Preventing Blindness and Saving Lives the Centenary of Vitamin A

Clinical Review & Education

Special Communication Preventing Blindness and Saving Lives The Centenary of Vitamin A

Alfred Sommer, MD, MHS

Within 20 years of its discovery 100 years ago, vitamin A was recognized as critical to normal eyes, growth, and survival. Clinical interest subsequently contracted to its importance in preventing xerophthalmia, until this ophthalmologist stumbled, quite accidently, on its role in

fighting life-threatening infections. Repeated, large-scale randomized clinical trials eventually Author Affiliation: Johns Hopkins convinced (and reminded) the pediatric and nutrition communities of its importance for child Bloomberg School of Public Health, survival. Vitamin A distribution programs are now credited with saving the sight and lives of Baltimore, Maryland. nearly half a million children every year. Corresponding Author: Alfred Sommer, MD, MHS, Johns Hopkins Bloomberg School of Public Health, JAMA Ophthalmol. 2014;132(1):115-117. doi:10.1001/jamaophthalmol.2013.5309 615 N Wolfe St, Ste E6527, Baltimore, MD 21205 ([email protected]).

he first 2 decades of the 20th century witnessed a revolu- Organization’s(WHO)officiallyrecommendedtreatmentwithwater- tion in nutritional science. Hopkins1 and then Funk2 popu- miscible, injectable vitamin A (which was not even commercially T larized the notion that animals could not survive on fat, pro- available at the time!).15,16 tein, and carbohydrates alone, recognizing that small amounts of The latter discovery was my first lesson that data alone do not other substances, so-called accessory factors or vital amines (be- change global health policy.8 These treatment trial data were pre- cause they were erroneously thought to be nitrogen-containing de- sented at a WHO/United Nations Children’s Fund (UNICEF) meet- rivatives of ammonia), were required for growth and survival. Os- ing; no one disbelieved the findings, but no one was willing to change borne and Mendel3 recognized the existence of some of these the existing recommendation. The most I accomplished was a tiny substances in butter fat, and McCollum and Davis,4 in 1913, identi- footnote:“Intheabsenceofwater-miscible,injectablevitaminA,oral, fied one such substance as fat soluble A. Over the next decade, oily vitamin A could be used in its place.” It took 10 years to reverse growth retardation, xerophthalmia, and increased susceptibility to the positions of these alternative treatment regimens.5 infection were all shown to accompany vitamin A deficiency in Although we had also confirmed that a large oral dose of vita- children.5 By 1928, Green and Mellanby6 had termed vitamin A the min A twice a year could prevent xerophthalmia entirely, most min- anti-infective agent. isters of health were unprepared to divert limited funding from child But the importance of vitamin A status for immune competence survival programs (principally childhood immunization) to prevent was largely forgotten following the introduction of powerful antimi- blindness. It is not that they were unsympathetic; rather, they ar- crobialsthatwerefarmorelikelytocureacuteinfections,suchaspneu- gued that they only had $2 per year to spend on each child’s health, mococcal pneumonia and puerperal sepsis, particularly in popula- and child survival was more critical.9 tions that were probably not particularly vitamin A deficient.7 Three years (and 1 book and dozens of eye-related articles) af- Common, but protean, manifestations of excessive childhood mor- ter leaving Indonesia, I had an entirely unexpected insight. While re- bidity and mortality in low-income countries, associated with unsani- viewing printouts on 4500 children in 6 villages we had attempted tary living conditions and the vicious, reinforcing cycles of infection to reexamine every 3 months (as a means of identifying why some and protein energy malnutrition to which hundreds of millions of im- children developed xerophthalmia while neighboring children did poverished children are exposed, ceased to be linked by nutritionists not), I noticed that children who had mild xerophthalmia (night blind- andpediatricianstovitaminAstatus.Ittookme,whoneverknewthere ness or Bitot spots) at their previous examination were far less likely was a relationship, to reestablish it (over the strong and, to some de- than their normal neighbors to show up for their next examination gree, continuing opposition of nutritional scientists) 60 years later. 3 months later. It turned out they had died in the interim; and the My studies of vitamin A deficiency began in earnest in 1976, more vitamin A deficient they had been, the higher their risk for when my family and I moved to Indonesia specifically to study the death. These results did not prove that vitamin A deficiency caused clinical course, origins, treatment, and prevention of xerophthalmia.8 higher mortality,but it strongly suggested it might. This became the The impetus had been reports suggesting that xerophthalmic blind- unlikelybasisofmyAmericanOphthalmologicalSocietythesis,which ness was far more common and widespread than had previously was published in both the Transactions of the American Ophthal- been thought.5 My initial field investigations proved that it was: an mological Society and The Lancet.17,18 The Lancet article failed to elicit estimated half a million children going blind worldwide every year.9 a response: no letters to the editor to support or criticize the find- I documented the clinical and histopathologic spectrum of the ings nor any interest (on other people’s part) to prove or disprove disease5,10-14 and proved that a 2-cent oral dose of oily vitamin A was the thesis that mild vitamin A deficiency might dramatically in- far cheaper, more practical, and just as effective as the World Health crease childhood mortality. This was the beginning of a 10-year

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struggle to convince the world’s nutrition and child-survival com- By 1992, there had been 8 large-scale randomized vitamin A de- munities that vitamin A status was critically important and that a ficiency prevention trials, 6 of which had been meticulously con- 2-cent, oral dose of vitamin A every 6 months might dramatically re- ducted in 4 different countries. The reductions in mortality among duce child mortality. children 6 months to 5 years of age ranged from 19% to 54%.5 But- We were already in the midst of planning a randomized clinical tressed by the complimentary data from 3 measles treatment trials, trial in Sumatra, Indonesia, to prove that twice-yearly large-dose vi- these results convinced me that enough was enough. With sup- tamin A supplementation would reduce the risk for keratomalacia port from the US Agency for International Development, UNICEF, and childhood blindness. Given this new finding on childhood sur- and WHO, I convened a workshop at the Rockefeller retreat in Bel- vival, we decided to add mortality as another primary outcome. The lagio, Italy,in hopes of reaching a consensus among investigators and results were even more dramatic than I had anticipated: there was experts in child survival on 3 (actionable) issues: (1) did mild vita- a one-third reduction in the death rate of children 6 months to 5 years min A deficiency increase a child’s risk for death, (2) would periodic of age in the 250 villages in which the vitamin A had been distrib- vitamin A supplements every 4 to 6 months (or any other ap- uted compared with those in randomly selected 250 villages where proach that improved vitamin A status materially) reduce subse- it had not.19 Unlike our previous report, which was virtually ig- quent childhood mortality, and (3) would immediate oral vitamin A nored, this time, The Lancet was flooded with letters, none of which dosing of children with severe measles reduce their risk for blind- were supportive.20 Pediatric and nutrition experts in child survival ness and death? After 4 days reviewing the available data, the group heatedly explained that poor children in the developing world suf- reached unanimity on each point. I drew up a brief document de- fered so much privation and were exposed to so many infectious claring our agreement, which everyone signed. Each participant was agents, it was absurd to think that 2 cents’ worth of vitamin A could asked to publish the workshop’s conclusions in their favorite medi- materially affect their survival. The nutrition and pediatric commu- cal journal. I published mine in The Lancet.25 nities had not only forgotten their discoveries of the early 20th cen- This Bellagio brief gave momentum to the movement. Within tury, they were also getting angry. a year, Hiroshi Nakajima, director general of the WHO, and Jim Grant, Convinced that clinically relevant data from meticulously con- executive director of UNICEF, jointly launched a new global health ducted trials could not be ignored, we planned our next trial in Albay policy: all countries should improve the vitamin A status of children Province, Philippines. With government support, we spent 2 years at risk for vitamin A deficiency by administering a large, oral vita- mapping and taking a census of the study villages, training field work- min A supplement every 6 months. Then, UNICEF added vitamin A ers, and establishing a data management center. Two weeks before coverage rates to its annual listing of country health metrics. Even theformallaunchofthetrial,alocalphysicianassociatedwiththecom- the American Academy of Pediatrics recommended vitamin A treat- munist insurgency proclaimed that our study was, in reality,an Ameri- ment of all cases of measles among children in the United States con- can plot to kill Filipino children. The opposite was the case, but it be- suming a traditional, developing world diet. came impossible to obtain the compliance we needed in the face of Vitamin A deficiency control is now a global imperative. this vicious public relations campaign. We sent our staff and comput- Nearly 70 countries have established national programs, 50 of ers to Nepal, where our first replication trial was eventually which claim more than 80% coverage. The Copenhagen Consen- completed.21 Wealsoencouragedotherinvestigatorstoconductsimi- sus, an influential group of economists that recommends the most lar trials elsewhere. Fortunately, several did; unfortunately, some of cost-effective ways to improve health and development, routinely these were so dismally designed and conducted, as we warned the cites vitamin A supplement distribution as one of the most cost- investigators from the start, that they muddled the issue instead of effective of all health interventions, as has the World Bank. Both clarifying it.5 However, most found results nearly identical to our own. UNICEF and the WHO estimate that existing programs, distribut- Our thesis was unexpectedly bolstered by a parallel set of stud- ing more than half a billion supplements each year, save the sight ies we conducted in African children when I was asked to investi- and lives of more than 350 000 children annually; the number gate the high rates of corneal ulceration and death associated with would be higher if all children who could benefit from the supple- severe measles. At least half the cases of corneal ulcers, and a larger ments received them. proportion of bilaterally blinding ulcers, were due to previously un- I have learned a number of lessons during this lengthy saga: good recognized vitamin A deficiency.5,22 Treating these children with vi- data are a starting point but do not expect them to speak for them- tamin A on 2 successive days reduced their case-fatality rate by half,23 selves, and established wisdom is hard to change, but persistence, just as it had, unbeknownst to us at the time, in a study of English andaccumulatingdata,canmakeadifference.8,20 And,bysheerluck, children hospitalized with measles 60 years earlier.24 I had engaged one of the few micronutrients whose deficiency is near The results of our studies of measles in African children were universal throughout the developing world; no matter where one fully consistent with our observation that vitamin A prophylaxis conducted a rigorously designed and executed prevention trial, it among Asian children had dramatically reduced their mortality, in was bound to have a positive impact. large part, by reducing their risk for death from measles by a similar It took an ophthalmologist to restore vitamin A, discovered 50%. These findings supported the growing evidence that vitamin exactly 100 years ago, to its rightful place in nutritional science and status was important for both sight and life.5 child health.

ARTICLE INFORMATION Previous Presentation: This article was presented REFERENCES Accepted for Publication: May 13, 2013. as a Verhoeff Lecture at the Annual Meeting of the 1. Hopkins FG. Feeding experiments illustrating the American Ophthalmological Society; May 17, 2013; Conflict of Interest Disclosures: None reported. importance of accessory factors in normal dietaries. La Jolla, CA. J Physiol. 1912;44(5-6):425-460.

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2. Funk C. On the chemical nature of the substance 11. Emran N, Tjakrasudjatma S. Clinical 18. Sommer A, Tarwotjo I, Hussaini G, Susanto D. which cures polyneuritis in birds induced by a diet characteristics of vitamin A responsive and Increased mortality in children with mild vitamin A of polished rice. J Physiol. 1911;43(5):395-400. nonresponsive Bitot’s spots. Am J Ophthalmol. deficiency. Lancet. 1983;2(8350):585-588. 3. Osborne TB, Mendel LB. The influence of 1980;90(2):160-171. 19. Sommer A, Tarwotjo I, Djunaedi E, et al. Impact butter-fat on growth. J Biol Chem. 12. Sommer A, Green WR, Kenyon KR. Bitot’s spots of vitamin A supplementation on childhood 1913;16(4):423-437. responsive and nonresponsive to vitamin A: mortality: a randomised controlled community trial. 4. McCollum EV, Davis M. The necessity of certain clinicopathologic correlations. Arch Ophthalmol. Lancet. 1986;1(8491):1169-1173. lipins in the diet during growth. J Biol Chem. 1981;99(11):2014-2027. 20. Sommer A. 1997 Albert Lasker Award for 1913;15(1):167-175. 13. Sommer A, Sugana T. Corneal xerophthalmia Clinical Research: clinical research and the human 5. Sommer A, West KP Jr. Vitamin A Deficiency: and keratomalacia. Arch Ophthalmol. condition: moving from observation to practice. Health, Survival, and Vision. New York, NY: Oxford 1982;100(3):404-411. Nat Med. 1997;3(10):1061-1063. University Press; 1996. 14. Sommer A, Green WR, Kenyon KR. 21. West KP Jr, Pokhrel RP, Katz J, et al. Efficacy of 6. Green HN, Mellanby E. Vitamin A as an Clinicohistopathologic correlations in vitamin A in reducing preschool child mortality in anti-infective agent. Br Med J. 1928;2(3537): xerophthalmic ulceration and necrosis. Arch Nepal. Lancet. 1991;338(8759):67-71. 691-696. Ophthalmol. 1982;100(6):953-963. 22. Foster A, Sommer A. Corneal ulceration, 7. Sommer A. Vitamin a deficiency and clinical 15. World Health Organization. Vitamin A measles, and childhood blindness in Tanzania. Br J disease: an historical overview. J Nutr. Deficiency and Xerophthalmia: Report of a Joint Ophthalmol. 1987;71(5):331-343. 2008;138(10):1835-1839. WHO/USAID Meeting: WHO Technical Report Series 23. Barclay AJG, Foster A, Sommer A. Vitamin A 590. Geneva, Switzerland: World Health supplements and mortality related to measles: 8. Sommer A. 10 Lessons in Public Health: Organization;1976:1-88. Inspiration for Tomorrow’s Leaders. Baltimore, MD: a randomised clinical trial. Br Med J (Clin Res Ed). Johns Hopkins University Press; 2013. 16. Sommer A, Muhilal, Tarwotjo I, Djunaedi E, 1987;294(6567):294-296. Glover J. Oral versus intramuscular vitamin A in the 9. Sommer A, Tarwotjo I, Hussaini G, Susanto D, 24. Ellison JB. Intensive vitamin therapy in treatment of xerophthalmia. Lancet. 1980;1(8168, measles. Br Med J. 1932;2(3745):708-711. Soegiharto T. Incidence, prevalence, and scale of pt 1):557-559. blinding malnutrition. Lancet. 1981;1(8235): 25. Sommer A. Vitamin A deficiency and childhood 1407-1408. 17. Sommer A. Mortality associated with mild, mortality. Lancet. 1992;339(8797):864. untreated xerophthalmia. Trans Am Ophthalmol doi:10.1016/0140-6736(92)90298-H. 10. Sommer A, Emran N, Tamba T. Vitamin Soc. 1983;81:825-853. A-responsive punctate keratopathy in xerophthalmia. Am J Ophthalmol. 1979;87(3):330-333.

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