Purpose of review

To review recent clinical and epidemiological studies regarding the prevention, diagnosis, and treatment of trachoma.

Recent findings

Newer studies propose novel diagnostic tests that appear sensitive for the detection of ocular chlamydial infection. For example, recent studies with ribosomal RNA-based nucleic acid amplification tests (NAATs) have demonstrated improved sensitivities compared to DNA-based NAATs; and the progression of scarring has now been characterized with confocal microscopy. Immunologic studies have further explored the etiology of clinical sequelae, suggesting that chronic inflammation can lead to progressive scarring even in the absence of Chlamydia. Mass oral azithromycin distributions remain a mainstay of treatment; studies have assessed the appropriate frequency and duration of treatment programs. Current studies have also explored ancillary effects of azithromycin distribution on mortality and bacterial infections.

Summary

Trachoma programs have had remarkable success at reducing chlamydial infection and clinical signs of trachoma. Recent work suggests improved methods to monitor infection and scarring, and better ways to distribute treatment. Whereas studies continue to demonstrate reduction in infection in hyperendemic areas, more work is necessary to achieve elimination of this blinding disease.

A cluster-randomized trial demonstrated that mass oral azithromycin distribution reduced childhood mortality 49.6% (Trachoma Amelioration in Northern Amhara [TANA]). The relative risk of childhood mortality was then estimated using two approaches: an expert survey and a Bayesian analysis. The survey asked public health experts to estimate the true effect of mass azithromycin distribution on childhood mortality. The Bayesian estimation used the TANA study's results and prior estimates of the efficacy of other effective population-level interventions. The experts believed mass azithromycin reduces childhood mortality (relative risk = 0.83, 95% credible intervals [CrI] = 0.70-1.00). The Bayesian analysis estimated a relative risk of 0.71 (95% CrI = 0.39-0.93). Both estimates suggest that azithromycin may have a true mortality benefit, though of a smaller magnitude than found in the single available trial. Prior information about nonantibiotic, population-level interventions may have informed the expert's opinions. Additional trials are needed to confirm a mortality benefit from mass azithromycin.

Purpose

Conjunctival infection with non-chlamydial bacteria may play an important role in the progression of trachoma, especially with regard to the development of corneal opacity and blindness. To further characterize the microbiological profile of bacterial conjunctival infections in cicatricial trachoma, a conjunctival swabbing of adults in rural Ethiopia was performed.

Methods

In a cross-sectional study conducted in nine Ethiopian villages with hyperendemic trachoma, persons 40 years of age or older with signs or symptoms consistent with trichiasis were recruited and conjunctival swabbing for bacterial pathogens was performed.

Results

Conjunctival examination and swabbing on 112 females and 36 males were performed. Of the 148 study participants, 101 (68.2%) were confirmed to have trichiasis, and 118 (80%) had conjunctival swabs positive for bacteria. In multivariate analyses, growth of pathogenic conjunctival bacteria was independently associated with trichiasis (odds ratio [OR] 6.93; 95% confidence interval [CI] 2.71-17.7) and female sex (OR 5.90; 95% CI 2.09-16.7). Females were more likely to have swabs positive for Streptococcus pneumoniae or Haemophilus influenzae than were males (OR 9.09; 95% CI 1.17-70.8).

Conclusions

In a region of Ethiopia with endemic trachoma, conjunctival bacterial growth was more common in females than that in males. S. pneumoniae and H. influenzae, both of which frequently colonize the nasopharynx of children, were more common in females, suggesting that the preponderance of infection in females may be attributable to close contact with children. This finding is consistent with the theory that childcare activities may preferentially expose females to ocular chlamydial infection. (ClinicalTrials.gov number, NCT00221364.).

Purpose

Trachoma surveillance is most commonly performed by direct observation, usually by non-ophthalmologists using the World Health Organization (WHO) simplified grading system. However, conjunctival photographs may offer several benefits over direct clinical observation, including the potential for greater inter-rater agreement. This study assesses whether inter-rater agreement of trachoma grading differs when trained graders review conjunctival photographs compared to when they perform conjunctival examinations in the field.

Methods

Three trained trachoma graders each performed an independent examination of the everted right tarsal conjunctiva of 269 children aged 0-9 years, and then reviewed photographs of these same conjunctivae in a random order. For each eye, the grader documented the presence or absence of follicular trachoma (TF) and intense trachomatous inflammation (TI) according to the WHO simplified grading system.

Results

Inter-rater agreement for the grade of TF was significantly higher in the field (kappa coefficient, κ, 0.73, 95% confidence interval, CI 0.67-0.80) than by photographic review (κ = 0.55, 95% CI 0.49-0.63; difference in κ between field grading and photo grading 0.18, 95% CI 0.09-0.26). When field and photographic grades were each assessed as the consensus grade from the three graders, agreement between in-field and photographic graders was high for TF (κ = 0.75, 95% CI 0.68-0.84).

Conclusions

In an area with hyperendemic trachoma, inter-rater agreement was lower for photographic assessment of trachoma than for in-field assessment. However, the trachoma grade reached by a consensus of photographic graders agreed well with the grade given by a consensus of in-field graders.

The common wisdom is that a trachoma program cannot eliminate ocular chlamydia from a community, just reduce infection to a level where blindness would be minimal. We describe the success of multiple mass antibiotic treatments, demonstrating that complete elimination of infection may be an attainable goal in an area with modest disease.

We assessed trachoma grading agreement among field graders using photographs that included the complete spectrum of disease and compared it with cases where there was consensus among experienced graders. Trained photographers took photographs of children's conjunctiva during a clinical trial in Ethiopia. We calculated κ-agreement statistics using a complete set of 60 cases and then recalculated the κ using a consensus set where cases were limited to those cases with agreement among experienced graders. When the complete set of 60 cases was used, agreement was moderate (κ = 0.61, 95% confidence interval [95% CI] = 0.56-0.67). When the consensus set was used, agreement improved significantly (κ = 0.75, 95% CI = 0.68-0.80). The κ of the consensus set was higher than the complete set by 0.14 (95% CI = 0.12-0.16) (P < 0.001). If testing sets remove difficult-to-grade cases, agreement in trachoma grading may be higher than actually seen in population-based trachoma surveys.

Purpose

To determine the intra-observer and inter-observer reliability of a novel ocular staining score among trained ophthalmologists.

Design

Reliability analysis within a prospective, observational, multicenter cohort study.

Methods

Those enrolled in the National Institutes of Health-funded Sjögren's International Collaborative Clinical Alliance (SICCA) who presented for follow-up at the University of California San Francisco, Aravind Eye Hospital, Johns Hopkins University, and the University of Pennsylvania were included. Study participants were graded using the ocular staining score by at least 2 masked SICCA-trained ophthalmologists. The primary outcome for this study was the intraclass correlation coefficient (ICC) for the total ocular staining score. ICCs were also calculated for tear break-up time (TBUT) and conjunctival and corneal staining.

Results

Total ocular staining score had an ICC of 0.91 for the right eye (95% confidence interval [CI] 0.85-0.96) and 0.90 for the left eye (95% CI 0.83-0.97). Corneal staining (right eye 0.86, 95% CI 0.76-0.93, left eye 0.90, 95% CI 0.81-0.95) and conjunctival staining (right eye 0.87, 95% CI 0.80-0.93, left eye 0.85, 95% CI 0.75-0.93) demonstrated excellent agreement. The ICC for TBUT was slightly lower (right eye 0.77, 95% CI 0.64-0.89; left eye 0.81, 95% CI 0.68-0.90).

Conclusions

Previous studies have shown that the ocular staining score is correlated with other diagnostic components of Sjögren syndrome. In this study, we demonstrate high reliability in grading among trained ophthalmologists, completing the validation of this test.

Background

A clinical trial of mass azithromycin distributions for trachoma created a convenient experiment to test the hypothesis that antibiotic use selects for clonal expansion of preexisting resistant bacterial strains.

Methods

Twelve communities in Ethiopia received mass azithromycin distributions every 3 months for 1 year. A random sample of 10 children aged 0-9 years from each community was monitored by means of nasopharyngeal swab sampling before mass azithromycin distribution and after 4 mass treatments. Swab specimens were tested for Streptococcus pneumoniae, and isolates underwent multilocus sequence typing.

Results

Of 82 pneumococcal isolates identified before treatment, 4 (5%) exhibited azithromycin resistance, representing 3 different sequence types (STs): 177, 6449, and 6494. The proportion of isolates that were classified as one of these 3 STs and were resistant to azithromycin increased after 4 mass azithromycin treatments (14 of 96 isolates [15%]; P = .04). Using a classification index, we found evidence for a relationship between ST and macrolide resistance after mass treatments (P < .0001). The diversity of STs-as calculated by the unbiased Simpson index-decreased significantly after mass azithromycin treatment (P = .045).

Conclusions

Resistant clones present before mass azithromycin treatments increased in frequency after treatment, consistent with the theory that antibiotic selection pressure results in clonal expansion of existing resistant strains.

Twenty-four Ethiopian communities were randomized to receive either (1) quarterly mass azithromycin distributions for trachoma for 1 year or (2) delayed treatment. Nasopharyngeal swabs collected from separate cross-sectional population-based samples of children were processed for Streptococcus pneumoniae Mass azithromycin did not significantly alter the pneumococcal serotype distribution, and hence it would not be expected to alter vaccine coverage.

Background

Antibiotics are a major tool in the WHO's trachoma control program. Even a single mass distribution reduces the prevalence of the ocular chlamydia that causes trachoma. Unfortunately, infection returns after a single treatment, at least in severely affected areas. Here, we test whether additional scheduled treatments further reduce infection, and whether infection returns after distributions are discontinued.

Methods

Sixteen communities in Ethiopia were randomly selected. Ocular chlamydial infection in 1- to 5-year-old children was monitored over four biannual azithromycin distributions and for 24 months after the last treatment.

Findings

The average prevalence of infection in 1- to 5-year-old children was reduced from 63.5% pre-treatment to 11.5% six months after the first distribution (P<0.0001). It further decreased to 2.6% six months after the fourth and final treatment (P = 0.0004). In the next 18 months, infection returned to 25.2%, a significant increase from six months after the last treatment (P = 0.008), but still far lower than baseline (P<0.0001). Although the prevalence of infection in any particular village fluctuated, the mean prevalence of the 16 villages steadily decreased with each treatment and steadily returned after treatments were discontinued.

Conclusion

In some of the most severely affected communities ever studied, we demonstrate that repeated mass oral azithromycin distributions progressively reduce ocular chlamydial infection in a community, as long as these distributions are given frequently enough and at a high enough coverage. However, infection returns into the communities after the last treatment. Sustainable changes or complete local elimination of infection will be necessary.

Trial registration

ClinicalTrials.gov NCT00221364.