COLLABORATIVE RESEARCH ON TROPICAL DISEASES (1985)  p. 2 of 12

E. THE SEVENTH PANDEMIC AND THE U.S. RESPONSE

          Pandemic number seven broke out in 1961 in Celebes (Sulawesi), Indonesia, and hit China and the Philippines the same year. At first it was called para-cholera, because the infecting organism was not the classical vibrio but a variety called El Tor. The El Tor vibrio had been discovered at a quarantine station of that name on the Sinai peninsula in 1907 in the bodies of hajis who had died of other causes. It appeared to cause only a mild variety of diarrhea, not real cholera.

          In 1937, El Tor showed up in the Celebes where, although the infection rate was low, it had a mortality rate of over 50%. Still, the disease did not take on epidemic characteristics until 1961, for reasons that can only be guessed at. Then it spread from East Asia to the Subcontinent and on to the Middle East, Southern Europe, and East and West Africa, where it seems likely to remain.

          As the pandemic spread, Phillips and his team developed an efficient procedure for responding to cholera epidemics in the Philippines, South Korea, South Vietnam, East Pakistan, Malaysia and Sarawak. The Navy offered their services as soon as news of an epidemic was received, and a team of three or four scientists and eight to ten technicians was dispatched by military aircraft as soon as an invitation arrived. They first indoctrinated local physicians and nurses in the Navy method of treatment, then requested permission to conduct research.

          The Navy treatment, with a mortality rate consistently under one percent, had evolved in Cairo and Bangkok. The specific gravity of the patient’s blood was measured to determine the volume of fluid needed to restore the plasma to normal levels. Fluid balance was rapidly restored intravenously and maintained thereafter by matching inflow with outflow. The fluids used contained minerals to match those lost in diarrhea, and sodium bicarbonate to counteract acidosis. The cholera cured itself, as Phillips said, like the common cold.

          This method of treatment was a definite advance over previously-used therapies, and Phillips received the Albert Lasker Clinical Research Award in 1967 in recognition of that fact. It had, however, practical limitations in dealing with large-scale epidemics in developing countries. The fluids had to be made from sterile, distilled water to avoid fevers, and they needed to be administered under medically controlled conditions. Patients would often require infusions of more than their own weight in liquids, placing a huge burden on logistical services.

          The NAMRU group was well aware of the shortcomings of their method. Much of the research they carried out after introducing their treatment to an epidemic area was devoted to the search for a means of oral rehydration. The principal problems were that fluids taken orally generally induced nausea and vomiting, and that even if they could be kept down, the body seemed unable to absorb needed sodium and chloride from them.

          In July 1962, in Manila, Phillips found, literally, the solution. Adding glucose to the swallowed fluid allowed sodium, chloride, and greater amounts of water to be absorbed by the body. Fluid balance was restored immediately. An editorial in the prestigious medical journal Lancet in 1978 valued the finding thus:  “The discovery that sodium transport and glucose transport are coupled in the small intestine, so that glucose accelerates absorption of solute and water, was potentially the most important medical advance this century.”

          Credit for this momentous discovery may rightly be shared by physiologists at Oxford, Harvard and Yale, and by the clinician N.S. Chatterjee, who in 1953 experimented with cholera patients; but in the history of science vs. cholera, the accolade is assigned by Van Heyningen and Seal to Phillips.  He was, for a long time, not himself convinced of the utility of his findings.

          Encouraged by the initial observation, a small NAMRU team treated 40 patients with the glucose solution, after initial intravenous rehydration, in September. Five died, drowned, technically, by water drawn to the lungs from their cells by an excessively salty solution. This failure soured Phillips on the oral rehydration notion, to the point that when he received the Lasker prize in 1967 he referred to the glucose solution as a hope that did not materialize. He also, as head of the PSCRL after 1965, actively restrained experimentation on oral rehydration, as we shall see later.

          In 1962, as Phillips was experimenting with oral rehydration, NAMRU was perfecting its epidemic response procedure, and the PSCRL was at last becoming operational in Dacca, another American medical research team set up shop in Calcutta. Under an NIH grant program that we will examine in more depth, Johns Hopkins University set up a Center for Medical Research and Training (JHCMRT) in Calcutta. They started a cholera research program because the disease was important to the site, not because the grant required work on cholera nor because Johns Hopkins was experienced in the disease.

          The Hopkins group found pre-NAMRU procedures in effect for dealing with cholera. Patients admitted for treatment at the Infectious Diseases Hospital in Calcutta, to which they were attached, had a mortality rate of 30%. Phillips’ work in Cairo in 1948 had gone unnoticed, perhaps because it was published in an obscure journal or because, as often happens in the Third World, the Hospital couldn’t afford the periodical in which it appeared. The major NAMRU advances during the Bangkok outbreak were more recent, and hadn’t been demonstrated in the Subcontinent. The Hopkins group arranged a controlled comparison of the methods used by the Indian physicians with those recommended by NAMRU. The dramatic differences in results led the Indians to abandon traditional therapy.

          The Hopkins group exchanged information and visits with the NIH scientists at the PSCRL regularly. Craig Wallace, who was with Phillips at NAMRU-2 and headed the Hopkins group from 1964-66, says that both Hopkins and PSCRL made important observations, but each would in time have done what the other accomplished. Their working conditions differed substantially. Hopkins was primarily a research group, admitting only a few patients per day for observation but caring for as many as several hundred a day. The PSCRL on the other hand was a front-line treatment center. During one period of Moslem-Hindu tension in East Pakistan, cholera broke out among a group of Hindus taking shelter in several cotton and jute mills. Patients were transported by the truckload to the Mitford Hospital, the hospital in Narayanganj, and the PSCRL, each receiving about a third of the victims. Within 48 hours all but two of the PSCRL patients had been discharged, with zero deaths, while 27% had died at Mitford and 47% at Narayanganj. Thereafter, the PSCRL was charged with treatment of all diarrheal cases in Dacca.

          The Hopkins team had advantageous conditions for conducting intensive clinical studies. They were attached to a large hospital where it was possible to develop excellent laboratory facilities. Their Indian colleagues, including S.N. De, who had already succeeded in identifying the cholera toxin, had vast experience with cholera. Links to the Johns Hopkins School of Medicine were also important, even though some of the field staff did not come directly from the parent institution.

          Among the achievements of the Calcutta group was the appreciation of the value of antibiotics in the treatment of cholera. It was known, from previous experiments by Chaudhuri in Calcutta and Phillips in NAMRU, that antibiotics would not alone reduce the death rate from cholera. Once the disease had damaged the lining of the gut, the damage was done. It takes a week for the damaged cells to grow back, by which time the cholera vibrios have gone away of their own accord, so Phillips saw no sense in using antibiotics for treatment. At Calcutta, the Hopkins group showed that using tetracycline, only half the volume of replacement fluids and half the hospitalization time were required for recovery.

          The Calcutta team also made important advances in identifying causes of severe diarrhea other than cholera. Early in their stay they noted that cholera vibrios could be identified in only about half of the patients in their care. In 1964, an unusual epidemic of non-cholera diarrhea broke out at the time of year cholera could be expected to appear. Of 145 patients studied, 86% did not have cholera, although they were just as sick as if they did. In 1968, Hopkins workers identified the causative agent as Escherichia coli, an organism that had been known to exist harmlessly in the large bowel, but was now found to act much like cholera in the small bowel. E. coli is not the only non-cholera diarrhea-producing organism by far, but it is one of the most dangerous world-wide for children under two years of age.

          The Hopkins advantage in having facilities for intensive clinical work was balanced in Dacca by the opportunity for field surveillance and epidemiological studies. One of the important missions of the PSCRL was to test the efficacy of cholera vaccines. This task required access to an area with a high incidence of cholera, in which comparisons could be made of cholera attack rates in people given a vaccine and control groups given placebos. PSCRL needed a cholera ward in which to treat those who contracted the disease, and ready access to a sizable population at risk. With the assistance of local authorities, a group of 23 villages in the Matlab thana, one of the most densely populated areas of East Pakistan, was selected. The thana was a subdivision of Comilla District, about 40 miles from Dacca. The villages were most easily reached by boat through rivers and canals.

          The Matlab thana surveillance area, and another developed shortly thereafter at Teknaf, remains a major resource for epidemiological research and experimental interventions, in such fields as nutrition and family planning as well as diarrheal diseases. Experiments there demonstrated conclusively that it is far cheaper and more effective for a poor country to devote its resources to providing therapy centers and gradually upgrading sanitation than to administering large-scale vaccination programs. The vaccines then and until now available are effective at most for three or four months and need to be administered a month before exposure to the disease. Therapy, particularly after an oral rehydration method became available, is relatively inexpensive.

          The Dacca and Calcutta units differed from the NAMRU approach in various ways. As a laboratory man, Phillips favored tests of blood specific gravity in order to determine the volume of replacement fluid needed. The more clinically oriented physicians at JHCHRT and PSCRL soon came to prefer quicker assessments made by judging the degree of dehydration by the fullness of the skin, assessing blood pressure by pulse, and other observations.

          In 1965 the stage was set for a grand finale to our story:  Phillips was appointed to direct the PSCRL. Phillips was at heart a laboratory scientist. He had little background or interest in epidemiology. His first concern was to understand the disease process, but he had relatively little interest in or appreciation of patient care. He was a physiologist, not a clinician. His attitudes were not shared by many of his Dacca colleagues, several of whom came from the Center for Disease Control, an organization dedicated to results in large populations.

          The second area where Phillips was swimming against the tide was oral rehydration. The 1962 setback in Manila apparently inhibited both Phillips and his colleague Wallace; both were extremely cautious in permitting clinical experimentation with oral rehydration in the units they ran during the next five years, Phillips in Dacca and Wallace in Calcutta. Yet the idea was far from forgotten, and Wallace continued to believe that it would work under proper conditions.

          Research on the glucose transporter continued at both PSCRL and JHGMRT in the field, and at Johns Hopkins and other laboratories in the United States. Results were encouraging, and the natural interest of the field staff in Dacca to try the oral technique were reinforced, in the winter of 1966-7, by the outbreak of the biggest cholera epidemic the PSCRL had yet witnessed, giving rise to the fear that they might run short of intravenous fluids. The first experiment, in Chittagong in 1967, was not a success, although not catastrophic as in Manila. The second attempt was more encouraging. Despite official opposition, from Phillips and NIH in Washington, a controlled field trial was conducted in 1969 in Matlab thana, in the midst of an epidemic in which a shortage of intravenous fluids actually did occur. The result was a powerful affirmation of the value of oral rehydration. The need for intravenous fluids was reduced by 80% and in mild cases it was not needed at all. Even Phillips became convinced again of the promise of the technique.

          In Calcutta, the Hopkins group were working along similar lines. They demonstrated in 1968 that oral rehydration could be used successfully to maintain balance after initial intravenous rehydration had been used, but they preferred to await further study before experimenting further. Their hands were forced by an outbreak of disease among a concentration of 350,000 refugees from the civil war in East Pakistan in May 1971. The death toll was huge; a fatality rate of 30% prevailed among patients in the refugee camps. There was no hope of producing the amounts of intravenous fluid needed for such numbers, nor of training the personnel to administer it. The Hopkins group consequently prepared packets of dry ingredients in their library in Calcutta and sent them to the camps, where an Indian team from the JHCMRT dissolved the packets in clean drinking water and dispensed the liquid to patients. Packets for 50,000 liters of solution were prepared. In all, 3,700 patients were treated, only the most seriously ill intravenously, with a mortality rate of 1% among those in the JHCMRT tent, and 3.6% for others using the solution.

          Indian resentment over American involvement in Vietnam, and over American policies on the Subcontinent in the early l970s, made the Hopkins situation in Calcutta increasingly uncomfortable. Had the program been designed to assist Indian research and treatment efforts, and in particular, had it been meant to train Indian scientists, it might have had more local support, but the NIH grants of the time were designed purposely and rather narrowly to support American research and training, not to build the competencies of their Third World colleagues. As it was, when cholera broke out among the Bengali refugees, no Americans were permitted to participate in their treatment. The next year, relations became so strained that Hopkins staff had problems obtaining visas to visit the unit and it was decided to abandon the Calcutta location. They moved the unit to Dacca and affiliated with the CRL.

          Civil turmoil also brought research to an end at the PSCRL at this time, as the Bengalis struggled for independence. The laboratory remained open for the treatment of patients -- indeed the conflict brought them the greatest number of cholera patients of their history -- but throughout 1971 most of the expatriate staff were kept elsewhere for security reasons.

          Fortuitously, another mechanism for advancing cholera research appeared on the scene in 1965. President Johnson received Prime Minister Sato of Japan in Washington to discuss, primarily, balance of payments problems between the two countries. The meeting produced few positive results on that score, and the President reportedly asked Colin MacLeod, a member of the ubiquitous Inner Circle who was then Deputy Science Advisor, to come up with a suitable topic for constructive cooperation in order to avoid too discouraging a final communique. MacLeod, after working all night, came up with an idea that became the U.S.-Japan Cooperative Medical Science Program. The purpose of the program was to expand cooperation between the two countries on human health problems “of great concern to all the peoples of Asia.”  Malaria, cholera, schistosomiasis, tuberculosis and stomach cancer were singled out for early attention.

          As a face-saving device, the US-Japan program served its purpose in the 24 hours in which such communiques are on anyone’s mind, but the program continues to be both popular and important to work on cholera. No money crosses borders under this program, and no collaborative research is supported. Each side funds its own research, and panels on each of the major diseases meet annually, alternating hosts, to report accomplishments.

          Initially, US participation in the program was guided and funded out of the Office of International Research at NIH, but later it came under NIAID. In the first ten years of the program, 58 grants and contracts were made in the cholera field in the US, and a similar number in Japan. The program was an important source of funds for researchers, but whether it still is, is questionable. NIH no longer carries the US-Japan program as a line item in its budget, although in 1983 roughly $11 million in grants were made under its aegis. All such grants are funded from regular NIH appropriations and it is not clear if the abolition of the program would have any effect at all on the awards made.

          It can be argued that the loss of the program would have a profound effect on the awards because of the authorizations question. The US-Japan program operates under the only active delegation of presidential authority to conduct research for international health purposes. This power is given to the President in the International Health Research Act of 1960. It has been delegated only three times, including the US-Japan case. Its broader use has consistently been opposed by the Department of State, to that Department’s lasting discredit.

          Now we are ready to return to strife-torn Dacca, endemic home of cholera and other diarrheal diseases, to see what happened to the PSCRL when Bangladesh gained independence.

F. PSCRL TO CRL TO ICDDR/B

          1971 was a difficult year for the SEATO center, and for Dacca generally. Strikes and riots disrupted research in February, and work came to a standstill in March when West Pakistani troops attacked the Bengalis. Months of fighting followed. The laboratory was untouched, but much of the surrounding area was bombed between March and December. The local staff, led by Deputy Director Mujibur Rahman, kept the laboratory open, working without regular salary and treating as many as 1500 patients a month. Research was of course impossible, but refrigerators and deep freezers were kept going to protect biological and chemical specimens until they could again be studied. Most of the American staff was evacuated in April and the remainder in December as intensive fighting took place.

          The People’s Republic of Bangladesh emerged from the conflict on December 16, 1971. The immediate consequence of independence for the laboratory was the loss of its SEATO affiliation and the loss of eligibility for PL-480 funds. The latter was the more critical. In early 1972 the laboratory was on the verge of bankruptcy and its future was much in doubt.

          Within a week of independence, a group of Americans who had worked at the laboratory formed themselves into a Committee for the Continuation of the Cholera Research Laboratory. The CCCRL was led by William B. Greenough III, a physician who had been among the first to serve in the SEATO lab and who was to later become director of the ICDDR/B. The Committee kept interest in the laboratory alive at AID and NIH, stimulating an interim AID grant of $500,00O to maintain the institution while its future was being negotiated.

          At NIH, the Director asked the Cholera Advisory Committee to determine the scientific justification for maintaining access to a population in which cholera was endemic. He was advised that the anticipated expenditure of $1,500,000 per year was justified. Although access to a cholera endemic population was not necessary for physiological or pharmacological research, it was necessary to carry out field trials on vaccines. Additional valuable studies could also be conducted in the field in search of a single method for rehydrating children and on other diarrheal diseases such as E. coli.

          Negotiations dragged on until mid-1974. The new government wanted NIH participation, but wanted the institution to be a Bengali laboratory in direction and operation, responsible to the Ministry of Health. This was unacceptable to NIH. Eventually a compromise was reached under which the laboratory would continue for three years as an autonomous body with a Directing Council of three Bengalis, two Americans, and one representative each from participating nations or international organizations. NIH organized the Scientific Review and Technical Advisory Committee to advise the Directing Council, and selected the director of the Cholera Research Laboratory (CRL).

          This was not meant to be a permanent arrangement. AID was no more eager to assume a continuing recurring cost burden than was ICA in 1959. AID’s motivation in seeking to internationalize the laboratory, however, went beyond a simple desire to share the financial burden. Diarrheal diseases are leading killers of children worldwide, and AID saw the value of developing the potential of this highly successful institution, attracting high-quality international staff, and lending permanence to the work.

          Between April 1976 and February 1978, no less than five reports were issued recommending expanding international participation in the CRL and broadening the scope of its activities. The two most influential of these reports came from W.F. Verwey, Director of CRL from 1974 to 1977, and W.H. Mosley, Chairman of the Department of Population Dynamics at Johns Hopkins and successor to Verwey as Director of CRL. Mosley knew the CRL well, having been the epidemiologist who set up the Matlab surveillance area in 1965.

          As recommended by Verwey and Mosley, AID opted for the internationalization of the CRL along the lines pioneered in the agricultural field, in the institutions supported by the Consultative Group for International Agricultural Research (CGIAR). That model involved funding from many private, international and national sources, an international board of trustees, a technical committee, and an international mandate that transcended Bangladesh concerns.

          Mosley, as Director, struggled to internationalize the institution. He received strong support from the Resident Representa­tive of the UNDP, who in turn was backed by the UNDP in New York. The Ford Foundation, which along with the Rockefeller Foundation was a founder of the original international agricultural research centers, played a key role in backing the internationalization idea with funds to cover contingency expenses.

          There was, however, opposition. WHO, aware of the rather marginal role FAO had played in the international agricultural research picture and more interested in primary health care, was distinctly opposed. AID and the UNDP made every effort to keep WHO informed and out of open opposition. Within Bangladesh there were some who opposed internationalization as a drain on their country’s resources; others saw the chance to take over a well-equipped institution if the broader effort failed.

          Planning and negotiation went on for two years, with the scope of the laboratory, its name and its mission constantly under debate. In early 1978 a review meeting at the CRL, attended by 20 international and six Bangladesh scientists and the senior staff of the CRL, examined the current scientific program at the laboratory, considered the arguments for internationalization and recommended a course of action. The consensus of the meeting favored a concentration on diarrheal diseases at the proposed center, with biological and demographic population studies relevant to these diseases, and nutritional studies with a focus on maternal and fetal malnutrition, breast-feeding, and weaning.

          Finally, a draft ordinance to establish the International Center for Diarrheal Disease Research, Bangladesh (ICDDR/B) was prepared, by an international committee consisting of representatives of WHO, Australia, Bangladesh, the Ford Foundation, the International Development Research Center of Canada, the United Nations Fund for Population Activities, UNICEF, the United Kingdom and the United States, under the chairmanship of the resident representative of the UNDP. The Bangladesh Government promulgated the ordinance on 6 December 1978. In February 1979 the UNDP sponsored an organizational meeting at WHO Headquarters in Geneva, and over 20 donor participants signed a memorandum of understanding. This memorandum and the Bangladesh ordinance constitute the ICDDR/B charter. President Ziaur Rahman formally inaugurated the ICDDR/B on 26 June 1979.

          We will return to the ICDDR/B in the next section. Here it remains to summarize the accomplishment of the SEATO laboratory and its bilateral successor before we review the main points of the cholera story for the purposes of this paper.

          The Cholera Research Laboratory’s major scientific value lay in its ability to conduct clinical research and field investigations of high standard in endemic areas. Studies at CRL revealed many of the abnormalities in intestinal functions associated with diarrhea, whether caused by cholera or not. They clarified the abnormal dehydration and fluid loss that must be corrected in treatment in order to lower the mortality rate from around 30% to less than 1%. Simplified treatment procedures were developed at CRL So that low mortality rates could be achieved in relatively primitive situations with minimal equipment and training.

          Field trials conducted by the CRL showed that cholera vaccine may be protective in an epidemic situation, but for only a limited duration. These results led the Public Health Service of the United States to abandon the cholera vaccination requirement for travelers to the United States from cholera-infected areas. WHO also no longer recommends cholera vaccination for travel to or from cholera-infected areas.

          The CRL proved to be a useful facility for testing and refining work begun elsewhere. Subsequent work at CRL, for example, confirmed the Hopkins findings that tetracycline was most effective against the cholera vibrio, and that oral administration of the antibiotic effectively shortened the duration of the disease. Oral rehydration therapy, initiated at NAMRU-2, was greatly refined and developed at CRL, leading to the development of a formula for the use of local materials in the preparation of soluble packets for administration by mothers or little-trained health workers. UNICEF and WHO made extensive use of this formula in their work around the world.

          CRL also pioneered research at the village level on the pros and cons of combining nutrition, family planning and oral rehydration therapy in local interventions. The CRL work on cholera thus extended all the way from physiological research to public health campaigns for countering the disease. This broad range of activity is extremely rare in medical institutions.

          One of the greatest benefits of the PSCRL and the CRL for the United States was the field experience it afforded a generation of young researchers who then made a lasting commitment to tropical disease problems. Many of them now occupy senior faculty positions at Johns Hopkins, Harvard and Case Western Reserve universities.

G. THE BEARING OF THE CHOLERA STORY ON OUR THEME

          The cholera story illustrates many of the points we will wish to make concerning the models of international collaboration examined below. Our purpose is to highlight the kind of contributions American scientists and institutions can make to combating tropical diseases.

          The cholera problem is not identical to all others, but the example is useful for several reasons. First, the connection between basic science and the development of an inexpensive cure for the disease is fairly straightforward, more so perhaps than for most diseases. An understanding of the glucose transporter system in the gut, and an awareness that it continues to function during diarrheal diseases, led to the development of a cure of such simplicity that in the 19th century it would surely have been called miraculous.

          Secondly, the disease was ignored by modern science for nearly a century at a cost of untold thousands of lives. A time lag of 75 years between Koch’s postulation of a toxin and its discovery by De, and of nearly 100 years between Latta’s experiments with rehydration and perfection of the technique by NAMRU, would have been scandalous for a disease of greater concern to us.

          A third striking feature is the speed with which progress was made when modern scientists did finally get into the fray. Some reasons why this was so include:

·            Cholera researchers benefited from research technologies developed in other, better funded, fields.

·            The Inner Circle monitored progress, set priorities, devised strategies, and shifted resources to combat cholera.

·            The value of scientific infrastructure is revealed by the knowledge explosion set off by the distribution of purified toxin to the scientific community. Informal communications, seminars and workshops, and publications also played important parts in advancing the frontier of understanding cholera.

          A fourth point is the variety of justifications that underlay official action. Phillips’ work in the NAMRUs was of course fueled by military considerations. Diplomatic factors led to the American response to the Bangkok outbreak in 1959 and to establishment of the SEATO laboratory. Political face-saving was initially behind the US-Japan program. The ICMRT program supporting the Johns Hopkins team in Calcutta was an effort to protect the health of Americans. Development and humanitarian factors led to the ICDDR/B. Scientific/medical concerns led to the distribution of the purified toxin and, of course, to many of the individual actions justified so variously above. All of these motivations are legitimate wellsprings of action, but the picture that emerges from this history is not one of a prudent, thoughtful blueprint for the conquest of disease. Indeed, it seems unlikely that we would have as coherent and a successful story to tell as we do were it not for the fortuitous interest in cholera taken by that remarkable group of old boys from the Rockefeller Institute.

          Fifth, the cholera experience illustrates the many types of research and experimentation required to learn to deal with a tropical disease, and the variety of social and economic factors that affect interventions at the village level. The process of science extends from the laboratory worker in an American university working on purified toxins, who may never have encountered a person with cholera, to the social scientist in Matlab thana concerned with sanitary and nutritional practices of village mothers.

          A final point is that medical science was advanced immeasurably by work on the disease; indeed it changed our approach to study of the gastro-intestinal tract. 



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