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Historical Keynote
Addresses
Sommer Delivers the 4th
Gordon Epidemiology Lecture at NIH
By at least one definition,
Alfred Sommer is an epidemiology hero. He has helped
identify a problem (vitamin A deficiency), developed methods to test
specific hypotheses (what causes mild xeropthalmia?), and then
experimented to prove or disprove a hypothesis (does vitamin A
supplementation reduce mortality?), and then applied good public
health and preventive medicine strategies to utilize the information
to reduce morbidity and mortality (Bellagio brief with WHO and UNICEF
recommendations to eliminate vitamin A deficiency by 2000).
But Sommer fits more than one
definition of a hero. In introducing him at NIH, Director Harold
Varmus said Sommer’s work “epitomizes the kind of extraordinary
contribution that epidemiology can make to medical science.” He has
been honored in clinical medicine and received the Lasker award in
1997 for clinical medical research. Some believe he deserves the Nobel
prize for his vitamin A work.
Lectureship
Sommer, Dean and Professor of
Epidemiology and International Health at the Johns Hopkins University
School of Hygiene and Public Health, was selected to be the 4th Gordon
Lecturer at NIH on January 27, 1999. The Robert S. Gordon Lectureship
was established in 1995 in tribute to Dr. Gordon for his outstanding
contributions to the field of epidemiology and for his distinguished
service to the National Institutes of Health. The award is made
annually to a scientist who has contributed significantly to research
in the field of epidemiology or clinical trials. Previous award
recipients have been Charles Hennekens (Harvard),
Joseph Fraumeni (NCI), and Jean MacCluer
(Southwest Foundation for Biomedical Research and the University of
Texas Health Science Center).
Lessons Learned
Dr. Sommer structured his talk
by telling the story of how he went from one set of studies to
another. He highlighted four conclusions from his experience. First,
epidemiology is simply a tool. He did not elaborate, but presumably
implied that it was only a means to an end in the vitamin A saga.
Secondly, his initial findings on vitamin A were a chance observation.
But he emphasized that chance favors the prepared mind as Pasteur
said. In Sommer’s case, he made his observation only because, as he
said, “I was mucking around in the data.” Thirdly, you must
progressively build an edifice of evidence one brick at a time until
the prevailing paradigm changes. This is what he accomplished with
vitamin A findings which initially were greeted with disbelief.
Finally, you have to like making a difference, that is, translating
insights into practice. According to Sommer, he cut his “epidemiologic
teeth” in 1970 as a CDC Epidemic Intelligence Service Officer assigned
to the Cholera Research Laboratory in Dacca founded by Bob
Gordon. In that experience, Sommer became, in his words,
“captured by the intellectual rigor, investigative strengths and
pragmatic powers of this discipline.”
Chance Observation
Sommer made his first
observation about the potential of vitamin A to have life saving
benefit in a study of approximately 4,000 children who were being
followed up every three months in six villages of Indonesia. He was
investigating why some children develop xeropthalmia and others do
not. When he made the chance observation that the N for children with
mild xeropthalmia was getting smaller over each subsequent follow up
interval, he reclassified the children into those with and without
xeropthalmia. He found that children with even mild xeropthalmia were
dying more frequently than children with normal eyes, and children
with more severe disease were dying at a higher rate, a dose response
phenomenon.
First Trial
Sommer published his results in
Lancet and then went on to conduct a trial which randomized 450
villages to either receive or not receive vitamin A capsules. Child
mortality per 1000 was evaluated at 12 - 71 months. Children in
vitamin A supplemented villages had a death rate of 4.9 versus 7.4 in
control villages (RR 1.51 CI 1.03-2.28). When adjusted for factors
such as true compliance with the supplement, the efficacy rose to 72%.
Sommer also published this in the Lancet and went on to conduct other
Asian trials in India and Nepal. The overall meta-analysis of the six
Asian trials showed a 34% reduction in child mortality achievable with
vitamin A supplementation.
African Studies
In Africa, Sommer was involved
in studies to examine if the measles associated corneal destruction
found there was working through the vitamin A deficiency mechanism.
Studies in Tanzania showed that as much as 50% of the corneal ulcers
due to measles were due to vitamin A deficiency. It was an easy step
from there to wonder about the impact of vitamin A on measles
mortality. Studies were carried out to add vitamin A to the routine
care that children receive when hospitalized for measles. The death
rate was reduced from 13.0 to 6.8% in the first hospital study in
Tanzania. Sommer reminded the audience at this point about the meaning
of “re-search” because he found a study in London published in 1932
which found the exact same result he had seen in Tanzania. British
children with measles who received cod liver oil had an approximately
50% reduction in death rate. Similar findings have also been
documented now in community trials in Nepal and India where children
receive vitamin A prior to the onset of measles.
Mechanism
The mechanism by which vitamin A
reduces mortality is not well understood. One hypothesis recognizes
the role of the vitamin in regulating cellular differentiation and
suggests that vitamin A may act in some way by maintaining the
integrity of epithelial barriers. Another hypothesis sees a role for
vitamin A in strengthening the immune response. Whatever the
mechanism, it works quickly since it benefits even children who have
been infected, as occurs with measles.
Goals
Sommer estimates that
approximately 10 million children in the world may be affected by
xeropthalmia and that vitamin A deficiency leads to one million deaths
per year. WHO has had a goal to eliminate vitamin A deficiency by the
year 2000. This goal will not be met according to Sommer; however, a
new goal has been set for 2020 and benchmarks have been defined to
monitor progress. For example, in 1970 only two countries had vitamin
A supplementation programs, but today at least 70 countries have such
programs, at least on paper.
Among the new directions
Sommer’s research is taking is in the area of maternal mortality. An
article in press in the BMJ shows a 35 - 50% reduction in maternal
mortality for pregnant women given vitamin A weekly through three
months post-delivery.
Published March 1999
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