Last data update: Jan 27, 2025. (Total: 48650 publications since 2009)
Records 1-27 (of 27 Records) |
Query Trace: Goodhew B[original query] |
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Integrated serosurveillance for onchocerciasis, lymphatic filariasis, and schistosomiasis in North Darfur, Sudan
Coalson JE , Noland GS , Nute AW , Goodhew EB , Martin DL , Abdalla Z , Zarroug I , Gabralla S , Ismail Haha , Secor WE , Callahan EK , Sanders AM , Elshafie B , Nash SD . Am J Trop Med Hyg 2024 Sudan is endemic for multiple neglected tropical diseases, including trachoma, onchocerciasis (OV), lymphatic filariasis (LF), and schistosomiasis (SCH). In 2019, dried blood spot samples were collected for a baseline trachoma serosurvey in three localities (El Seraif, Kotom, and Saraf Omrah) in North Darfur State. None were classified previously as OV- or LF-endemic, although low levels of SCH had been identified in all three. Approximately 30 households from 25 communities in each locality were selected by multistage cluster random sampling. Collections of DBSs were analyzed by multiplex bead assay for antibodies to multiple pathogens. This paper presents data on OV (Ov16), LF (Wb123, Bm14, Bm33), and SCH (soluble egg antigen [SEA], Sm25) antibodies among 8,322 individuals from 2,119 households. The survey-adjusted seroprevalence estimates for Ov16 were <0.3% in all localities. Lymphatic filariasis-antigen seroprevalences were discordant. Seroprevalence estimates ranged from 4.6-6.0% (Wb123), 0.99-1.4% (Bm14), and 29.2-33.3% (Bm33). Schistosomiasis seroprevalence estimates among school-aged children ranged from 2.7-8.0% (SEA) and 10.9-15.6% (Sm25). Ov16 seropositivity was low and supported the localities' classification as nonendemic. The results suggested LF exposure, but discordance between antigens, challenges defining seropositivity thresholds, and the absence of programmatic guidance based on antibody serology alone for Wuchereria bancrofti indicate a need for remapping surveys to confirm transmission. Schistosomiasis antibody levels were high enough to warrant further mapping to guide treatment decisions. The lack of gold standards limited interpretation of results, particularly for LF, but in resource-challenged areas, integrated serological surveillance offers the possibility of efficient monitoring of exposure to multiple diseases. |
Serological responses to trachoma antigens prior to the start of mass drug administration: Results from population-based baseline surveys, North Darfur, Sudan
Sanders AM , Elshafie BE , Abdalla Z , Simmons C , Goodhew EB , Gonzalez TA , Nute AW , Mohammed A , Callahan EK , Martin DL , Nash SD . Am J Trop Med Hyg 2024 After years of programmatic inaccessibility, in 2019-2020 the Sudan Federal Ministry of Health Trachoma Control Program conducted population-based trachoma surveys in three localities (districts) in North Darfur state, Sudan. These baseline surveys were to determine the prevalence of trachomatous inflammation-follicular (TF) among children aged 1-9 years and to further use serological markers to understand the historical trachoma burden within this mass drug administration (MDA)-naive area. Trained and certified graders collected trachoma clinical data, and trained nurses collected dried blood spot (DBS) samples. The DBSs were assayed on a multiplex bead array for antibody responses to the Chlamydia trachomatis antigens Pgp3 and CT694. Across the three localities, 3,613 individuals aged 1-9 years and 3,542 individuals aged ≥15 years were examined for clinical signs, and 8,322 DBSs were collected. The prevalence of TF among children aged 1-9 years was endemic (≥5%) in two localities (El Seraif, 15.6%, and Saraf Omrah, 11.0%) and below the TF elimination threshold (<5%) in the third (Kotom, 1.4%). The Pgp3 seroprevalence among children aged 1-9 years was 34.1% in El Seraif, 35.0% in Saraf Omrah, and 11.0% in Kotom. Locality prevalence results were similar for Pgp3 and CT694. Seroprevalence increased with age in all three localities. Serological data collected within these surveys demonstrate that all three localities have had a long history of exposure to Chlamydia trachomatis and that two of the three localities require MDA to reach elimination as a public health problem threshold. |
Effect of biannual azithromycin distribution on antibody responses to malaria, bacterial, and protozoan pathogens among children: A cluster-randomized, placebo-controlled trial in Niger (preprint)
Arzika AM , Maliki R , Goodhew EB , Rogier E , Priest JW , Lebas E , O'Brien KS , Le V , Oldenburg CE , Doan T , Porco TC , Keenan JD , Lietman TM , Martin DL , Arnold BF . medRxiv 2021 2021.04.23.21255957 Background The Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) trial in Niger, Malawi, and Tanzania found that biannual mass distribution of azithromycin to children younger than 5 years led to a 13.5% reduction in all-cause mortality. Additional endpoints in the trial have attempted to elucidate the mechanisms for mortality reduction. In this pre-specified secondary analysis, we assessed the effect of azithromycin compared with placebo on IgG- based measures of infectious disease exposure with a multiplex bead assay that included antigens to malaria parasites (Plasmodium falciparum, P. vivax, P. malariae, P. ovale), bacterial pathogens (Campylobacter spp., enterotoxigenic Escherichia coli, Vibrio cholerae, Salmonella enterica, Streptococcus pyogenes) and protozoans (Cryptosporidium parvum, Giardia duodenales).Methods and Findings Thirty communities in rural Niger were randomized 1:1 to biannual distributions of azithromycin or placebo among children ages 1-59 months. The analysis included 5,642 blood specimens collected from 3,814 children ages 1-59 months, measured at 6, 12, 24, and 36 months of follow-up in a repeated cross-sectional design. Campylobacter spp. seroprevalence averaged over all study visits was lower in azithromycin communities compared to placebo (91% vs 94%, difference = –3%, 95% CI: –5%, –1%; P=0.03), which corresponded to a 29% lower seroconversion rate (1.30 versus 1.84 seroconversions per year, hazard ratio = 0.71, 95% CI: 0.56, 0.89; P=0.004). Antibody-based measures of infection with P. falciparum and group A streptococcus were consistently lower in azithromycin communities, but were not statistically different from placebo, and there were no other differences across pathogens. Strengths of the study included masking of participants, investigators, and analysts, high treatment coverage, large sample size, and objective outcomes. Principal limitations included the timing of blood collection with respect to treatment (approximately 6 months later, which could have missed transient effects in the weeks immediately following treatment), and the durability of IgG response following clearance of infection. Both limitations would lead the trial to under-estimate effects on antibody-based measures of infection.Conclusions The reduction in Campylobacter spp. despite these limitations suggests an effect on carriage, findings which align with an independent metagenomic analysis of rectal swabs collected in the same villages and with previously reported reductions in dysentery-associated mortality. Given significant sequelae of Campylobacter infection among preschool aged children, our results support at least one possible mechanism through which biannual mass distribution of azithromycin likely reduced mortality in this study population.Competing Interest StatementThis work was supported by the Bill & Melinda Gates Foundation (award no. OPP1032340 to TML) and was supported in part by an unrestricted grant from Research to Prevent Blindness and by the National Institute of Allergy and Infectious Diseases (award no. K01-AI119180 to BFA). The Gates Foundation approved the study design, but had no role in data collection, data analysis, data interpretation, or writing of the report. The authors declare no competing interests. The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the Public Health Service or by the U.S. Department of Health and Human Services. Clinical TrialNCT02048007Funding StatementThis work was supported by the Bill & Melinda Gates Foundation (award no. OPP1032340 to TML) and was supported in part by an unrestricted grant from Research to Prevent Blindness and by the National Institute of Allergy and Infectious Diseases (award no. K01-AI119180 to BFA). The Gates Foundation approved the study design, but had no role in data collection, data nalysis, data interpretation, or writing of the report.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The trial protocol was reviewed and approved by the Committee on Human Research at the University of California, San Francisco, and the Niger Ministry of Health's Ethical Committee. Parents or guardians of enrolled children provided oral consent before each azithromycin or placebo treatment and at each specimen collection visit. Parents or guardians were instructed to report any adverse event within 7 days of treatment by contacting their village representative, who then reported events to the site coordinator and UCSF. An independent Data and Safety Monitoring Committee provided additional oversight. CDC researchers had access to de-identified samples for analysis (no personally identifying information).All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData and computational notebooks used to conduct the analyses are available through the Open Science Framework (https://osf.io/954bt) and Dryad (xx DOI forthcoming xx). Analyses used R statistical software, version 4.0.2. https://osf.io/954bt |
Enteropathogen antibody dynamics and force of infection among children in low-resource settings (preprint)
Arnold BF , Martin DL , Juma J , Mkocha H , Ochieng JB , Cooley GM , Omore R , Goodhew EB , Morris JF , Costantini V , Vinje J , Lammie PJ , Priest JW . bioRxiv 2019 522920 Little is known about enteropathogen seroepidemiology among children in low-resource settings. We measured serological IgG responses to eight enteropathogens (Giardia intestinalis, Cryptosporidium parvum, Entamoeba histolytica, Salmonella enterica, enterotoxigenic Escherichia coli, Vibrio cholerae, Campylobacter jejuni, norovirus) in cohorts from Haiti, Kenya, and Tanzania. We studied antibody dynamics and force of infection across pathogens and cohorts. Enteropathogens shared common seroepidemiologic features that enabled between-pathogen comparisons of transmission. Overall, exposure was intense: for most pathogens the window of primary infection was <3 years old; for highest transmission pathogens primary infection occurred within the first year. Longitudinal profiles revealed significant IgG boosting and waning above seropositivity cutoffs, underscoring the value of longitudinal designs to estimate force of infection. Seroprevalence and force of infection were rank-preserving across pathogens, illustrating the measures provide similar information about transmission heterogeneity. Our findings suggest multiplex antibody assays are a promising approach to measure population-level enteropathogen transmission in serologic surveillance. |
Monitoring transmission intensity of trachoma with serology: a multi-country study (preprint)
Tedijanto C , Solomon AW , Martin DL , Nash SD , Keenan JD , Lietman TM , Lammie PJ , Aiemjoy K , Amza A , Aragie S , Arzika AM , Callahan EK , Carolan S , Dawed AA , Goodhew EB , Gwyn S , Hammou J , Kadri B , Kalua K , Maliki R , Nassirou B , Seife F , Tadesse Z , West SK , Wittberg DM , Zeru T , Arnold BF . medRxiv 2023 16 Trachoma, caused by ocular Chlamydia trachomatis infection, is targeted for global elimination as a public health problem by 2030. To provide evidence for use of antibodies to monitor C. trachomatis transmission, we collated IgG responses to Pgp3 antigen, PCR positivity, and clinical observations from 19,811 children aged 1-9 years in 14 populations. We demonstrate that age-seroprevalence curves consistently shift along a gradient of transmission intensity: rising steeply in populations with high levels of infection and active trachoma and becoming flat in populations near elimination. Seroprevalence (range: 0-54%) and seroconversion rates (range: 0-15 per 100 person-years) correlate with PCR prevalence (r: 0.88, 95% CI: 0.77, 0.93). A seroprevalence threshold of 13.5% (seroconversion rate 2.75 per 100 person-years) identifies clusters with any infection at high sensitivity (>90%) and moderate specificity (69-75%). Antibody responses in young children provide a robust, generalizable approach to monitor population progress toward and beyond trachoma elimination. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license. |
Changes in trachoma indicators in Kiribati with two rounds of azithromycin mass drug administration, measured in serial population-based surveys
Goodhew EB , Taoaba R , Harding-Esch EM , Gwyn SE , Bakhtiari A , Butcher R , Cama A , Guagliardo SAJ , Jimenez C , Mpyet CD , Tun K , Wickens K , Solomon AW , Martin DL , Tekeraoi R . PLoS Negl Trop Dis 2023 17 (7) e0011441 Baseline mapping in the two major population centers of Kiribati showed that trachoma was a public health problem in need of programmatic interventions. After conducting two annual rounds of antibiotic mass drug administration (MDA), Kiribati undertook trachoma impact surveys in 2019, using standardized two-stage cluster surveys in the evaluation units of Kiritimati Island and Tarawa. In Kiritimati, 516 households were visited and in Tarawa, 772 households were visited. Nearly all households had a drinking water source and access to an improved latrine. The prevalence of trachomatous trichiasis remained above the elimination threshold (0.2% in ≥15-year-olds) and was virtually unchanged from baseline. The prevalence of trachomatous inflammation-follicular (TF) in 1-9-year-olds decreased by approximately 40% from baseline in both evaluation units but remained above the 5% TF prevalence threshold for stopping MDA. TF prevalence at impact survey was 11.5% in Kiritimati and 17.9% in Tarawa. Infection prevalence in 1-9-year-olds by PCR was 0.96% in Kiritimati and 3.3% in Tarawa. Using a multiplex bead assay to measure antibodies to the C. trachomatis antigen Pgp3, seroprevalence in 1-9-year-olds was 30.2% in Kiritimati and 31.4% in Tarawa. The seroconversion rate, in seroconversion events/100 children/year, was 9.0 in Kiritimati and 9.2 in Tarawa. Seroprevalence and seroconversion rates were both assessed by four different assays, with strong agreement between tests. These results show that, despite decreases in indicators associated with infection at impact survey, trachoma remains a public health problem in Kiribati, and provide additional information about changes in serological indicators after MDA. |
Monitoring transmission intensity of trachoma with serology
Tedijanto C , Solomon AW , Martin DL , Nash SD , Keenan JD , Lietman TM , Lammie PJ , Aiemjoy K , Amza A , Aragie S , Arzika AM , Callahan EK , Carolan S , Dawed AA , Goodhew EB , Gwyn S , Hammou J , Kadri B , Kalua K , Maliki R , Nassirou B , Seife F , Tadesse Z , West SK , Wittberg DM , Zeru Tadege T , Arnold BF . Nat Commun 2023 14 (1) 3269 Trachoma, caused by ocular Chlamydia trachomatis infection, is targeted for global elimination as a public health problem by 2030. To provide evidence for use of antibodies to monitor C. trachomatis transmission, we collated IgG responses to Pgp3 antigen, PCR positivity, and clinical observations from 19,811 children aged 1-9 years in 14 populations. We demonstrate that age-seroprevalence curves consistently shift along a gradient of transmission intensity: rising steeply in populations with high levels of infection and active trachoma and becoming flat in populations near elimination. Seroprevalence (range: 0-54%) and seroconversion rates (range: 0-15 per 100 person-years) correlate with PCR prevalence (r: 0.87, 95% CI: 0.57, 0.97). A seroprevalence threshold of 13.5% (seroconversion rate 2.75 per 100 person-years) identifies clusters with any PCR-identified infection at high sensitivity ( >90%) and moderate specificity (69-75%). Antibody responses in young children provide a robust, generalizable approach to monitor population progress toward and beyond trachoma elimination. |
Validation of immunoassays for the Chlamydia trachomatis antigen Pgp3 using a chimeric monoclonal antibody
Goodhew B , Tang X , Goldstein J , Lee J , Martin D , Gwyn S . Sci Rep 2023 13 (1) 7281 Seroepidemiology, or measuring antibodies to pathogens to estimate population-level exposure, can provide useful public health data. The tests used, however, often lack sufficient validation data due to absence of a gold standard. For many pathogens, serum antibodies can be detected long after resolution of infection, but infection status is often used as a gold standard for antibody positivity. To ensure that recently developed antibody tests for seroepidemiology of Chlamydia trachomatis (Ct), the causative agent of urogenital chlamydia and the blinding eye disease trachoma, have high performance, we generated a chimeric antibody to the immunodominant Ct antigen Pgp3. Two clones were selected to evaluate the test performance of three assays to measure antibodies to Pgp3: multiplex bead assay (MBA), enzyme-linked immunosorbent assay (ELISA), and lateral flow assay (LFA). Overall, each assay demonstrated high accuracy and precision when tested using either clone, and the clones were stable when stored at - 20 °C and 4 °C for almost 2 years. The limit of detection was similar for MBA and LFA, but almost a log-fold higher (i.e. less sensitive) using ELISA. Overall, the chimeric antibodies represent stable control reagents for tests with robust performance and will facilitate deployment of these tests to other laboratories. |
Effect of biannual mass azithromycin distributions to preschool-aged children on trachoma prevalence in Niger: A cluster randomized clinical trial
Arzika AM , Mindo-Panusis D , Abdou A , Kadri B , Nassirou B , Maliki R , Alsoudi AF , Zhang T , Cotter SY , Lebas E , O'Brien KS , Callahan EK , Bailey RL , West SK , Goodhew EB , Martin DL , Arnold BF , Porco TC , Lietman TM , Keenan JD . JAMA Netw Open 2022 5 (8) e2228244 IMPORTANCE: Because transmission of ocular strains of Chlamydia trachomatis is greatest among preschool-aged children, limiting azithromycin distributions to this age group may conserve resources and result in less antimicrobial resistance, which is a potential advantage in areas with hypoendemic trachoma and limited resources. OBJECTIVE: To determine the efficacy of mass azithromycin distributions to preschool-aged children as a strategy for trachoma elimination in areas with hypoendemic disease. DESIGN, SETTING, AND PARTICIPANTS: In this cluster randomized clinical trial performed from November 23, 2014, until July 31, 2017, thirty rural communities in Niger were randomized at a 1:1 ratio to biannual mass distributions of either azithromycin or placebo to children aged 1 to 59 months. Participants and study personnel were masked to treatment allocation. Data analyses for trachoma outcomes were performed from October 19, 2021, through June 10, 2022. INTERVENTIONS: Every 6 months, a single dose of either oral azithromycin (20 mg/kg using height-based approximation for children who could stand or weight calculation for small children) or oral placebo was provided to all children aged 1 to 59 months. MAIN OUTCOMES AND MEASURES: Trachoma was a prespecified outcome of the trial, assessed as the community-level prevalence of trachomatous inflammation-follicular and trachomatous inflammation-intense through masked grading of conjunctival photographs from a random sample of 40 children per community each year during the 2-year study period. A secondary outcome was the seroprevalence of antibodies to C trachomatis antigens. RESULTS: At baseline, 4726 children in 30 communities were included; 1695 children were enrolled in 15 azithromycin communities and 3031 children were enrolled in 15 placebo communities (mean [SD] proportions of boys, 51.8% [4.7%] vs 52.0% [4.2%]; mean [SD] age, 30.8 [2.8] vs 30.6 [2.6] months). The mean coverage of study drug for the 4 treatments was 79% (95% CI, 75%-83%) in the azithromycin group and 82% (95% CI, 79%-85%) in the placebo group. The mean prevalence of trachomatous inflammation-follicular at baseline was 1.9% (95% CI, 0.5%-3.5%) in the azithromycin group and 0.9% (95% CI, 0-1.9%) in the placebo group. At 24 months, trachomatous inflammation-follicular prevalence was 0.2% (95% CI, 0-0.5%) in the azithromycin group and 0.8% (95% CI, 0.2%-1.6%) in the placebo group (incidence rate ratio adjusted for baseline: 0.18 [95% CI, 0.01-1.20]; permutation P = .07). CONCLUSIONS AND RELEVANCE: The findings of this trial do not show that biannual mass azithromycin distributions to preschool-aged children were more effective than placebo, although the underlying prevalence of trachoma was low. The sustained absence of trachoma even in the placebo group suggests that trachoma may have been eliminated as a public health problem in this part of Niger. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02048007. |
Effect of biannual azithromycin distribution on antibody responses to malaria, bacterial, and protozoan pathogens in Niger
Arzika AM , Maliki R , Goodhew EB , Rogier E , Priest JW , Lebas E , O'Brien KS , Le V , Oldenburg CE , Doan T , Porco TC , Keenan JD , Lietman TM , Martin DL , Arnold BF . Nat Commun 2022 13 (1) 976 The MORDOR trial in Niger, Malawi, and Tanzania found that biannual mass distribution of azithromycin to children younger than 5 years led to a 13.5% reduction in all-cause mortality (NCT02048007). To help elucidate the mechanism for mortality reduction, we report IgG responses to 11 malaria, bacterial, and protozoan pathogens using a multiplex bead assay in pre-specified substudy of 30 communities in the rural Niger placebo-controlled trial over a three-year period (n = 5642 blood specimens, n = 3814 children ages 1-59 months). Mass azithromycin reduces Campylobacter spp. force of infection by 29% (hazard ratio = 0.71, 95% CI: 0.56, 0.89; P = 0.004) but serological measures show no significant differences between groups for other pathogens against a backdrop of high transmission. Results align with a recent microbiome study in the communities. Given significant sequelae of Campylobacter infection among preschool aged children, our results support an important mechanism through which biannual mass distribution of azithromycin likely reduces mortality in Niger. |
Enteropathogen antibody dynamics and force of infection among children in low-resource settings
Arnold BF , Martin DL , Juma J , Mkocha H , Ochieng JB , Cooley GM , Omore R , Goodhew EB , Morris JF , Costantini V , Vinje J , Lammie PJ , Priest JW . Elife 2019 8 Little is known about enteropathogen seroepidemiology among children in low-resource settings. We measured serological IgG responses to eight enteropathogens (Giardia intestinalis, Cryptosporidium parvum, Entamoeba histolytica, Salmonella enterica, enterotoxigenic Escherichia coli, Vibrio cholerae, Campylobacter jejuni, norovirus) in cohorts from Haiti, Kenya, and Tanzania. We studied antibody dynamics and force of infection across pathogens and cohorts. Enteropathogens shared common seroepidemiologic features that enabled between-pathogen comparisons of transmission. Overall, exposure was intense: for most pathogens the window of primary infection was <3 years old; for highest transmission pathogens primary infection occurred within the first year. Longitudinal profiles demonstrated significant IgG boosting and waning above seropositivity cutoffs, underscoring the value of longitudinal designs to estimate force of infection. Seroprevalence and force of infection were rank-preserving across pathogens, illustrating the measures provide similar information about transmission heterogeneity. Our findings suggest antibody response can be used to measure population-level transmission of diverse enteropathogens in serologic surveillance. |
The utility of serology for elimination surveillance of trachoma
Pinsent A , Solomon AW , Bailey RL , Bid R , Cama A , Dean D , Goodhew B , Gwyn SE , Jack KR , Kandel RP , Kama M , Massae P , Macleod C , Mabey DCW , Migchelsen S , Muller A , Sandi F , Sokana O , Taoaba R , Tekeraoi R , Martin DL , White MT . Nat Commun 2018 9 (1) 5444 Robust surveillance methods are needed for trachoma control and recrudescence monitoring, but existing methods have limitations. Here, we analyse data from nine trachoma-endemic populations and provide operational thresholds for interpretation of serological data in low-transmission and post-elimination settings. Analyses with sero-catalytic and antibody acquisition models provide insights into transmission history within each population. To accurately estimate sero-conversion rates (SCR) for trachoma in populations with high-seroprevalence in adults, the model accounts for secondary exposure to Chlamydia trachomatis due to urogenital infection. We estimate the population half-life of sero-reversion for anti-Pgp3 antibodies to be 26 (95% credible interval (CrI): 21-34) years. We show SCRs below 0.015 (95% confidence interval (CI): 0.0-0.049) per year correspond to a prevalence of trachomatous inflammation-follicular below 5%, the current threshold for elimination of active trachoma as a public health problem. As global trachoma prevalence declines, we may need cross-sectional serological survey data to inform programmatic decisions. |
Evaluation of a single dose of azithromycin for trachoma in low-prevalence communities
Wilson N , Goodhew B , Mkocha H , Joseph K , Bandea C , Black C , Igietseme J , Munoz B , West SK , Lammie P , Kasubi M , Martin DL . Ophthalmic Epidemiol 2018 26 (1) 1-6 PURPOSE: Trachoma, caused by repeated ocular infection with Chlamydia trachomatis, is the leading infectious cause of blindness worldwide and is targeted for elimination as a public health problem. We sought to determine whether a one-time azithromycin mass treatment would reduce trachomatous inflammation-follicular (TF) levels below the elimination threshold of 5% in communities with disease prevalence between 5 and 9.9%. METHODS: The study was conducted in 96 sub-village units (balozis) in the Kongwa district of Tanzania which were predicted from prior prevalence surveys to have TF between 5 and 9.9%. Balozis were randomly assigned to the intervention and control arms. The intervention arm received a single mass drug administration of azithromycin. At baseline and 12-month follow-up, ocular exams for trachoma, ocular swabs for detection of chlamydial DNA, and finger prick blood for analysis of anti-chlamydial antibody were taken. RESULTS: Comparison of baseline and 12-month follow-up showed no significant difference in the overall TF1-9 prevalence by balozi between control and treatment arms. In the treatment arm there was a significant reduction of ocular infection 12 months after treatment (p = 0.004) but no change in the control arm. No change in Pgp3-specific antibody responses were observed after treatment in the control or treatment arms. Anti-CT694 responses increased in both study arms (p = 0.009 for control arm and p = 0.04 for treatment arm). CONCLUSION: These data suggest that a single round of MDA may not be sufficient to decrease TF levels below 5% when TF1-9 is between 5 and 9.9% at baseline. |
Impact of ivermectin mass drug administration for lymphatic filariasis on scabies in eight villages in Kongwa District, Tanzania
Martin D , Wiegand R , Goodhew B , Lammie P , Mkocha H , Kasubi M . Am J Trop Med Hyg 2018 99 (4) 937-939 Scabies was recently added to the World Health Organization list of neglected tropical diseases. The ability to treat scabies with oral ivermectin makes a mass drug administration (MDA) campaign a feasible option for scabies control. Ivermectin MDA in communities endemic for lymphatic filariasis (LF) or onchocerciasis may already be having an impact on scabies. We examined the effect of ivermectin MDA for LF on scabies prevalence over 4 years in eight Tanzanian villages. At baseline, 4.4% (95% confidence interval [CI]: 3.7-5.4) of individuals tested positive for scabies, decreasing to 0.84% (95% CI: 0.51-1.4) after one round of ivermectin MDA but increased in Year 3 (2.5% [95% CI: 1.9-3.3]) and Year 4 (2.9% [95% CI: 2.2-3.8]). Most scabies cases were seen in children younger than 15 years. The data suggest that single-dose ivermectin MDA may not be effective in attaining long-term decreases when scabies prevalence is less than 5%. |
Latent class modeling to compare testing platforms for detection of antibodies against the Chlamydia trachomatis antigen Pgp3
Wiegand RE , Cooley G , Goodhew B , Banniettis N , Kohlhoff S , Gwyn S , Martin DL . Sci Rep 2018 8 (1) 4232 Latent class modeling can be used to combine the results of multiple tests to compare the sensitivity and specificity of those tests in the absence of a gold standard. Seroepidemiology for chlamydia infection may be useful for determining the cumulative risk of infection within a population. Initial studies using the Chlamydia trachomatis immunodominant antigen Pgp3 have shown utility for seroepidemiology of sexually transmitted chlamydia and the eye disease trachoma. We present our latent class modeling results for comparison of antibody data obtained from three different Pgp3-based platforms - multiplex bead array, ELISA, and lateral flow assay. Sensitivity and specificity estimates from the best fitting latent class models were similar to estimates derived from those previously obtained using a nucleic acid amplification test as a gold standard for sensitivity and non-endemic pediatric specimens for specificity, although the estimates from latent class models had wider confidence intervals. The modeling process and evaluation highlighted the importance of including as many antibody tests as possible when fitting a latent class model to ensure that as many patterns as possible are available for evaluation. Future studies designed to evaluate antibody test performance in the absence of a gold standard should utilize as many tests as possible. |
Comparison of platforms for testing antibody responses against the Chlamydia trachomatis Antigen Pgp3
Gwyn S , Cooley G , Goodhew B , Kohloff S , Banniettis N , Wiegand R , Martin DL . Am J Trop Med Hyg 2017 97 (6) 1662-1668 Antibody responses to Chlamydia trachomatis (CT) antigens may be useful tools for surveillance of trachoma by estimating cumulative prevalence of infection within a population. Data were compared from three different platforms-multiplex bead array (MBA), enzyme-linked immunosorbent assay (ELISA), and lateral flow assay (LFA)-measuring antibody responses against the CT antigen protein plasmid gene product 3 (Pgp3). Sensitivity was defined as the proportion of specimens testing antibody positive from a set of dried blood spots from Tanzanian 1-9-year olds who were positive for CT nucleic acid of all nucleic acid amplification test (NAAT)-positive individuals (N = 103). The sensitivity of the LFA could not be determined because of the use of dried blood spots for this test; this specimen type has yet to be adapted to LFA. Specificity was defined as the proportion of sera from U.S. and Bolivian 1-9-year olds that had previously tested negative by the Chlamydia microimmunofluorescence (MIF) assay testing negative to Pgp3-specific antibodies (N = 154). The sensitivity for MBA and ELISA was the same-93.2 (95% confidence interval [CI]: 88.3-98.1). Specificity ranged across platforms from 96.1 (95% CI: 91.8-98.2) to 99.4% (95% CI: 98.2-100). ELISA performance was similar regardless of whether the plates were precoated or freshly coated with antigen. Sensitivity and specificity of control panels were similar if the cutoff was determined using receiver operator curves or a finite mixture model, but the cutoffs themselves differed by approximately 0.5 OD using the different methodologies. These platforms show good sensitivity and specificity and show good agreement between tests at a population level, but indicate variability for ELISA outcomes depending on the cutoff determination methodology. |
Multiplex serologic assessment of schistosomiasis in Western Kenya: Antibody responses in preschool aged children as a measure of reduced transmission
Won KY , Kanyi HM , Mwende FM , Wiegand RE , Goodhew EB , Priest JW , Lee YM , Njenga SM , Secor WE , Lammie PJ , Odiere MR . Am J Trop Med Hyg 2017 96 (6) 1460-1467 Currently, impact of schistosomiasis control programs in Schistosoma mansoni-endemic areas is monitored primarily by assessment of parasitologic indicators only. Our study was conducted to evaluate the use of antibody responses as a way to measure the impact of schistosomiasis control programs. A total of 3,612 serum samples collected at three time points from children 1-5 years of age were tested for antibody responses to two schistosome antigens (soluble egg antigen [SEA] and Sm25) by multiplex bead assay. The overall prevalence of antibody responses to SEA was high at baseline (50.0%). After one round of mass drug administration (MDA), there was minimal change in odds of SEA positivity (odds ratio [OR] = 1.02, confidence interval [CI] = 0.79-1.32, P = 0.89). However, after two rounds of treatment, there was a slight decrease in odds of SEA positivity (OR = 0.80, CI = 0.63-1.02, P = 0.08). In contrast to the SEA results, prevalence of antibody responses to Sm25 was lowest at baseline (14.1%) and higher in years 2 (19.8%) and 3 (18.4%). After one round of MDA, odds of Sm25 positivity increased significantly (OR = 1.51, CI = 1.14-2.02, P = 0.005) and remained significantly higher than baseline after two rounds of MDA (OR = 1.37, CI = 1.07-1.76, P = 0.01). There was a significant decrease in the proportion of 1-year-olds with positive SEA responses from 33.1% in year 1 to 13.2% in year 3 and a corresponding decrease in the odds (OR = 3.25, CI = 1.75-6.08, P < 0.001). These results provide preliminary evidence that schistosomiasis program impact can be monitored using serologic responses. |
Evaluation of multiplex-based antibody testing for use in large scale surveillance for yaws: a comparative study
Cooley GM , Mitja O , Goodhew B , Pillay A , Lammie PJ , Castro A , Moses P , Chen C , Ye T , Ballard R , Martin DL . J Clin Microbiol 2016 54 (5) 1321-5 BACKGROUND: WHO has targeted yaws for global eradication by 2020. Program goals are to achieve interruption of transmission in endemic countries and to certify previously-endemic countries as yaws-free. No new rapid plasmin reagin (RPR) sero-reactivity in young children is required for certification of elimination at a country level. We sought to evaluate if antibody responses to specific treponemal antigens measured in a high-throughput multiplex bead array (MBA) assay differentiate past versus current infection, and whether a non-treponemal, lipoidal antigen test could be incorporated into the MBA. METHODS: Serum and dried blood spot specimens collected for yaws surveillance projects in Ghana, Vanuatu, and Papua New Guinea were run on MBA to measure antibodies against recombinant p17 (rp17) and TmpA treponemal antigens. Results were compared to standard treponemal laboratory (TPPA or TPHA; "TPP(H)A ") and quantitative RPR test data. FINDINGS: Of 589 specimens, 241 were TPP(H)A+/RPR+, 88 were TPP(H)A+/RPR-, 6 were TPP(H)A -/RPR+ and 254 were negative for both tests. Compared to TPP(H)A, reactive concordance of rp17 was 93.7%, while reactive concordance of TmpA was only 81.9%. TmpA-specific reactivity showed good correlation with RPR titers (R2 = 0.41, p<0.0001). IgG responses to the lipoidal antigen used in RPR testing (cardiolipin) were not detected in the MBA. INTERPRETATION: Our results suggest that TmpA can be used as a treponemal antigen marker for recent or active infection and potentially replace RPR in. a high-throughput multiplex tool for large-scale yaws surveillance. |
Serological measures of trachoma transmission intensity
Martin DL , Wiegand R , Goodhew B , Lammie P , Black CM , West S , Gaydos CA , Dize L , Mkocha H , Kasubi M , Gambhir M . Sci Rep 2015 5 18532 Ocular infection with Chlamydia trachomatis can lead to trachoma, a leading infectious cause of blindness. Trachoma is targeted for elimination by 2020. Clinical grading for ocular disease is currently used for evaluating trachoma elimination programs, but serological surveillance can be a sensitive measure of disease transmission and provide a more objective testing strategy than clinical grading. We calculated the basic reproduction number from serological data in settings with high, medium, and low disease transmission based on clinical disease. The data showed a striking relationship between age seroprevalence and clinical data, demonstrating the proof-of-principle that age seroprevalence predicts transmission rates and therefore could be used as an indicator of decreased transmission of ocular trachoma. |
Serology for trachoma surveillance after cessation of mass drug administration
Martin DL , Bid R , Sandi F , Goodhew EB , Massae PA , Lasway A , Philippin H , Makupa W , Molina S , Holland MJ , Mabey DC , Drakeley C , Lammie PJ , Solomon AW . PLoS Negl Trop Dis 2015 9 (2) e0003555 BACKGROUND: Trachoma, caused by Chlamydia trachomatis (Ct), is the leading infectious cause of blindness worldwide. Yearly azithromycin mass drug administration (MDA) plays a central role in efforts to eliminate blinding trachoma as a public health problem. Programmatic decision-making is currently based on the prevalence of the clinical sign "trachomatous inflammation-follicular" (TF) in children. We sought to test alternative tools for trachoma surveillance based on serology in the 12-year cohort of Kahe Mpya, Rombo District, Tanzania, where ocular chlamydial infection was eliminated with azithromycin MDA by 2005. METHODOLOGY AND PRINCIPAL FINDINGS: The present study was a community-based cross-sectional survey in Kahe Mpya. Of 989 residents, 571 people aged 6 months to 87 years were enrolled: 58% of the total population and 73% of 1-9 year olds, the key WHO indicator age group. Participants were examined for TF, had conjunctival swabs collected for nucleic acid amplification test (NAAT)-based detection of Ct, and blood collected for analysis of antibodies to the Ct antigens pgp3 and CT694 by multiplex bead-based immunoassay. Seroconversion rate was used to estimate changes in the force of infection in a reversible catalytic model. No conjunctival swabs tested positive for Ct infection by NAAT. Among 1-9 year olds, TF prevalence was 6.5%, whereas only 3.5% were seropositive. Force of infection modelling indicated a 10-fold decrease in seroconversion rate at a time corresponding to MDA commencement. Without baseline serological data, the inferences we can make about antibody status before MDA and the longevity of the antibody response are limited, though our use of catalytic modelling overcomes some of these limitations. CONCLUSIONS/SIGNIFICANCE: Serologic tests support NAAT findings of very low to zero prevalence of ocular Ct in this community and have potential to provide objective measures of transmission and useful surveillance tools for trachoma elimination programs. |
Longitudinal analysis of antibody responses to trachoma antigens before and after mass drug administration
Goodhew EB , Morgan SM , Switzer AJ , Munoz B , Dize L , Gaydos C , Mkocha H , West SK , Wiegand RE , Lammie PJ , Martin DL . BMC Infect Dis 2014 14 (1) 216 BACKGROUND: Blinding trachoma, caused by the bacteria Chlamydia trachomatis, is a neglected tropical disease targeted for elimination by 2020. A major component of the elimination strategy is mass drug administration (MDA) with azithromycin. Currently, program decisions are made based on clinical signs of ocular infection, but we have been investigating the use of antibody responses for post-MDA surveillance. In a previous study, IgG responses were detected in children lacking clinical evidence of trachoma, suggesting that IgG responses represented historical infection. To explore the utility of serology for program evaluation, we compared IgG and IgA responses to trachoma antigens and examined changes in IgG and IgA post-drug treatment. METHODS: Dried blood spots and ocular swabs were collected with parental consent from 264 1-6 year olds in a single village of Kongwa District, central Tanzania. Each child also received an ocular exam for detection of clinical signs of trachoma. MDA was given, and six months later an additional blood spot was taken from these same children. Ocular swabs were analyzed for C. trachomatis DNA and antibody responses for IgA and total IgG were measured in dried bloods spots. RESULTS: Baseline antibody responses showed an increase in antibody levels with age. By age 6, the percentage positive for IgG (96.0%) was much higher than for IgA (74.2%). Antibody responses to trachoma antigens declined significantly six months after drug treatment for most age groups. The percentage decrease in IgA response was much greater than for IgG. However, no instances of seroreversion were observed. CONCLUSIONS: Data presented here suggest that focusing on concordant antibody responses in children will provide the best serological surveillance strategy for evaluation of trachoma control programs. |
Trypanosoma cruzi survival following cold storage: possible implications for tissue banking
Martin DL , Goodhew B , Czaicki N , Foster K , Rajbhandary S , Hunter S , Brubaker SA . PLoS One 2014 9 (4) e95398 While Trypanosoma cruzi, the etiologic agent of Chagas disease, is typically vector-borne, infection can also occur through solid organ transplantation or transfusion of contaminated blood products. The ability of infected human cells, tissues, and cellular and tissue-based products (HCT/Ps) to transmit T. cruzi is dependent upon T. cruzi surviving the processing and storage conditions to which HCT/Ps are subjected. In the studies reported here, T. cruzi trypomastigotes remained infective 24 hours after being spiked into blood and stored at room temperature (N = 20); in 2 of 13 parasite-infected cultures stored 28 days at 4 degrees C; and in samples stored 365 days at -80 degrees C without cryoprotectant (N = 28), despite decreased viability compared to cryopreserved parasites. Detection of viable parasites after multiple freeze/thaws depended upon the duration of frozen storage. The ability of T. cruzi to survive long periods of storage at +4 and -80 degrees C suggests that T. cruzi-infected tissues stored under these conditions are potentially infectious. |
Regional variation in the correlation of antibody and T-cell responses to Trypanosoma cruzi
Martin DL , Marks M , Galdos-Cardenas G , Gilman RH , Goodhew B , Ferrufino L , Halperin A , Sanchez G , Verastegui M , Escalante P , Naquira C , Levy MZ , Bern C . Am J Trop Med Hyg 2014 90 (6) 1074-81 Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is a major cause of morbidity and mortality in Central and South America. Geographic variations in the sensitivity of serologic diagnostic assays to T. cruzi may reflect differences in T. cruzi exposure. We measured parasite-specific T-cell responses among seropositive individuals in two populations from South America with widely varying antibody titers against T. cruzi. Antibody titers among seropositive individuals were significantly lower in Arequipa, Peru compared with Santa Cruz, Bolivia. Similarly, the proportion of seropositive individuals with positive T-cell responses was lower in Peru than Bolivia, resulting in overall lower frequencies of interferon-gamma (IFNgamma) -secreting cells from Peruvian samples. However, the magnitude of the IFNgamma response was similar among the IFNgamma responders in both locations. These data indicate that immunological discrepancies based on geographic region are reflected in T-cell responses as well as antibody responses. |
Clinical and immunological aspects of post-kala-azar dermal leishmaniasis in Bangladesh
Islam S , Kenah E , Bhuiyan MA , Rahman KM , Goodhew B , Ghalib CM , Zahid MM , Ozaki M , Rahman MW , Haque R , Luby SP , Maguire JH , Martin D , Bern C . Am J Trop Med Hyg 2013 89 (2) 345-53 We conducted active surveillance for kala-azar and post-kala-azar dermal leishmaniasis (PKDL) in a population of 24,814 individuals. Between 2002 and 2010, 1,002 kala-azar and 185 PKDL cases occurred. Median PKDL patient age was 12 years; 9% had no antecedent kala-azar. Cases per 10,000 person-years peaked at 90 for kala-azar (2005) and 28 for PKDL (2007). Cumulative PKDL incidence among kala-azar patients was 17% by 5 years. Kala-azar patients younger than 15 years were more likely than older patients to develop PKDL; no other risk factors were identified. The most common lesions were hypopigmented macules. Of 98 untreated PKDL patients, 48 (49%) patients had resolution, with median time of 19 months. Kala-azar patients showed elevated interferon-gamma (IFNgamma), tumor necrosis factor-alpha (TNFalpha), and interleukin 10 (IL-10). Matrix metalloproteinase 9 (MMP9) and MMP9/tissue inhibitors of matrix metalloproteinases ratio were significantly higher in PKDL patients than in other groups. PKDL is frequent in Bangladesh and poses a challenge to the current visceral leishmaniasis elimination initiative in the Indian subcontinent. |
Drug library screening against metronidazole-sensitive and metronidazole-resistant Trichomonas vaginalis isolates
Goodhew EB , Secor WE . Sex Transm Infect 2013 89 (6) 479-84 OBJECTIVES: Metronidazole and tinidazole are effective treatments for most patients with trichomoniasis but not for individuals who are infected with very resistant strains of Trichomonas vaginalis or persons with hypersensitivity to the 5-nitroimidazole drugs. Thus, there is a need for additional oral therapies to treat trichomoniasis. METHODS: We screened the US Drug Collection Library against metronidazole-susceptible and resistant strains of T vaginalis. Activity was measured by incubating parasites and drugs for 48 h in the presence of tritiated thymidine. Growth inhibition was determined by the reduction of incorporated radioactivity by compounds at 20 mcM in comparison to media control. Drugs that showed good initial activity were further tested to calculate IC50 values. Drugs with the most promise were tested together with metronidazole to see if there was any combinatorial effect. RESULTS: Of the 1040 drugs in the library, 83 (8%) reduced growth of a metronidazole-susceptible T vaginalis strain by at least 20%. Of these, IC50 values were calculated for 27 compounds and 8 drugs were evaluated in combination with metronidazole. Disulfiram and nithiamide were non-5-nitroimidazole drugs that showed the best activity against parasites when used alone. Albendazole and coenzyme B12 were the most promising compounds to boost the efficacy of metronidazole. CONCLUSIONS: No one drug was as effective as any of the 5-nitroimidazole compounds. However, disulfiram and nithiamide may be useful to treat individuals with hypersensitivity to 5-nitroimidazole drugs and albendazole and coenzyme B12 may be helpful in combination with metronidazole or tinidazole for treatment of persons with highly resistant T vaginalis infections. |
CT694 and pgp3 as serological tools for monitoring trachoma programs
Goodhew EB , Priest JW , Moss DM , Zhong G , Munoz B , Mkocha H , Martin DL , West SK , Gaydos C , Lammie PJ . PLoS Negl Trop Dis 2012 6 (11) e1873 BACKGROUND: Defining endpoints for trachoma programs can be a challenge as clinical signs of infection may persist in the absence of detectable bacteria. Antibody-based tests may provide an alternative testing strategy for surveillance during terminal phases of the program. Antibody-based assays, in particular ELISAs, have been shown to be useful to document C. trachomatis genital infections, but have not been explored extensively for ocular C. trachomatis infections. METHODOLOGY/PRINCIPAL FINDINGS: An antibody-based multiplex assay was used to test two C. trachomatis antigens, pgp3 and CT694, for detection of trachoma antibodies in bloodspots from Tanzanian children (n=160) collected after multiple rounds of mass azithromycin treatment. Using samples from C. trachomatis-positive (by PCR) children from Tanzania (n=11) and control sera from a non-endemic group of U.S. children (n=122), IgG responses to both pgp3 and CT694 were determined to be 91% sensitive and 98% specific. Antibody responses of Tanzanian children were analyzed with regard to clinical trachoma, PCR positivity, and age. In general, children with more intense ocular pathology (TF/TI=2 or most severe) had a higher median antibody response to pgp3 (p=0.0041) and CT694 (p=0.0282) than those with normal exams (TF/TI=0). However, 44% of children with no ocular pathology tested positive for antibody, suggesting prior infection. The median titer of antibody responses for children less than three years of age was significantly lower than those of older children. (p<0.0001 for both antigens). CONCLUSIONS/SIGNIFICANCE: The antibody-based multiplex assay is a sensitive and specific additional tool for evaluating trachoma transmission. The assay can also be expanded to include antigens representing different diseases, allowing for a robust assay for monitoring across NTD programs. |
Development of a new platform for neglected tropical disease surveillance
Lammie PJ , Moss DM , Brook Goodhew E , Hamlin K , Krolewiecki A , West SK , Priest JW . Int J Parasitol 2012 42 (9) 797-800 An expanded global focus on the control and elimination of neglected tropical diseases (NTDs) has called attention to the need to develop and validate surveillance strategies that are cost effective and can be integrated across diseases. Here, we describe a multiplex tool for the sensitive detection of antibody responses to NTDs as well as vaccine preventable diseases, malaria, and waterborne and zoonotic infections. The assay platform is robust, can be performed with either serum or dried blood spots and can be adapted to local epidemiological conditions and public health priorities. Multiplex assays open the door to conducting routine serosurveillance for NTDs through demographic health surveillance or malaria indicator surveys. |
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