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1.  A Cross-Sectional Study of ‘Yaws’ in Districts of Ghana Which Have Previously Undertaken Azithromycin Mass Drug Administration for Trachoma Control 
PLoS Neglected Tropical Diseases  2015;9(1):e0003496.
Yaws, caused by Treponema pallidum ssp. pertenue, is reportedly endemic in Ghana. Mass distribution of azithromycin is now the cornerstone of the WHO yaws eradication campaign. Mass distribution of azithromycin at a lower target dose was previously undertaken in two regions of Ghana for the control of trachoma. Ongoing reporting of yaws raises the possibility that resistance may have emerged in T. pallidum pertenue, or that alternative infections may be responsible for some of the reported cases. We conducted a cross-sectional survey in thirty communities in two districts of Ghana where MDA for trachoma had previously been conducted. Children aged 5–17 years with ulcerative lesions compatible with yaws were enrolled. Samples for treponemal serology and lesion PCR were collected from all children. 90 children with 98 lesions were enrolled. Syphilis serology was negative in all of them. PCR for T. pallidum ssp pertenue was negative in all children, but Haemophilus ducreyi DNA was detected in 9 lesions. In these communities, previously treated for trachoma, we found no evidence of ongoing transmission of yaws. H. ducreyi was associated with a proportion of skin lesions, but the majority of lesions remain unexplained. Integration of diagnostic testing into both pre and post-MDA surveillance systems is required to better inform yaws control programmes.
Author Summary
Yaws is a chronic bacterial infection of the skin and bones that is endemic in Ghana. Since 2012, mass distribution of the antibiotic azithromycin has become the cornerstone of the WHO yaws eradication campaign. Accurate surveillance data are necessary to guide decisions about where MDA is required. Many national surveillance systems report only clinical cases without laboratory confirmation, which may lead to misdiagnosis. Mass distribution of azithromycin, at a lower dose than is used for yaws, is also used in the control of the eye disease trachoma. Between 2001 and 2008, two regions of Ghana undertook distribution of azithromycin to eliminate trachoma. These regions still report cases of yaws, and it is unclear if these are due to drug resistant yaws or other causes. We conducted a survey of patients with skin ulcers that looked like yaws in one of these regions of Ghana. Blood tests for yaws were negative in all the individuals examined and molecular testing of the ulcers did not show evidence of yaws caused by drug resistant Treponema pallidum ssp. pertenue. Our data suggest that previous treatment for trachoma may have also treated yaws in these districts. These findings highlight the need for yaws control programmes to integrate diagnostic testing into surveillance.
doi:10.1371/journal.pntd.0003496
PMCID: PMC4310597  PMID: 25632942
2.  Anthropometric indices of Gambian children after one or three annual rounds of mass drug administration with azithromycin for trachoma control 
BMC Public Health  2014;14(1):1176.
Background
Mass drug administration (MDA) with azithromycin, carried out for the control of blinding trachoma, has been linked to reduced mortality in children. While the mechanism behind this reduction is unclear, it may be due, in part, to improved nutritional status via a potential reduction in the community burden of infectious disease. To determine whether MDA with azithromycin improves anthropometric indices at the community level, we measured the heights and weights of children aged 1 to 4 years in communities where one (single MDA arm) or three annual rounds (annual MDA arm) of azithromycin had been distributed.
Methods
Data collection took place three years after treatment in the single MDA arm and one year after the final round of treatment in the annual MDA arm. Mean height-for-age, weight-for-age and weight-for-height z scores were compared between treatment arms.
Results
No significant differences in mean height-for-age, weight-for-age or weight-for-height z scores were found between the annual MDA and single MDA arms, nor was there a significant reduction in prevalence of stunting, wasting or underweight between arms.
Conclusions
Our data do not provide evidence that community MDA with azithromycin improved anthropometric outcomes of children in The Gambia. This may suggest reductions in mortality associated with azithromycin MDA are due to a mechanism other than improved nutritional status.
doi:10.1186/1471-2458-14-1176
PMCID: PMC4251859  PMID: 25407464
Mass drug administration; Azithromycin; Trachoma control; Anthropometry
3.  The conjunctival microbiome in health and trachomatous disease: a case control study 
Genome Medicine  2014;6(11):99.
Background
Trachoma, caused by Chlamydia trachomatis, remains the world’s leading infectious cause of blindness. Repeated ocular infection during childhood leads to scarring of the conjunctiva, in-turning of the eyelashes (trichiasis) and corneal opacity in later life. There is a growing body of evidence to suggest non-chlamydial bacteria are associated with clinical signs of trachoma, independent of C. trachomatis infection.
Methods
We used deep sequencing of the V1-V3 region of the bacterial 16S rRNA gene to characterize the microbiome of the conjunctiva of 220 residents of The Gambia, 105 with healthy conjunctivae and 115 with clinical signs of trachoma in the absence of detectable C. trachomatis infection. Deep sequencing was carried out using the Roche-454 platform. Sequence data were processed and analyzed through a pipeline developed by the Human Microbiome Project.
Results
The microbiome of healthy participants was influenced by age and season of sample collection with increased richness and diversity seen in younger participants and in samples collected during the dry season. Decreased diversity and an increased abundance of Corynebacterium and Streptococcus were seen in participants with conjunctival scarring compared to normal controls. Abundance of Corynebacterium was higher still in adults with scarring and trichiasis compared to adults with scarring only.
Conclusions
Our results indicate that changes in the conjunctival microbiome occur in trachomatous disease; whether these are a cause or a consequence is yet unknown.
Electronic supplementary material
The online version of this article (doi:10.1186/s13073-014-0099-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13073-014-0099-x
PMCID: PMC4256740  PMID: 25484919
4.  Does Mass Azithromycin Distribution Impact Child Growth and Nutrition in Niger? A Cluster-Randomized Trial 
Background
Antibiotic use on animals demonstrates improved growth regardless of whether or not there is clinical evidence of infectious disease. Antibiotics used for trachoma control may play an unintended benefit of improving child growth.
Methodology
In this sub-study of a larger randomized controlled trial, we assess anthropometry of pre-school children in a community-randomized trial of mass oral azithromycin distributions for trachoma in Niger. We measured height, weight, and mid-upper arm circumference (MUAC) in 12 communities randomized to receive annual mass azithromycin treatment of everyone versus 12 communities randomized to receive biannual mass azithromycin treatments for children, 3 years after the initial mass treatment. We collected measurements in 1,034 children aged 6–60 months of age.
Principal Findings
We found no difference in the prevalence of wasting among children in the 12 annually treated communities that received three mass azithromycin distributions compared to the 12 biannually treated communities that received six mass azithromycin distributions (odds ratio = 0.88, 95% confidence interval = 0.53 to 1.49).
Conclusions/Significance
We were unable to demonstrate a statistically significant difference in stunting, underweight, and low MUAC of pre-school children in communities randomized to annual mass azithromycin treatment or biannual mass azithromycin treatment. The role of antibiotics on child growth and nutrition remains unclear, but larger studies and longitudinal trials may help determine any association.
Author Summary
Recent studies suggest that antibiotic use could have an effect on growth in humans. Azithromycin is an antibiotic used for trachoma control, and hence, may have an unintended benefit of improving child growth. Niger is a trachoma-endemic country where mass antibiotic distributions for trachoma take place and where malnutrition is widespread among children. In addition, azithromycin may have an effect on common childhood diseases associated with malnutrition, such as diarrhea, pneumonia, and malaria. In a community-randomized trachoma trial in Matameye, Niger, we assessed child growth by measuring height, weight, and mid-upper arm circumference of pre-school children who have received 3 years of annual or biannual mass azithromycin treatment. While these measures were better in the biannually treated communities, the difference was not statistically significant. Thus, further research will help determine the impact of antibiotics on child growth and nutrition.
doi:10.1371/journal.pntd.0003128
PMCID: PMC4161345  PMID: 25210836
5.  Serosurveillance of Orientia tsutsugamushi and Rickettsia typhi in Bangladesh 
Scrub and murine typhus infections are under-diagnosed causes of febrile illness across the tropics, and it is not known how common they are in Bangladesh. We conducted a prospective seroepidemiologic survey across six major teaching hospitals in Bangladesh by using an IgM enzyme-linked immunosorbent assay. Results indicated recent exposure (287 of 1,209, 23.7% seropositive for Orientia tsutsugamushi and 805 of 1,209, 66.6% seropositive for Rickettsia typhi). Seropositive rates were different in each region. However, there was no geographic clustering of seropositive results for both organisms. There was no difference between those from rural or urban areas. Rickettsia typhi seroreactivity was positively correlated with age. Scrub typhus and murine typhus should be considered as possible causes of infection in Bangladesh.
doi:10.4269/ajtmh.13-0570
PMCID: PMC4155564  PMID: 25092819
6.  Risk Factors for Active Trachoma and Ocular Chlamydia trachomatis Infection in Treatment-Naïve Trachoma-Hyperendemic Communities of the Bijagós Archipelago, Guinea Bissau 
Background
Trachoma, caused by ocular infection with Chlamydia trachomatis, is hyperendemic on the Bijagós Archipelago of Guinea Bissau. An understanding of the risk factors associated with active trachoma and infection on these remote and isolated islands, which are atypical of trachoma-endemic environments described elsewhere, is crucial to the implementation of trachoma elimination strategies.
Methodology/Principal Findings
A cross-sectional population-based trachoma prevalence survey was conducted on four islands. We conducted a questionnaire-based risk factor survey, examined participants for trachoma using the World Health Organization (WHO) simplified grading system and collected conjunctival swab samples for 1507 participants from 293 randomly selected households. DNA extracted from conjunctival swabs was tested using the Roche Amplicor CT/NG PCR assay. The prevalence of active (follicular and/or inflammatory) trachoma was 11% (167/1508) overall and 22% (136/618) in 1–9 year olds. The prevalence of C. trachomatis infection was 18% overall and 25% in 1–9 year olds. There were strong independent associations of active trachoma with ocular and nasal discharge, C. trachomatis infection, young age, male gender and type of household water source. C. trachomatis infection was independently associated with young age, ocular discharge, type of household water source and the presence of flies around a latrine.
Conclusions/Significance
In this remote island environment, household-level risk factors relating to fly populations, hygiene behaviours and water usage are likely to be important in the transmission of ocular C. trachomatis infection and the prevalence of active trachoma. This may be important in the implementation of environmental measures in trachoma control.
Author Summary
Trachoma, caused by ocular infection with Chlamydia trachomatis, is the leading infectious cause of blindness worldwide. The World Health Organization elimination strategy includes community mass treatment with oral antibiotics, education regarding hygiene and facial cleanliness and environmental improvements. Population-based trachoma prevalence surveys are essential to determine whether community interventions are required. Knowledge of risk factors associated with trachoma and C. trachomatis infection in a particular setting may help prioritise trachoma elimination activities. We conducted a trachoma prevalence survey to establish the prevalence of active (follicular and/or inflammatory) trachoma and C. trachomatis infection on the Bijagós Archipelago of Guinea Bissau. We also collected household risk factor data from survey participants. Active trachoma prevalence was 11% overall and 22% in children aged 1–9 years. C. trachomatis infection prevalence was 18% overall and 25% in children aged 1–9 years. Active trachoma and the presence of C. trachomatis infection were strongly correlated. Risk factors for disease and infection were similar. In this environment, measures of facial cleanliness (ocular and nasal discharge) and household-level risk factors relating to fly populations, hygiene behaviours and water usage are likely to be important in C. trachomatis transmission. This may have implications in the implementation of trachoma elimination activities.
doi:10.1371/journal.pntd.0002900
PMCID: PMC4072588  PMID: 24967629
7.  Conjunctival Scarring in Trachoma Is Associated with the HLA-C Ligand of KIR and Is Exacerbated by Heterozygosity at KIR2DL2/KIR2DL3 
Background
Chlamydia trachomatis is globally the predominant infectious cause of blindness and one of the most common bacterial causes of sexually transmitted infection. Infections of the conjunctiva cause the blinding disease trachoma, an immuno-pathological disease that is characterised by chronic conjunctival inflammation and fibrosis. The polymorphic Killer-cell Immunoglobulin-like Receptors (KIR) are found on Natural Killer cells and have co-evolved with the Human Leucocyte Antigen (HLA) class I system. Certain genetic constellations of KIR and HLA class I polymorphisms are associated with a number of diseases in which modulation of the innate responses to viral and intracellular bacterial pathogens is central.
Methodology
A sample of 134 Gambian pedigrees selected to contain at least one individual with conjunctival scarring in the F1 generation was used. Individuals (n = 830) were genotyped for HLA class I and KIR gene families. Family Based Association Tests and Case Pseudo-control tests were used to extend tests for transmission disequilibrium to take full advantage of the family design, genetic model and phenotype.
Principle findings
We found that the odds of trachomatous scarring increased with the number of genome copies of HLA-C2 (C1/C2 OR = 2.29 BHP-value = 0.006; C2/C2 OR = 3.97 BHP-value = 0.0004) and further increased when both KIR2DL2 and KIR2DL3 (C2/C2 OR = 5.95 BHP-value = 0.006) were present.
Conclusions
To explain the observations in the context of chlamydial infection and trachoma we propose a two-stage model of response and disease that balances the cytolytic response of KIR expressing NK cells with the ability to secrete interferon gamma, a combination that may cause pathology. The data presented indicate that HLA-C genotypes are important determinants of conjunctival scarring in trachoma and that KIR2DL2/KIR2DL3 heterozygosity further increases risk of conjunctival scarring in individuals carrying HLA-C2.
Author Summary
Chlamydia trachomatis is a pathogen that causes sexually transmitted infections (STIs) and the blinding disease trachoma. Natural Killer (NK) cells are part of the host immune system's first line of defence against infection. NK cell functions are genetically encoded and differences between individuals mean that some people are better able to respond to infections than others. We found that in certain combinations, specific variants of the gene HLA-C (Human Leucocyte Antigen, C) and of a complex set of genes called the Killer-cell Immunoglobulin-like Receptors (KIR) were associated with a six-fold increase in the relative risk of scarring tissue damage resulting from ocular C. trachomatis infection (trachoma). This combination of genetic variants may reduce the host's ability to effectively resolve infections and result in a harmful immune response that ultimately leads to tissue damage and scarring. KIR+ NK cells are potential cellular mediators of the damaging immune response. Previous studies have identified that the same HLA-KIR genetic constellation that associates with trachoma is actually protective against infectious diseases such as malaria and tuberculosis. The high frequency of the trachoma-associated constellation in African populations may therefore be explained by the evolutionary benefits of protection from the complications of severe disease.
doi:10.1371/journal.pntd.0002744
PMCID: PMC3961204  PMID: 24651768
8.  Towards a safe and effective chlamydial vaccine: Lessons from the eye 
Vaccine  2014;32(14):1572-1578.
Highlights
•Chlamydia trachomatis is the leading infectious cause of blindness.•Vaccine trials against ocular C. trachomatis infection were conducted in the 1960s.•Whole organism vaccines induced short-lived, strain-specific protective immunity.•Many correlates of protective immunity and pathology have been defined.•Important lessons have been learned to inform the development of a chlamydial vaccine.
As well as being the most common bacterial sexually transmitted infection, Chlamydia trachomatis (Ct) is the leading infectious cause of blindness. The pathogenesis of ocular chlamydial infection (trachoma) is similar to that of genital infection. In the 1960s the efficacy of Ct vaccines against ocular infection was evaluated in major field trials in Saudi Arabia, Taiwan, The Gambia, India and Ethiopia. These trials showed that it was possible to induce short term immunity to ocular infection, and to reduce the incidence of inflammatory trachoma, by parenteral immunisation with killed or live whole organism vaccines. In one study, it was also shown that the incidence of scarring sequelae was reduced in vaccinated children. Detailed studies in non-human primates conducted at this time suggested that vaccination could lead to more severe inflammatory disease on subsequent challenge. Since that time there have been many studies on the immunological correlates of protective immunity and immunopathology in ocular Ct infection in humans and non-human primates, and on host genetic polymorphisms associated with protection from adverse sequelae. These have provided important information to guide the development and evaluation of a human Ct vaccine.
doi:10.1016/j.vaccine.2013.10.016
PMCID: PMC3991328  PMID: 24606636
Chlamydia; Vaccine; Trachoma; Protective immunity; Immunopathology
9.  Plasmid Copy Number and Disease Severity in Naturally Occurring Ocular Chlamydia trachomatis Infection 
Journal of Clinical Microbiology  2014;52(1):324-327.
The Chlamydia trachomatis plasmid is a virulence factor. Plasmid copy number, C. trachomatis load and disease severity were assessed in a treatment-naive population where trachoma is hyperendemic. By using droplet digital PCR, plasmid copy number was found to be stable (median, 5.34 [range, 1 to 18]) and there were no associations with C. trachomatis load or disease severity.
doi:10.1128/JCM.02618-13
PMCID: PMC3911420  PMID: 24197878
11.  Correction: Assessment of Transmission in Trachoma Programs over Time Suggests No Short-Term Loss of Immunity 
PLoS Neglected Tropical Diseases  2013;7(7):10.1371/annotation/c64f02de-c1f1-48ee-ac79-06b5a6c7b65a.
doi:10.1371/annotation/c64f02de-c1f1-48ee-ac79-06b5a6c7b65a
PMCID: PMC3729331
12.  Association between Ocular Bacterial Carriage and Follicular Trachoma Following Mass Azithromycin Distribution in The Gambia 
Background
Trachoma, caused by ocular Chlamydia trachomatis infection, is the leading infectious cause of blindess, but its prevalence is now falling in many countries. As the prevalence falls, an increasing proportion of individuals with clinical signs of follicular trachoma (TF) is not infected with C. trachomatis. A recent study in Tanzania suggested that other bacteria may play a role in the persistence of these clinical signs.
Methodology/Principal Findings
We examined associations between clinical signs of TF and ocular colonization with four pathogens commonly found in the nasopharnyx, three years after the initiation of mass azithromycin distribution. Children aged 0 to 5 years were randomly selected from 16 Gambian communitites. Both eyes of each child were examined and graded for trachoma according to the World Health Organization (WHO) simplified system. Two swabs were taken from the right eye: one swab was processed for polymerase chain reaction (PCR) using the Amplicor test for detection of C. trachomatis DNA and the second swab was processed by routine bacteriology to assay for the presence of viable Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus and Moraxella catarrhalis. Prevalence of TF was 6.2% (96/1538) while prevalence of ocular C. trachomatis infection was 1.0% (16/1538). After adjustment, increased odds of TF were observed in the presence of C. trachomatis (OR = 10.4, 95%CI 1.32–81.2, p = 0.03), S. pneumoniae (OR = 2.14, 95%CI 1.03–4.44, p = 0.04) and H. influenzae (OR = 4.72, 95% CI 1.53–14.5, p = 0.01).
Conclusions/Significance
Clinical signs of TF can persist in communities even when ocular C. trachomatis infection has been controlled through mass azithromycin distribution. In these settings, TF may be associated with ocular colonization with bacteria commonly carried in the nasopharnyx. This may affect the interpretation of impact surveys and the determinations of thresholds for discontinuing mass drug administration.
Author Summary
Trachoma, the world's leading infectious cause of blindness, is caused by ocular infection with the bacterium Chlamydia trachomatis. In low-prevalence settings and following mass treatment campaigns, clinically active follicular trachoma (TF) can be found in the absence of C. trachomatis infection. We carried out this study to investigate associations between ocular carriage of non-chlamydial pathogens and a clinical diagnosis of TF following a mass treatment campaign in The Gambia. We found that children who carried Streptococcus pneumoniae or Haemophilus influenza in their eyes were more likely to have been diagnosed with TF than children who did not carry these pathogens. In The Gambia, non-chlamydial pathogens may be inducing or exacerbating TF in the absence of C. trachomatis infection.
doi:10.1371/journal.pntd.0002347
PMCID: PMC3723595  PMID: 23936573
13.  Assessment of Transmission in Trachoma Programs over Time Suggests No Short-Term Loss of Immunity 
Trachoma programs have dramatically reduced the prevalence of the ocular chlamydia that cause the disease. Some have hypothesized that immunity to the infection may be reduced because of program success in reducing the incidence of infection, and transmission may then increase. Longitudinal studies of multiple communities would be necessary to test this hypothesis. Here, we quantify transmission using an estimated basic reproduction number based on 32 communities during the first, second, and third years of an antibiotic treatment program. We found that there is little to no increase in the basic reproduction number over time. The estimated linear trend in the basic reproduction number, , was found to be −0.025 per year, 95% CI −0.167 to 0.117 per year. We are unable to find evidence supporting any loss of immunity over the course of a 3-year program. This is encouraging, as it allows the possibility that repeated mass antibiotic distributions may eliminate infection from even the most severely affected areas.
Author Summary
Trachoma, caused by repeated infections by the ocular strains of Chlamydia trachomatis, is the most common infectious cause of blindness in the world. Treatment for trachoma includes mass azithromycin treatments to the entire community. To reduce the prevalence of infection, the World Health Organization (WHO) advocates at least three annual community-wide distributions of oral antibiotics in affected areas, with further mass treatments based on the prevalence of trachoma. Trachoma programs have dramatically reduced the community prevalence of infection, and some have argued that lowered prevalence of infection may lead to reductions in immunity, and that less immunity may in turn lead to increased transmission from what infection remains. Here, we used a stochastic transmission model to analyze data collected from a 3-year antibiotic treatment program (a 32-community, cluster-randomized clinical trial in Tanzania) to assess whether or not transmission actually increases during elimination campaigns. We found no evidence supporting any increase in transmission over the course of the program. The absence of a short term increase in transmission as the prevalence decreases is good news for trachoma programs.
doi:10.1371/journal.pntd.0002303
PMCID: PMC3708821  PMID: 23875038
14.  Development and Evaluation of a Next-Generation Digital PCR Diagnostic Assay for Ocular Chlamydia trachomatis Infections 
Journal of Clinical Microbiology  2013;51(7):2195-2203.
Droplet digital PCR (ddPCR) is an emulsion PCR process that performs absolute quantitation of nucleic acids. We developed a ddPCR assay for Chlamydia trachomatis infections and found it to be accurate and precise. Using PCR mixtures containing plasmids engineered to include the PCR target sequences, we were able to quantify with a dynamic range between 0.07 and 3,160 targets/μl (r2 = 0.9927) with >95% confidence. Using 1,509 clinical conjunctival swab samples from a population in which trachoma is endemic in Guinea Bissau, we evaluated the specificity and sensitivity of the quantitative ddPCR assay in diagnosing ocular C. trachomatis infections by comparing the performances of ddPCR and the Roche Amplicor CT/NG test. We defined ddPCR tests as positive when we had ≥95% confidence in a nonzero estimate of target load. The sensitivity of ddPCR against Amplicor was 73.3% (95% confidence interval [CI], 67.9 to 78.7%), and specificity was 99.1% (95% CI, 98.6 to 99.6%). Negative and positive predictive values were 94.6% (95% CI, 93.4 to 95.8%) and 94.5% (95% CI, 91.3 to 97.7%), respectively. Based on Amplicor CT/NG testing, the estimated population prevalence of C. trachomatis ocular infection was ∼17.5%. Receiver-operator curve analysis was used to select critical cutoff values for use in clinical settings in which a balance between higher sensitivity and specificity is required. We concluded that ddPCR is an effective diagnostic technology suitable for both research and clinical use in diagnosing ocular C. trachomatis infections.
doi:10.1128/JCM.00622-13
PMCID: PMC3697714  PMID: 23637300
15.  Using a Nonparametric Multilevel Latent Markov Model to Evaluate Diagnostics for Trachoma 
American Journal of Epidemiology  2013;177(9):913-922.
In disease control or elimination programs, diagnostics are essential for assessing the impact of interventions, refining treatment strategies, and minimizing the waste of scarce resources. Although high-performance tests are desirable, increased accuracy is frequently accompanied by a requirement for more elaborate infrastructure, which is often not feasible in the developing world. These challenges are pertinent to mapping, impact monitoring, and surveillance in trachoma elimination programs. To help inform rational design of diagnostics for trachoma elimination, we outline a nonparametric multilevel latent Markov modeling approach and apply it to 2 longitudinal cohort studies of trachoma-endemic communities in Tanzania (2000–2002) and The Gambia (2001–2002) to provide simultaneous inferences about the true population prevalence of Chlamydia trachomatis infection and disease and the sensitivity, specificity, and predictive values of 3 diagnostic tests for C. trachomatis infection. Estimates were obtained by using data collected before and after mass azithromycin administration. Such estimates are particularly important for trachoma because of the absence of a true “gold standard” diagnostic test for C. trachomatis. Estimated transition probabilities provide useful insights into key epidemiologic questions about the persistence of disease and the clearance of infection as well as the required frequency of surveillance in the postelimination setting.
doi:10.1093/aje/kws345
PMCID: PMC3639724  PMID: 23548755
diagnosis; latent Markov model; multilevel; nonparametric model; trachoma
16.  Conjunctival MicroRNA Expression in Inflammatory Trachomatous Scarring 
Purpose
Trachoma is a fibrotic disease of the conjunctiva initiated by Chlamydia trachomatis infection. This blinding disease affects over 40 million people worldwide yet the mechanisms underlying its pathogenesis remain poorly understood. We have investigated host microRNA (miR) expression in health (N) and disease (conjunctival scarring with (TSI) and without (TS) inflammation) to determine if these epigenetic differences are associated with pathology.
Methods
We collected two independent samples of human conjunctival swab specimens from individuals living in The Gambia (n = 63 & 194). miR was extracted, and we investigated the expression of 754 miR in the first sample of 63 specimens (23 N, 17 TS, 23 TSI) using Taqman qPCR array human miRNA genecards. Network and pathway analysis was performed on this dataset. Seven miR that were significantly differentially expressed between different phenotypic groups were then selected for validation by qPCR in the second sample of 194 specimens (93 N, 74 TS, 22 TSI).
Results
Array screening revealed differential expression of 82 miR between N, TS and TSI phenotypes (fold change >3, p<0.05). Predicted mRNA targets of these miR were enriched in pathways involved in fibrosis and epithelial cell differentiation. Two miR were confirmed as being differentially expressed upon validation by qPCR. miR-147b is significantly up-regulated in TSI versus N (fold change = 2.3, p = 0.03) and miR-1285 is up-regulated in TSI versus TS (fold change = 4.6, p = 0.005), which was consistent with the results of the qPCR array.
Conclusions
miR-147b and miR-1285 are up-regulated in inflammatory trachomatous scarring. Further investigation of the function of these miR will aid our understanding of the pathogenesis of trachoma.
Author Summary
Trachoma is a debilitating disease that affects 40 million people worldwide. It can cause progressive fibrosis of the upper eyelid and blindness, yet the mechanism is poorly understood. We have investigated the expression of short sequences of genetic material (microRNA) that regulate gene expression. We screened for the expression of 754 microRNA sequences (miR) in genetic material isolated from conjunctival swab samples from individuals in trachoma-endemic communities in The Gambia. This sample included healthy controls, individuals with trachomatous scarring and individuals with trachomatous scarring in the presence of clinically significant inflammation. We found 82 miR that were differentially expressed. Computer simulations predict that these miR regulate genes in epithelial cell differentiation, inflammation and fibrosis pathways, all of which are involved in the scarring process. We then validated the expression of seven of these differentially expressed miR in a second larger biological sample set from The Gambia. We confirmed that miR-147b and miR-1285 have increased expression in individuals with trachomatous scarring in the presence of clinically significant inflammation. Further investigation into the functions of these miR will aid our understanding of this disease and present opportunities to develop treatments for ocular fibrotic diseases.
doi:10.1371/journal.pntd.0002117
PMCID: PMC3597489  PMID: 23516655
17.  The Easiest Children to Reach Are Most Likely to Be Infected with Ocular Chlamydia trachomatis in Trachoma Endemic Areas of Niger 
Background
Control programs for trachoma use mass antibiotic distributions to treat ocular Chlamydia trachomatis in an effort to eliminate this disease worldwide. To determine whether children infected with ocular Chlamydia are more likely to present later for examination than those who are uninfected, we compare the order of presentation for examination of children 0–5 years, and the presence of ocular Chlamydia by PCR in 4 villages in Niger where trachoma is endemic.
Methods
We conducted a cluster-randomized, controlled trial where 48 randomly selected villages in Niger are divided into 4 study arms of different mass treatment strategies. In a substudy of the main trial, we randomly selected 1 village from each of the 4 study arms (4 total villages) and we evaluated the odds of ocular Chlamydia versus the rank order of presentation for examination and laboratory assessment before treatment was offered.
Findings
We found the odds of harboring ocular Chlamydia dropped by more than 70% from the first child examined to the last child examined (OR 0.27, 95% CI 0.13–0.59, P = 0.001) in the 4 randomly selected villages. We found the odds of active trachoma dropped by 80% from the first child examined to the last child examined (OR 0.20, 95% CI 0.10–0.4, P<0.0001) in the 48 villages in the main trial.
Interpretation
This study demonstrates that even if the WHO recommended 80% treatment coverage is not reached in certain settings, children 0–5 years with the greatest probability of ocular Chlamydia have higher odds of receiving attention because they are the first to present. These results suggest there may be diminishing returns when using scarce resources to track down the last few children in a mass treatment program.
Trial Registration
ClinicalTrials.gov NCT00792922
Author Summary
Trachoma is the most common cause of blindness from an infection in the world. The bacterium that causes trachoma is called Chlamydia trachomatis and it can be treated with the antibiotic azithromycin. Experts recommend trying to reach at least 80% of children for treatment in a community but it is unknown if this is necessary. We began a clinical trial in Niger in 48 villages in the summer of 2010 with mass drug administration (MDA) of azithromycin. We found that the odds of an eye infection were the highest in the first children to come for an examination. This means the extra time and money needed to reach all of the children in a village may provide diminishing returns because the easiest children to reach have the highest odds of infection. Perhaps it would be better to try to reach more villages for MDA instead of spending a lot of time and money trying to reach every single child in every single village.
doi:10.1371/journal.pntd.0001983
PMCID: PMC3542188  PMID: 23326612
18.  A Cluster-Randomized Controlled Trial Evaluating the Effects of Mass Azithromycin Treatment on Growth and Nutrition in Niger 
Antimicrobials are used primarily to treat infectious disease, but they have other effects. Here, we assess anthropometry measurements in children 6–60 months in 24 communities randomized to one or two mass azithromycin distributions over a 1-year period in Niger. We compared the prevalence of wasting, low mid-upper arm circumference, stunting, and underweight in communities in the two treatment arms. We were unable to prove that there was a difference in the prevalence of wasting in the 12 communities that received one mass azithromycin distribution versus the 12 communities that received two mass azithromycin distributions (odds ratio = 0.75, 95% confidence interval = 0.46–1.23). Likewise, we were unable to detect a difference in the two treatment arms for low mid-upper arm circumference, stunting, and underweight. There may not be an association between antibiotic use and improved growth in humans, or this trial was not powerful enough to detect an association if it exists.
doi:10.4269/ajtmh.2012.12-0284
PMCID: PMC3541724  PMID: 23208876
19.  Post-Operative Recurrent Trachomatous Trichiasis Is Associated with Increased Conjunctival Expression of S100A7 (Psoriasin) 
Background
Surgery for trachomatous trichiasis (TT) is a key component of the SAFE Strategy for trachoma control. Unfortunately, recurrent TT following surgery is common, probably due to various surgical and disease factors. To develop strategies to reduce recurrence rates it is necessary to understand its pathological basis. In this study we investigated the relationship between recurrent trichiasis and the expression of various cytokines and fibrogenic genes during a two-year follow-up period.
Methodology/Principal Findings
Individuals undergoing surgery for TT were examined at baseline (pre-operative), 6, 12, 18 and 24 months. Conjunctival swab samples were collected from the tarsal conjunctiva for RNA isolation on each occasion. Individuals who developed recurrent TT with at least 3 lashes touching the eye on one or more occasion were designated “cases” and an equal number of “controls” were randomly selected from those without recurrent TT, frequency matched for age and baseline TT severity. The expression of the following genes was measured by quantitative RT-PCR: S100A7, IL1B, CXCL5, TNFA, NOS2A, CTGF, MMP7, MMP9 and MMP12. Thirteen hundred individuals were enrolled and underwent surgery. By two years 122 had developed recurrent TT with at least 3 lashes touching the eye. Recurrent TT was consistently associated across multiple time points with about a 2-fold increase in S100A7 expression (p = 0.008). Clinically visible conjunctival inflammation was associated with increased S100A7, IL1B, CXCL5, MMP9 and MMP12 expression.
Conclusions/Significance
Increased S100A7 expression was associated with trachomatous conjunctival scarring and may be linked to the pathophysiology of recurrent TT. S100A7 expression could be a potential biomarker for this disease process. As part of the epithelial innate immune response S100A7 has multiple actions, potentially contributing to a chronic pro-inflammatory response, which may lead to ongoing tissue damage and increased scarring.
Author Summary
Trachoma causes blindness through corneal damage from in-turned eyelashes (trachomatous trichiasis [TT]). Trichiasis is treated surgically to correct the anatomical abnormality. Unfortunately, TT frequently returns following surgery, which again puts the person at risk of sight loss. Recurrent trichiasis is multifactorial. We investigated the possible role of various immuno-fibrogenic factors. To do this we operated on 1300 people with TT and followed them up every six months for a two-year period. On each occasion a conjunctival swab was collected for human gene expression analysis. We measured various factors that are thought to be important in inflammation and scarring diseases. The gene expression profile of people who developed recurrent TT was compared to a sample of those that did not have a recurrence. Recurrent TT was associated with increased expression of psoriasin (S100A7) before surgery and on multiple occasions during a two-year follow-up period. S100A7 is able to promote inflammation and may contribute to the development of the scarring process in trachoma.
doi:10.1371/journal.pntd.0001985
PMCID: PMC3527350  PMID: 23285311
20.  Genome-Wide Identification of Chlamydia trachomatis Antigens Associated with Trachomatous Trichiasis 
Purpose.
Chlamydia trachomatis is the leading infectious cause of blindness. The goal of the current study was to search for biomarkers associated with C. trachomatis–induced ocular pathologies.
Methods.
We used a whole genome scale proteome array to systematically profile antigen specificities of antibody responses to C. trachomatis infection in individuals from trachoma-endemic communities with or without end-stage trachoma (trichiasis) in The Gambia.
Results.
When 61 trichiasis patients were compared with their control counterparts for overall antibody reactivity with organisms of different chlamydial species, no statistically significant difference was found. Both groups developed significantly higher titers of antibodies against C. trachomatis ocular serovars A and B than ocular serovar C, genital serovar D, or Chlamydia psittaci, whereas the titers of anti–Chlamydia pneumoniae antibodies were the highest. When antisera from 33 trichiasis and 26 control patients (with relatively high titers of antibodies to C. trachomatis ocular serovars) were reacted with 908 C. trachomatis proteins, 447 antigens were recognized by at least 1 of the 59 antisera, and 10 antigens by 50% or more antisera, the latter being designated as immunodominant antigens. More importantly, four antigens were preferentially recognized by the trichiasis group, with antigens CT414, CT667, and CT706 collectively reacting with 30% of trichiasis antisera but none from the normal group, and antigen CT695 reacting with 61% of trichiasis but only 31% of normal antisera. On the other hand, eight antigens were preferentially recognized by the control group, with antigens CT019, CT117, CT301, CT553, CT556, CT571, and CT709 together reacting with 46% of normal antisera and none from the trichiasis group, whereas antigen CT442 reacted with 35% of normal and 19% of trichiasis antisera respectively.
Conclusions.
The current study, by mapping immunodominant C. trachomatis antigens and identifying antigens associated with both ocular pathology and protection, has provided important information for further understanding chlamydial pathogenesis and the development of subunit vaccines.
Whole genome scale profiling of antigen specificities of anti–Chlamydia trachomatis antibodies in trachoma patients led to the identification of antigens associated with ocular pathology.
doi:10.1167/iovs.11-9212
PMCID: PMC3366722  PMID: 22427578
22.  Seroepidemiological surveillance of Burkholderia pseudomallei in Bangladesh 
Melioidosis (Burkholderia pseudomallei infection) has yet to be demonstrated systematically in Bangladesh. A prospective, cross-sectional serological survey was conducted in 2010 at six Bangladeshi hospitals. Age, gender, occupation and residential address were recorded. Of 1244 patients, 359 (28.9%) were positive for B. pseudomallei by indirect haemagglutination assay. Farmers had an increased risk of seropositivity (risk ratio = 1.4, 95% CI 1.0–1.8; p = 0.03). There was no clear geographic clustering of seropositives. Melioidosis should be considered as a possible cause of febrile illness in Bangladesh. Further studies are needed to establish the incidence of clinical disease and distribution of environmental risk.
doi:10.1016/j.trstmh.2012.06.003
PMCID: PMC3424416  PMID: 22795754
Burkholderia pseudomallei; Melioidosis; Indirect haemagglutination assay; Seroprevalence; Epidemiological surveillance; Bangladesh
24.  Community Risk Factors for Ocular Chlamydia Infection in Niger: Pre-Treatment Results from a Cluster-Randomized Trachoma Trial 
Background
Trachoma control programs utilize mass azithromycin distributions to treat ocular Chlamydia trachomatis as part of an effort to eliminate this disease world-wide. But it remains unclear what the community-level risk factors are for infection.
Methods
This cluster-randomized, controlled trial entered 48 randomly selected communities in a 2×2 factorial design evaluating the effect of different treatment frequencies and treatment coverage levels. A pretreatment census and examination established the prevalence of risk factors for clinical trachoma and ocular chlamydia infection including years of education of household head, distance to primary water source, presence of household latrine, and facial cleanliness (ocular discharge, nasal discharge, and presence of facial flies). Univariate and multivariate associations were tested using linear regression and Bayes model averaging.
Findings
There were a total of 24,536 participants (4,484 children aged 0–5 years) in 6,235 households in the study. Before treatment in May to July 2010, the community-level prevalence of active trachoma (TF or TI utilizing the World Health Organization [WHO] grading system) was 26.0% (95% CI: 21.9% to 30.0%) and the mean community-level prevalence of chlamydia infection by Amplicor PCR was 20.7% (95% CI: 16.5% to 24.9%) in children aged 0–5 years. Univariate analysis showed that nasal discharge (0.29, 95% CI: 0.04 to 0.54; P = 0.03), presence of flies on the face (0.40, 95% CI: 0.17 to 0.64; P = 0.001), and years of formal education completed by the head of household (0.07, 95% CI: 0.07 to 0.13; P = 0.03) were independent risk factors for chlamydia infection. In multivariate analysis, facial flies (0.26, 95% CI: 0.02 to 0.49; P = 0.03) and years of formal education completed by the head of household (0.06, 95% CI: 0.008 to 0.11; P = 0.02) were associated risk factors for ocular chlamydial infection.
Interpretation
We have found that the presence of facial flies and years of education of the head of the household are risk factors for chlamydia infection when the analysis is done at the community level.
Trial Registration
ClinicalTrials.gov NCT00792922
Author Summary
Trachoma is one of the most important neglected tropical diseases because it is the leading cause of blindness from an infection in the world. There are about 1.3 million persons blind from the disease and many more at risk of blindness in the future. It is caused by the common bacterium Chlamydia trachomatis and can be treated with mass drug administrations (MDA) of azithromycin. We have begun a clinical trial in Niger, a country with limited resources in Africa, to determine the best treatment strategy. Our study from May to July 2010, which began before MDA's were given, showed that 26% of children aged 0–5 years were infected with the disease. In these children, we found that discharge from the nose, presence of flies on the face, and the number of years of education completed by the head of the household were risk factors for infection in 48 different communities. We hope to use this information about risk factors of infection to help guide future studies for trachoma and also to help with the WHO goal of eliminating the disease worldwide by the year 2020.
doi:10.1371/journal.pntd.0001586
PMCID: PMC3335874  PMID: 22545165
25.  What Is Causing Active Trachoma? The Role of Nonchlamydial Bacterial Pathogens in a Low Prevalence Setting 
Active trachoma in a low prevalence setting was associated with nonchlamydial bacterial infection but not Chlamydia trachomatis. This may partly explain the persistence of clinical signs in formally endemic communities.
Purpose.
In low prevalence settings, clinically active follicular trachoma (TF) is often found in the absence of detectable Chlamydia trachomatis. The reasons for this persistent follicular phenotype are not well understood; one possible explanation is that other bacterial species are provoking the inflammatory response. This study investigated the relationship between TF, C. trachomatis, and nonchlamydial bacterial infection.
Methods.
A cross-sectional survey was conducted in a trachoma endemic village in Tanzania. All available children were examined for trachoma and swabs were collected for microbiologic culture (blood and chocolate agar) and C. trachomatis PCR (Amplicor).
Results.
Four hundred seventy-three children under 10 years of age were recruited for this study. The prevalences of TF and C. trachomatis were 13.7% and 5.3%, respectively, and were not associated. Bacteria were cultured from 305 (64.5%) swab samples; 162 (34.3%) grew a pathogen (with or without a commensal organism) and 143 (30.2%) grew commensal bacteria only. The most common pathogens were Streptococcus pneumoniae and Haemophilus influenzae (type B and non–type B). The presence of bacterial pathogens was associated with TF (odds ratio, 4.68; 95% confidence interval, 2.31–9.50; P < 0.001).
Conclusions.
In regions with low levels of endemic trachoma, it is possible that much of the TF that is observed is attributable to nonchlamydial bacterial pathogens. It is plausible that individuals who have previously developed a follicular conjunctivitis in response to C. trachomatis may more readily reform conjunctival follicles when challenged with certain other bacterial species.
doi:10.1167/iovs.11-7326
PMCID: PMC3176035  PMID: 21693601

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