Infectious diseases like AIDS, tuberculosis, and malaria are responsible for a significant global health burden. But other, less well-known, and often neglected, infections also account for staggering levels of disease and disability, especially in lower income countries. One example is trachoma, a bacterial infection of the eye that is currently the leading cause of preventable blindness worldwide.
Although the infection primarily affects children, trachoma’s most devastating effects manifest in adulthood, when individuals who sustained repeated infections eventually become blind, unable to care for themselves and their families.
Treatment of trachoma became possible in the 1990s following the discovery of an antibiotic against the bacterium, Chlamydia trachomatis. Since then, NEI-funded research has played a critical role in assessing the effectiveness of administering this antibiotic to entire communities. This research is now helping to guide global efforts to eliminate trachoma within the next decade.
Interview with Sheila K. West
Striking the poorest communities
In the United States, C. trachomatis causes over one million reported cases of Chlamydia, a sexually transmitted disease that damages reproductive organs if not treated with antibiotics.1 However, trachoma is an even greater public health concern in many developing countries - especially in regions that suffer from overcrowding, water shortages, and poor hygienic conditions.
Trachoma spreads from person to person, usually children, through contact from hands, clothes, or flies that carry discharge from the eyes. Over the years, repeated infections cause scarring on the inside of the eyelid. As a result of the scarring, the eyelashes turn in—a condition known as trichiasis—scraping and irritating the cornea and eventually leading to severe vision loss and blindness. The World Health Organization (WHO) estimates that 40.6 million people suffer from active trachoma and 8.2 million have trichiasis (Mariotti, Pascolini, & Rose-Nussbaumer, 2009). Due to their close contact with children, trachoma prevalence in women is three times that in men.
Up until the last century, trachoma was rampant throughout Europe and North America, but by the 1950s, it disappeared from these regions, largely due to improved hygienic conditions following the industrial revolution. In many communities in less developed countries, however, where crowding is common and access to clean water and sanitation remain inadequate, trachoma is still endemic. According to the WHO, the infection is widespread in the Middle East, North and Sub-Saharan Africa, parts of India, Southern Asia, and China. In some villages, as many as 60% of preschool children have active infection (West et al., 1996).
An antibiotic for treating trachoma
Azithromycin was originally discovered in the early 1990s by researchers at Pfizer Corporation as an antibiotic against Chlamydia—the genital strain of the bacterium that causes trachoma. Subsequent studies showed that Azithromycin is also effective against trachoma. Since living conditions in regions where trachoma is endemic are unlikely to improve dramatically in the near future, large scale antibiotic strategies are being investigated. Is it possible to effectively treat all individuals in a community, termed mass treatment, with azithromycin to eliminate trachoma in that community?
The idea behind mass treatment is similar to vaccinating an entire population to eliminate a disease - drugs are administered to both infected and non-infected individuals in a community at a single point in time. Mass treatment with azithromycin became economically feasible in 1998, when the Edna McConnell Clark Foundation and Pfizer founded the International Trachoma Initiative to make large doses of the antibiotic available for free.
How to eliminate trachoma
Treating entire communities with an antibiotic presents several challenges. When trachoma control programs first started, it was not known whether mass distribution of the antibiotic would be effective or how many individuals in a given community would have to be treated, how often, and for how long. Scientists also wanted to know if periodic mass antibiotic treatment would increase the prevalence of drug-resistant strains in the future.
In keeping with NIH’s commitment to translational research and global health, NEI addressed these important concerns by conducting several large-scale trials in different trachoma endemic regions. The data obtained through these trials not only demonstrate that mass antibiotic treatments are an effective strategy for eliminating trachoma, but azithromycin may also help treat other serious infections and improve the outcome of trichiasis surgery.
Early trials of mass treatment with azithromycin showed that a single dose was effective in reducing the prevalence of C. trachomatisinfection in a community, however, infection returned within a year in the most severely affected communities. Subsequent clinical trials funded by NEI established that long-term reduction, and even elimination, of ocular chlamydial infection is feasible with repeated antibiotic treatments. A trial completed in 2006 in 16 rural Ethiopian villages determined that providing azithromycin twice a year to everyone resulted in a dramatic reduction of active trachoma infection from over 30% to less than 1% of the population at the end of the two year trial2 (Melese et al., 2008).
It is important to note that after trials with azithromycin end, the treated communities are still left with the endemic problems of poor hygiene and dirty water. Active disease levels increase unless periodic mass treatments are administered. However, repeated treatments could result in Chlamydia developing resistance to azithromycin. Sustained resistance was observed, for example, when cotrimoxazole or penicillin were administered for certain infections. Alternatively, resistance of another bacterium, Streptococcus pneumoniae, to azithromycin develops but diminishes several months after treatment is stopped (Batt et al., 2003). Fortunately, there is no evidence that Chlamydia develops resistance to azithromycin. In another NEI funded study, researchers found that repeated cycles of administration over several years are required to eliminate trachoma from a village. “NEI funded an important program that sent a message to WHO that these elimination efforts take a long time,” says study leader Sheila West, Ph.D., from the Wilmer Eye Institute at Johns Hopkins University in Baltimore, MD.
Cost-effective strategy: Treat the children
One challenge of treating entire communities is that it is usually not feasible to administer an antibiotic to every individual living in that community. However, with vaccines, it has been shown that immunizing a portion of the community against an infectious disease is sufficient to protect most individuals—a phenomenon sometimes referred to as “herd immunity.” It was not, however, known whether the same was also true for antibiotic treatment.
Working in collaboration with the Carter Center and the Ministry of Health in Ethiopia, NEI-funded researcher, Thomas Lietman, and his research group from the University of California, San Francisco, led a clinical trial in 2007 involving 24 communities in Amhara, Ethiopia, to determine whether treating only children, the core group for trachoma transmission, is sufficient to protect the entire community. The researchers provided mass treatments to children under 11 years of age. After one year, the prevalence of infection among those treated children had decreased dramatically from 48% to less than 4%. Importantly, even the prevalence of infection of older untreated children (and adults) also dropped significantly. Thus, young children appear to transmit the disease to older individuals, so that repeated treatments of children alone might be a sufficient and cost-effective strategy to control the infection throughout the community as expected if the herd effect is similar to that seen with vaccinations (House et al., 2009).
Additional benefits of azithromycin
Because trachoma itself is not a deadly disease in children, Dr. Leitman and colleagues conducted another large clinical trial of azithromycin treatment for trachoma in 48 communities in Ethiopia where they examined child mortality. They found that the mortality rate of children in treated communities was cut in half compared to the untreated groups (Porco et al., 2009). The study is consistent with the notion that reduced mortality is due to the effectiveness of azithromycin against other types of potentially lethal infections, such as respiratory tract infections, diarrhea and malaria, thus providing a strong additional incentive for mass treatments with azithromycin.
Addressing trichiasis recurrence
Mass antibiotic treatment does not prevent vision loss in individuals who have already developed trichiasis. The only way to treat trichiasis and prevent blindness is through surgery. Yet, up to 50% of people who have surgery have a recurrence of trichiasis, indicating that current surgical procedures alone are inadequate (West, et al., 2007).
To help address the recurrence of in-turned eyelashes, NEI funded the Surgery for Trichiasis, Antibiotics to Prevent Recurrence (STAR) trial. One randomized group of participants enrolled in the trial received oral azithromycin following trichiasis surgery; the other group received the standard post-surgical care, which consisted of topical tetracycline administration, a different antibiotic. The researchers found that azithromycin reduced overall trichiasis recurrence by one third and severe trichiasis by 47% compared to standard treatment (West, et al., 2007). These results could lead to improving post-surgical protocols to include a dose of azithromycin.
Global effort to eliminate trachoma
NEI-funded research over the past decade has laid the groundwork for other organizations to get involved in trachoma-elimination efforts. The Bill & Melinda Gates Foundation recently awarded Johns Hopkins University a grant of $10 million to maintain progress toward eliminating the disease. In part, these funds will support additional clinical trials of azithromycin for trachoma elimination in the Gambia, where the disease is on the verge of elimination; in Tanzania, where treatment programs are in place, and the disease is on the decline; and in Ethiopia, where treatment programs have not yet started. The research is being conducted by the Partnership for the Rapid Elimination of Trachoma, or PRET, which involves NEI grantees at Johns Hopkins and the University of California, San Francisco, and at the London School of Hygiene and Tropical Medicine. Other supporting organizations include Pfizer; the WHO; Becton, Dickinson and Company; and the Trachoma Control Programs at the ministries of health in Tanzania, Ethiopia, and the Gambia. “NEI stepped up to the plate early on by funding trachoma research, hoping that would lead to other partners to come in and fill in the gaps,” says West, “and that has now happened.”
The WHO’s trachoma elimination strategy, called “SAFE,” involves Surgery for in-turned lashes, Antibiotics for active disease, Facial cleanliness, and Environmental improvement. In addition to the antibiotic trials and surgical intervention trials, the NEI supported studies to test the efficacy of building latrines and improving hygienic conditions. However, the greatest successes to date have been with controlled azithromycin distribution which avoids the cultural, political and economic difficulties presented by effective environmental changes. Working with local governments and agencies to distribute azithromycin to affected communities, the WHO set a goal of reducing trachoma disease burden to a level where it is no longer a public health concern by the year 2020. The concerted global efforts against trachoma might make “2020 vision” a reality.
- Batt, S. L., Charalambous, B. M., Solomon, A. W., Knirsch, C., Massae, P. A., Safari, S., … Gillespie, S. H. (2003). Impact of azithromycin administration for trachoma control on the carriage of antibiotic-resistant Streptococcus pneumonia. Antimicrobial Agents and Chemotherapy, 47, 2765-2769.
- House JI, Ayele B, Porco TC, Zhou Z, Hong KC, Gebre T, Ray KJ, Keenan JD, Stoller NE, Whitcher JP, Gaynor BD, Emerson PM, Lietman TM. (2009). Assessment of herd protection against trachoma due to repeated mass antibiotic distributions: a cluster-randomised trial. Lancet, 373 (9669):1111-8.
- Mariotti, S. P., Pascolini, D., & Rose-Nussbaumer, J. (2009). Trachoma: Global magnitude of a preventable cause of blindness. British Journal of Ophthalmology, 93, 563-568.
- Melese, M., Alemayehu, W., Lakew, T., Yi, E., House, J., Chidambaram, J. D., Lietman, T. M. (2008). Comparison of annual and biannual mass antibiotic administration for elimination of infectious trachoma. JAMA, 299, 778-784.
- Porco, T.C., Gebre, T., Ayele, B., House, J., Keenan, J., Zhou, Z., Hong, K.C., Stoller, N., Ray, K.J., Emerson, P., Gaynor, B.D., Lietman, T.M. (2009) Effect of mass distribution of azithromycin for trachoma control on overall mortality in Ethiopian children: a randomized trial. JAMA. 302(9):962-968.
- West, S., Munoz, B., Lynch, M., Kayongoya, A., Mmbaga, B.B.O., Taylor, H.R. (1996). Risk Factors for Constant, Sever Trachoma among Preschool Children in Kongwa, Tanzania. Am J of Epidemiology, 143:1, 73-78.
- West, S., Alemayehu, W., Munoz, B., & Gower, E. W. (2007). Azithromycin prevents recurrence of severe trichiasis following trichiasis surgery: STAR trial. Ophthalmic Epidemiology,14, 273-277.
- Centers for Disease Control and Prevention - Chlamydia Fact Sheet
- Babies less than one year of age were excluded from treatment.