Research Agenda for Global Blindness Prevention:

Clinical Conditions: 2. Trachoma

Research opportunities

1. Trichiasis surgery
   
   
2. Infection and Antibiotics
   
   
3. Face Washing/Environmental Sanitation
   
   
4. Other

Trachoma is the second leading cause of avoidable blindness and visual impairment.

Recent analyses suggest the burden on quality of life attributable to the discomfort of trichiasis may be as great as that traditionally attributed to the reduction in visual acuity.

Active (and blinding) trachoma occurs in a highly focal pattern among poor populations.

While it is reasonably well established that recurrent reinfection with Chlamydia trachomatis results in chronic inflammation, scarring, trichiasis, and corneal opacification, the exact relationships between these entities is unclear.

What is particularly vexing, but serves as grounds for optimism and research-based enlightenment, is the way in which trachoma has spontaneously disappeared from many areas of the world: not just Appalachia (US) or Finland (in the 1940s), but more recently Indonesia, Mali, and much of India and Pakistan.

Saudi Arabia experienced a dramatic decline in incidence, associated with infrastructure development (roads, water supplies).

It would appear, in most instances, that early, relatively modest increases in socio-economic status are related to critical changes in the environment and/or behavior that brought this about.

Epidemiologic studies have identified personal hygiene and communal sanitation as potentially important determinants of blinding disease. These and other insights resulted in the recently launched GET 20/20 (Global Eradication of Trachoma by the Year 2020) and a public-private collaboration, the ITI (International Trachoma Initiative).

These are based on the (SAFE) S(urgery), A(ntibiotic), F(acial cleanliness/facewashing), E(nvironmental Cleanup) strategy: "surgery" to correct triachisis and reduce the burden of existing lid scarring; "antibiotic," particularly highly effective Zithromax, to eliminate an individual's C. trachomatis infection; and "face washing" (to ensure facial "cleanliness") and "environmental cleanup" to reduce the risk of infection/reinfection.

The effectiveness of each of the components of the "SAFE" strategy, alone and particularly in combination, remain poorly documented; a better understanding of the value of these interventions, particularly their timing for maximal synergy, should lead to more effective outcomes.

Five important, generic research issues relate to:

1. Improving surgical outcome of trichiasis surgery. At present, the relapse rate, even for well-trained ophthalmic surgeons, is high.
   
   
2. Elucidating the role of acute/recurrent/chronic infection in the pathogenesis of conjunctival scarring.
   
   
3. Documenting the dynamics of infection/ reinfection (e.g., what serves as the reservoir of C. trachomatis following mass antibiotic treatment; how is it re-introduced into a community; how does it spread between individuals?)
   
   
4. Determining what is required to sustain the reduction in prevalence of infection and active disease following antibiotic treatment (and thereby block development of blinding trachoma?)
   
   
5. Demonstrating how SAFE can be most effectively delivered

While ITI and GET 20/20 have settled on the SAFE strategy, successful global eradication programs (e.g., smallpox) have demonstrated the critical importance of maintaining a vigorous, parallel research program to enhance program effectiveness and overcome obstacles to interventions that prove ineffective.

A. Trichiasis Surgery

Short-Term:

• Identify factors that influence the recurrence of trichiasis following seemingly successful lid surgery?
  
  
• Develop improved surgical approaches (by employing the latest plastic surgery techniques), and test these in clinical trials.
  
  
• Identify barriers to surgical uptake and ways to reduce cost and increase access (e.g., minimal equipment and supplies; efficient and effectives procedures and the training of lid surgeons; ways to increase demand/compliance).
  
  
• Test simplified systems of surgical audit and evaluation of surgical outcomes.

Medium- to Long-Term:

Identify:

• The pathogenesis of lid scarring (role of infection, immunologic and inflammatory response, etc.)
  
  
• The optimal time in the evolution of trachomatous scarring to intervene surgically.

B. Infection and Antibiotics

Short-Term:

Determine the:

• Origins of reinfection (latent infection; re-introduction by visitors or spread from adjacent communities)
  
  
• Degree of treatment coverage vs. impact/sustained reduction in infection and progression of disease under differing conditions of endemicity
  
  
• Relationship between the frequency of antibiotic (Zithromax) dosing and its duration of impact (reinfection/re-emergence of active or scarring diseases)
  
  
• Cost-effectiveness/ cost-benefit of antibiotic use, based on benefits to both ocular and non-ocular diseases (STD, respiratory disease, etc.)

Medium-Term:

Determine by whom, and for how long and how intensively, should antiobiotics be used for sustained impact (e.g., R/x only children; mothers and children; the family; or the whole community? How often and for how long?)

C. Face Washing/Environmental Sanitation

Short- to Medium-Term:

Determine:

• The key personal hygiene/environmental factors that are responsible for infection/reinfection
  
  
• The degree to which "F&E" has an additive (synergistic?) benefit when added to treatment with antibiotics
  
  
• The long-term impact of alternative "F&E" interventions
  
  
• Which factors (behavioral) determine compliance and adoption of personal/community "F&E" interventions
  
  
• Whether markers of facial "cleanliness" can identify populations in which the promotion of "face-washing" is unnecessary and redundant

Two potential (Model) studies:

1. After reducing the prevalence of infection with baseline systemic antibiotics, compare the impact of alternative F&E strategies. These should cover populations of varying density and over varying distances from a central point in order to trace the rate and route of reinfection.
   
   

   (This will establish whether a wider "F&E" "cordon sanitaire" more effectively reduces reinfection, by comparing route and reinfection rate from the periphery to the center of the intervention population; and with it, the source of reinfection. Altering the intensity and extent of "F&E" strategies should reveal the synergy of "F&E" when added to the use of antibiotics, and the potential value of "F&E" in sustaining [or maintaining] reduced levels of infection/reinfection.)

2. Once an optimal "F&E" strategy is identified (in [1] above), combine it with alternative antibiotic dosing regimens (frequency; duration) to identify the ideal F-A-E intervention, for differing levels of endemicity and population density, and the duration of antibiotic use needed before "F&E" can sustain control on its own.

D. Other

Short-Term:

• Calculate the cost-benefit/cost-effectiveness of alternative interventions
  
  
• Refine estimates of the "burden of disease" caused by trachoma, including non-ocular disease

Medium-Term:

• Develop simplified, inexpensive diagnostic tests for infection suitable for program evaluation and monitoring

Long-Term:

• Elucidate the pathobiology of the disease (interactions between microbe and host)
  
  
• Develop a vaccine (against infection; against inflammation and blinding scarring)

Next: 3. Onchocerciasis

Also see: Table of Contents of the Research Agenda for Global Blindness Prevention