lower overall (95% confidence interval [CI], 6.7 to 19.8) in communities that received azithromycin than in communities that received placebo (P<0.001); the rate was 5.7% lower in Malawi (95% CI, -9.7 to 18.9), 18.1% lower in Niger (95% CI, 10.0 to 25.5), and 3.4% lower in Tanzania (95% CI, -21.2 to 23.0). Children in the age group of 1 to 5 months had the greatest effect from azithromycin (24.9% lower mortality than that with placebo; 95% CI, 10.6 to 37.0). Serious adverse events occurring within a week after administration of the trial drug or placebo were uncommon, and the rate did not differ significantly between the groups. Evaluation of selection for antibiotic resistance is ongoing. CONCLUSIONS: Among postneonatal, preschool children in sub-Saharan Africa, childhood mortality was lower in communities randomly assigned to mass distribution of azithromycin than in those assigned to placebo, with the largest effect seen in Niger. Any implementation of a policy of mass distribution would need to strongly consider the potential effect of such a strategy on antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation; MORDOR ClinicalTrials.gov number, NCT02047981 .).

A New Surgical Technique for Postoperative Trachomatous Trichiasis.

INTRODUCTION: The World Health Organization has identified management of postoperative trichiasis (PTT) as one of the key remaining areas of focus needed to eliminate blinding trachoma as a public health problem. We developed the Bevel-Rotation Advancement Procedure (B-RAP) to treat individuals who need repeat trichiasis surgery. METHODS: Scarring caused by trichiasis surgery can cause the eyelid to become thick and distorted, making repeat surgery more difficult. To minimize eyelid thickness following B-RAP, a beveled incision of the tarsus is made allowing a marginal rotation of the eyelash fragment. Dissection between the anterior and posterior lamellae above the beveled incision and removal of scar tissue allows the marginal rotation to be combined with a posterior lamellar advancement to treat severely scarred eyelids with PTT and eyelid contour abnormalities (ECAs). RESULTS: Two surgeons performed B-RAP on 44 eyelids of 30 patients with PTT. The number of prior trachomatous trichiasis (TT) surgeries ranged from 2 to more than 4. At the 3-6 months postoperative visit, 37 eyelids (84%) had no recurrence of PTT. Three eyelids had central lashes touching; the remaining eyelids with recurrent PTT had nasal and temporal lashes touching. Fifteen eyelids (34%) had ECAs, but only 1 was severe. CONCLUSIONS: B-RAP was developed considering the altered eyelid anatomy found in the postsurgical eyelid with TT. Thinning of the eyelash fragment and removal of postoperative scar tissue improves the ability to advance and stabilize the eyelash fragment after external rotation. B-RAP shows promise as a procedure for improving outcomes of repeat trichiasis surgery.

Morbidity in a Longitudinal Cohort of Children Residing in Villages Randomized to Biannual Treatment With Azithromycin Versus Placebo.

BACKGROUND: The mechanisms underlying the finding of reduced child mortality in communities with biannual treatment with azithromycin remain unclear. We determined if there was a difference in morbidity in a cohort of children aged 1-36 months, residing in communities randomized to biannual treatment of preschool-aged children with azithromycin or placebo. METHODS: Thirty villages in Kilosa, Tanzania, were randomly assigned to receive biannual treatment of all children aged 1-59 months with either azithromycin (20/mg/kg single dose) or placebo. Children who were aged 1-36 months and participated in the baseline survey were enrolled in this cohort study and followed prospectively for 2 years. Children were monitored every 6 months for signs and symptoms of diarrheal disease, acute respiratory illness, and anemia. Mixed-effects models that include age, time, treatment arm, and the interaction of treatment arm and time as independent predictors were used to evaluate differences between children by treatment assignment over time. RESULTS: There was no difference in rates of diarrhea, fever, or anemia by treatment arm at baseline and at all phases of follow-up. The decline over time in reported cough was statistically significant in the children residing in the azithromycin communities, but not in the placebo communities. Once adjusting for clustering and age, the difference in decline between the 2 treatment arms was not significant (P = .09). CONCLUSIONS: A beneficial effect of azithromycin treatment on morbidity outcomes was not evident at biannual surveys. CLINICAL TRIALS REGISTRATION: NCT02048007.

Mass Oral Azithromycin for Childhood Mortality: Timing of Death After Distribution in the MORDOR Trial.

In a large community-randomized trial, biannual azithromycin distributions significantly reduced postneonatal childhood mortality in sub-Saharan African sites. Here, we present a prespecified secondary analysis showing that much of the protective effect was in the first 3 months postdistribution. Distributing more frequently than biannually could be considered if logistically feasible. Clinical Trials Registration. NCT02047981.

The impact on malaria of biannual treatment with azithromycin in children age less than 5 years: a prospective study.

BACKGROUND: The MORDOR study, a cluster randomized clinical trial, showed that single-dose azithromycin (20 mg/kg) administered biannually for 2 years to preschool children reduced mortality; a study was conducted to determine its effect on clinical symptomatic episodes of malaria as a potential mechanism for mortality benefit. METHODS: A randomized control trial (RCT) was conducted, whereby 30 randomly selected communities in Kilosa District, Tanzania were randomized to receive 6-monthly treatment of children ages 1-59 months with single-dose azithromycin (20 mg/kg) vs. placebo. A prospective cohort study was nested within the RCT: children, aged 1 to 35 months at baseline, were randomly selected in each community and evaluated at 6-monthly intervals for 2 years. At each visit, the children were assessed for recent or ongoing fever and anti-malarial treatment; a rapid diagnostic test (RDT) for malaria was performed. The two major outcomes of interest were prevalence of RDT positivity and clinical malaria. The latter was defined as RDT-positivity with fever at time of evaluation and/or reported fever in the 3 days prior to evaluation. Methods that account for correlations at community level and within individuals over time were used to evaluate associations. RESULTS: At baseline, the prevalence rates in the children in the azithromycin and placebo arms were 17.6% vs. 15.5% for RDT positivity (p = 0.76) and 6.1% vs. 4.3% (p = 0.56) for clinical malaria. There was a decline in both RDT-positivity and clinical malaria over time in both arms. The difference by treatment assignment was not significant for clinical malaria; it was significant for RDT-positivity with greater odds of decline in the placebo arm (p = 0.01). CONCLUSIONS: Lack of evidence for a significant difference in the prevalence of clinical malaria in children at any visit following treatment suggests that the effect of single-dose azithromycin on malaria is at best transient and limited in scope. Chance overrepresentation of non-seasonal transmission in the communities in the azithromycin arm may account for higher rates of RDT-positivity and less decline over time. Trial registration Clinicaltrials.gov NCT02047981.

The impact of modified incision height and surgical procedure on trichiasis surgery outcomes: Results of the maximizing trichiasis surgery success (MTSS) randomized trial.

BACKGROUND: Poor surgical outcomes remain a problem in trachoma-endemic countries working to reach elimination thresholds. Methods to improve outcomes could positively impact programmatic success. METHODS: This parallel, three-armed clinical trial conducted in Ethiopia randomized individuals with previously unoperated trachomatous trichiasis (TT) to receive surgery utilizing one of three approaches: bilamellar tarsal rotation with a 3 mm incision height (BLTR-3), BLTR with 5 mm incision height (BLTR-5) and posterior lamellar tarsal rotation (PLTR). We followed participants for one year. The primary outcome was post-operative trichiasis (PTT). Secondary outcomes were eyelid contour abnormalities (ECA) and pyogenic granulomata. FINDINGS: We randomized and operated on 4,914 individuals with previously unoperated TT (6,940 eyes). Primary analyses include 6,815 eyes with follow-up. Overall, 1,149 (16.9%) eyes developed PTT. The risk difference for PTT was minimal comparing BLTR-3 and PLTR (adjusted risk difference [aRD] 1.8% (98.3%CI: -0.5-4.2%)), but significantly higher for BLTR-5 surgeries compared to BLTR-3 (aRD: 6.7% (3.9-9.4%)) and PLTR (aRD: 8.6% (5.9-11.3%)). BLTR-5 had the lowest ECA (6.1% versus 9.6% BLTR-3, 11.2% PLTR) and granuloma rates (5.2% versus 6.5% BLTR-3 and 7.5% PLTR). One eyelid operated with PLTR experienced an eyelid margin division; four BLTR-3 and eight BLTR-5 eyelids experienced excessive bleeding. INTERPRETATION: We do not recommend modifying the BLTR incision height of 3 mm. Overall, we did not find a significant difference in PTT between BLTR-3 and PLTR in terms of PTT or ECA. TRIAL REGISTRATION: Registration number: NCT03100747; ClinicalTrials.gov Full study protocol available at (https://doi.org/10.15139/S3/QHZXWD).

Causes of death after biannual azithromycin treatment: A community-level randomized clinical trial.

The MORDOR study, a masked, community-level randomized clinical trial conducted in Niger, Malawi and Tanzania (2015 to 2017), showed that biannual administration of single-dose azithromycin to preschool children reduced all-cause mortality. We sought to evaluate its impact on causes of death in children aged 1-59 months in Tanzania. A random sampling of 614 communities was conducted in Kilosa District, Tanzania, with simple random assignment of communities to receive either azithromycin or placebo. In these communities, a census was carried out every 6 months and children aged 1-59 months received biannual (every 6 months), single-dose azithromycin (~20mg/kg) or placebo depending on community assignment, over a 2-year period. Mortality was determined at the time of the biannual census. For child deaths, a verbal autopsy was performed to ascertain the cause using a standardized diagnostic classification. A total of 190- (0.58 /100 person-years) and 200 deaths (0.59/100 person-years) were reported in the azithromycin and placebo arms, respectively. Malaria, pneumonia and diarrhea, accounted for 71% and 68% of deaths in the respective arms. Overall, the mortality was not different by treatment arm, nor were the distribution of causes of death after adjusting for community clustering. The cause-specific mortality for diarrhea/pneumonia was no different over time. In children aged 1-5 months, 32 deaths occurred in the placebo arm and 25 deaths occurred in the azithromycin arm; 20 (62.5%) deaths in the placebo- and 10 (40%) in the azithromycin arm were attributed to diarrhea or pneumonia. Neither differences in the number of deaths nor the diarrhea/pneumonia attribution was statistically significant after adjusting for community clustering. In conclusion, azithromycin was not associated with a significant decline in deaths by specific causes compared to placebo. The non-significant lower rates of diarrhea or pneumonia in children <6 months who received azithromycin merit further investigation in high-mortality settings. Trial registration: NCT02048007.

Impact of Biannual Azithromycin on Anemia in Preschool Children in Kilosa District, Tanzania: A Cluster-Randomized Clinical Trial.

A cluster-randomized clinical trial showed that biannual single-dose azithromycin reduced mortality in preschool children; we sought to determine the effect on anemia. A simple random sample of 30 communities from Kilosa district, Tanzania, were themselves randomized to receive either 6-monthly treatment of children aged 1-59 months with single-dose azithromycin or placebo. From each community, 40 preschool children were randomly selected at baseline, 12 months, and 24 months. At surveys, the children underwent hemoglobin testing; WHO definitions for anemia were applied. After adjusting for community clustering, the prevalence of anemia was not significantly different by treatment assignment at baseline, 12 months, and 24 months. In each of the cross-sectional surveys, anemia prevalence was associated with younger age; the odds of being anemic was highest in those aged < 12 months. There was also a general decrease in the prevalence of anemia during the study. Although azithromycin was not shown to affect anemia, significantly, the study highlights burden of anemia in rural, African communities.

Biannual Treatment of Preschool Children with Single Dose Azithromycin to Reduce Mortality: Impact on Azithromycin Resistance in the MORDOR Trial in Tanzania.

The Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance study showed that administration of biannual, single-dose azithromycin to preschool children reduces mortality. We sought to evaluate its impact on azithromycin resistance. Thirty randomly selected communities in Kilosa district, Tanzania, were randomized to receive 6-monthly single-dose azithromycin (∼20 mg/kg) versus placebo treatment of children aged 1-59 months. From each community, 40 children (aged 1-59 months) were randomly selected at baseline, 12 and 24 months. Isolation and resistance testing of Streptococcus pneumoniae and Escherichia coli were evaluated using nasopharyngeal and rectal swabs, respectively. The carriage prevalence and the proportion of azithromycin-resistant isolates were determined using disk diffusion. At baseline, the characteristics of the randomly selected children were similar by treatment arms. Both at baseline and in annual cross-sectional surveys, rates of S. pneumoniae and E. coli isolation between treatment arms were similar. The proportions of azithromycin-resistant S. pneumoniae isolates in the children in communities treated with azithromycin versus placebo at baseline, 12 months, and 24 months were 26.5% (18.1%; P = 0.26), 26.8% (16.5%; P = 0.29), and 13.4% (17.0%; P = 0.57), respectively. The proportions of azithromycin-resistant E. coli isolates at baseline, 12 months, and 24 months in the azithromycin (versus placebo) arms were 14.9% (18.9%; P = 0.16), 21.5% (16.6%; P = 0.10), and 14.9% (14.7%; P = 0.95), respectively. Over the 24 months, the mean treatment coverage for the azithromycin and placebo was 76.9% and 74.8%, respectively (P = 0.49). Biannual administration of single-dose azithromycin to children did not appear to result in excess azithromycin resistance in S. pneumoniae and E. coli isolates over 24 months of follow-up.

A Cross-Sectional Study of the Availability of Azithromycin in Local Pharmacies and Associated Antibiotic Resistance in Communities in Kilosa District, Tanzania.

Mass drug administration (MDA) for trachoma control using azithromycin has generated concern for the development of resistant organisms. However, the contribution from azithromycin available in local pharmacies has not been studied. In Kilosa district, Tanzania, MDA stopped over 4 years ago, and this study sought to determine the availability of azithromycin in local pharmacies and correlate it with azithromycin resistance in children born after MDA. A cross-sectional survey was conducted in 644 randomly selected hamlets in Kilosa district, in which the presence of a pharmacy and the availability of azithromycin and erythromycin were determined. In 30 randomly selected hamlets, a random sample of 60 children less than 5 years were tested for azithromycin-resistant Streptococcus pneumoniae (Spn) and Escherichia coli (Ec), from nasopharyngeal and rectal swabs, based on disk diffusion criteria. Only 26.6% of hamlets had a pharmacy. Azithromycin and erythromycin were available in 30.8% and 89.1% of pharmacies closest to the hamlets, respectively. In the 30 communities tested for resistance, the overall prevalence of azithromycin-resistant Spn isolates was 14%. Six of seven (87%) hamlets where azithromycin was available had resistant Spn, compared with 14 of 23 (61%) hamlets without availability. Similarly, six of seven (87%) hamlets where azithromycin was available had resistant Ec isolates compared with 21 of 23 (70%) hamlets without availability. However, the differences were not statistically significant (P = 0.46 and 0.49, respectively). The availability of azithromycin in pharmacies in the district was limited, and a strong correlation with azithromycin-resistant Spn or Ec was not observed.

The Babesia observational antibody (BAOBAB) study: A cross-sectional evaluation of Babesia in two communities in Kilosa district, Tanzania.

BACKGROUND: Babesia, a tick-borne genus of intraerythrocytic parasites, is understudied in humans outside of established high-endemic areas. There is a paucity of data on Babesia in Africa, despite evidence that it is regionally present. A pilot study suggested that Babesia was present in a rural district of Tanzania. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional study was conducted July-August 2017: residents in a case hamlet that had clustering of subjects with high signal-to-cut off (S/CO) ratios for antibodies against B. microti in the pilot study, and a control hamlet that had lacked significant signal, were evaluated for B. microti. Subjects aged ≥15yrs (n = 299) underwent clinical evaluation and household inspections; 10ml whole blood was drawn for Babesia transcription mediated amplification (TMA), B. microti indirect fluorescent antibody testing (IFA) and rapid diagnostic testing (RDT) for Plasmodium spp. Subjects aged <15yrs (n = 266) underwent a RDT for Plasmodium and assessment by ELISA for B. microti antibodies. A total of 570 subjects participated (mean age 22 [<1 to 90yrs]) of whom 50.7% were female and 145 (25.5%) subjects were Plasmodium RDT positive (+). In those <15yrs, the median ELISA S/CO was 1.11 (IQR 0.80-1.48); the median S/CO in the case (n = 120) and control (n = 146) hamlets was 1.19 (IQR 0.81-1.48) and 1.06 (IQR 0.80-1.50) respectively (p = 0.4). Children ≥5yrs old were more likely to have a higher S/CO ratio than those <5yrs old (p<0.001). One hundred (38%) subjects <15yrs were Plasmodium RDT+. The median S/CO ratio (children <15yrs) did not differ by RDT status (p = 0.15). In subjects ≥15yrs, no molecular test was positive for Babesia, but four subjects (1.4%) were IFA reactive (two each at titers of 128 and 256). CONCLUSIONS/SIGNIFICANCE: The findings offer further support for Babesia in rural Tanzania. However, low prevalence of seroreactivity questions its clinical significance.

Babesia microti and Malaria Infection in Africa: A Pilot Serosurvey in Kilosa District, Tanzania.

Babesia is a tick-borne intraerythrocytic parasite that is clinically and diagnostically similar to malaria parasite, conferring risk of misdiagnosis in areas where both parasites are endemic. Data on Babesia in humans in Africa are lacking, despite evidence that it is present in regional animal populations. Samples that were collected in November 2014 to July 2015 in Kilosa district, Tanzania, were evaluated for evidence of malaria and Babesia infection. Clinical data and laboratory samples (i.e., hemoglobin, rapid diagnostic testing [RDT] for malaria, peripheral blood smear, and dried blood spots) from a routine survey were available for analysis. Dried blood spots were tested using an investigational enzyme linked immunosorbent assay (ELISA) against Babesia microti. A total of 1,030 children aged 1 month to < 5 years were evaluated; 186 (18.1%) were malaria RDT positive, 180 (96.8%) of whom had peripheral smears reviewed; 70/180 (38.9%) were smear positive for parasites. The median (inter quartile range) and range of B. microti ELISA signal to cutoff (S/C) ratio was 0.10 (0.06-0.15) and 0.01-1.65, respectively; the S/C ratios were significantly higher in subjects ≥ 1 year as compared with those < 1 year old (P < 0.001). There was also a statistically significant association between a positive RDT for malaria and the Babesia S/C (median 0.09 versus 0.13 in RDT negative versus RDT positive, respectively; P < 0.001). The highest S/C ratios were disproportionately clustered in a few hamlets. The findings suggest that Babesia may be present in Kilosa district, Tanzania. However, serological cross-reactivity and false positivity, notably between Babesia and Plasmodium spp., cannot be definitively excluded and have implications for testing in other settings.

Antibiotic Resistance in Young Children in Kilosa District, Tanzania 4 Years after Mass Distribution of Azithromycin for Trachoma Control.

Mass administration of azithromycin (MDA) is integral to trachoma control. Recent studies suggest that MDA may increase drug-resistant pathogens, yet findings from prior studies suggest little long-term impact on resistance. This disparity may be linked to differences in pre-MDA community-level resistance patterns. We describe carriage prevalence and antibiotic resistance patterns for Streptococcus pneumoniae (Spn) (nasopharyngeal swab collection), Staphylococcus aureus (SA) (nasopharyngeal swabs), and Escherichia coli (EC) (rectal swabs) in 1,047 children ages 1-59 months in a district with MDA cessation 4 years ago. Antibiotic susceptibility was evaluated by disk diffusion and Etest. The carriage rates for Spn, SA, and EC were 43.5% (455/1,047), 13.2% (138/1,047), and 61.7% (646/1,047), respectively. Resistance to AZM was observed in 14.3%, 29.0%, and 16.6% of the Spn, SA, and EC isolates, respectively. Spn resistance was variable (0-67%) by hamlet. Future analyses will assess the influence of pre-MDA antibiotic resistance patterns on those observed following MDA.

Can We Use Antibodies to Chlamydia trachomatis as a Surveillance Tool for National Trachoma Control Programs? Results from a District Survey.

BACKGROUND: Trachoma is targeted for elimination by 2020. World Health Organization advises districts to undertake surveillance when follicular trachoma (TF) <5% in children 1-9 years and mass antibiotic administration has ceased. There is a question if other tools could be used for surveillance as well. We report data from a test for antibodies to C. trachomatis antigen pgp3 as a possible tool. METHODOLOGY: We randomly sampled 30 hamlets in Kilosa district, Tanzania, and randomly selected 50 children ages 1-9 per hamlet. The tarsal conjunctivae were graded for trachoma (TF), tested for C. trachomatis infection (Aptima Combo2 assay: Hologic, San Diego, CA), and a dried blood spot processed for antibodies to C. trachomatis pgp3 using a multiplex bead assay on a Luminex 100 platform. PRINCIPAL FINDINGS: The prevalence of trachoma (TF) was 0.4%, well below the <5% indicator for re-starting a program. Infection was also low, 1.1%. Of the 30 hamlets, 22 had neither infection nor TF. Antibody positivity overall was low, 7.5% and increased with age from 5.2% in 1-3 year olds, to 9.3% in 7-9 year olds (p = 0.015). In 16 of the 30 hamlets, no children ages 1-3 years had antibodies to pgp3. CONCLUSIONS: The antibody status of the 1-3 year olds indicates low cumulative exposure to infection during the surveillance period. Four years post MDA, there is no evidence for re-emergence of follicular trachoma.