Mefloquine

Preventive medicine requires an understanding not only of the disease to be prevented, but a complete understanding of conditions affecting the disease transmission, human nature, and the historic situation of the target group. An analysis of a new drug introduction (Atabrine) during World War II is viewed from multiple perspectives and is compared with the introduction of mefloquine during the mission to Somalia 50 years later. Common themes of educational failure at the end-user and policy-maker levels are shown as barriers to effective preventive medicine efforts.

Introduction

Preventive medicine is generally regarded as superior to curative methods of disease management and public health. Although this view seems intrinsically valid and is widely accepted as central to current health doctrine, the application of this principal in practice has proven to be elusive. Preventive medicine is a difficult and complex approach to health that encompasses issues as diverse as sustainable resources, social stability, medical research, and education.

This paper describes the preventive medicine efforts in the delivery of antimalarial prophylaxis to U.S. military personnel. It is argued here that a lack of education, on several levels, is a common theme that hindered the successful prevention of malaria both during World War II (WWII) and during the recent U.S. involvement in Somalia. Through consideration of these conflicts, which occurred decades apart, there is a validation of Santayana's warning that when experience is not retained, as among savages, infancy is perpetual. Those who cannot remember the past are condemned to repeat it."'

Malaria

Malaria has a long and infamous history of morbidity and mortality. Clinical descriptions can be found from the fifth century BC, with characterizations by Hippocrates, and reports of periodic fevers are found even earlier in Hindu and Chinese writings. Reports of the parasite's effect on military forces date back to Alexander the Great's attempt to conquer the known world and his death from malaria in 323 BC. This parasite poses a health concern even today: transmission occurs in more than 100 countries, with more than 1.6 billion people at risk of infection. With an estimated annual global incidence of 200 million clinical cases, malaria has shown remarkable resistance to our efforts to control it.

Quinine was the mainstay of modern chemotherapy for about 300 years of malaria's history. Events leading to the outbreak of WWII changed that for the United States. Japan's shortage of natural resources, especially oil for mechanized warfare, was a major factor in its decision to secure the virtually undefended resources of southeast Asia. Among the resources captured were the cinchona plantations in Java, essentially the only source for the world's supply of quinine.

World War II and Atabrine

Ironically, the drug that was destined to become the center of the Allies' antimalarial campaign for WWII was a German discovery. During World War I, Germany was unable to secure quinine for its own troops and therefore set about investigating synthetic substitutes. Among the list of synthetic compounds produced, Atabrine (quinacrine, mepacrine) was discovered in 1930.

Unfortunately, acceptance of the widespread suppressive and prophylactic use of Atabrine would have to wait until 1943 for some convincing work done by Fairley and his team.2 Early recognition of this drug's potential was documented in Circular Letter No. 56, Office of the Surgeon General, dated June 9, 1941, which contained the following directive: `"The use of quinine or Atabrine for prophylaxis is not recommended as a routine procedure, as the available information indicates that these drugs do not prevent infection. However, they are of definite military value in that they do prevent the appearance of the clinical symptoms of malaria so long as they are taken...."

Following the advice given in Circular Letter No. 56, troops were placed on Atabrine suppression. Nonetheless, the effect of malaria on U.S. forces in the South Pacific during the early part of the war was devastating, with as many as 600 malaria cases for every 1,000 American servicemen by December 1, 1942.

British Field Marshall Sir William Slim, commenting on malaria's effect on British troops, reported, "In 1943, for every man evacuated with wounds we had one hundred and twenty evacuated sick. The annual malaria rate alone was eighty-four per cent per annum of the total strength of the army and still higher among the forward troops.... A simple calculation showed me that in a matter of months at this rate my army would have melted away. Indeed, it was doing so under my eyes."3

Reasons for Atabrine's early failure were diverse. Atabrine was thought to be a poor substitution for the drug of choice, quinine. Atabrine was also associated with side effects such as nausea, vomiting, diarrhea, skin staining, psychosis, lichen planus, and exfoliative dermatitis. One common explanation for some of the minor side effects involves the fact that Atabrine was often given for the first time aboard ship. Anxiety, seasickness, and gastrointestinal upset were therefore blamed on the drug when other factors could have been responsible. A reported difference in manufacture from German standards was also thought to lead to impurities in the drug.

Whatever the reasons for early failure, something had to be done to correct the problem. One approach was to recognize commanders' responsibility for the health of their troops. Sir Neil Cantlie, Director General of British Army Medical Services, was one of the first to do this: "You doctors think you can prevent malaria, but you can't. I can and I'm going to. 2 This statement is considered the vital turning point in attitude that made victory in the WWII possible.

Sir William Slim's method for ensuring command responsibility was to organize surprise checks on units to assess the compliance with Atabrine discipline: "If the overall result was less than ninety-five per cent positive, I sacked the commanding officer. I only had to sack three; by then the rest had got my meaning."3 With regard to these events, Cantlie stated, "When for the first time in history a combatant officer was considered unfit to command a unit on the grounds that he had allowed his men to become ineffective through disease, a new day in military medicine dawned. The clouds of forgetfulness must not be allowed to overshadow the brightness of that day."2

Despite this new awareness, malaria continued to occur throughout the areas of fighting, and it even appeared in England and the United States. Areas thought to be free of malaria were suddenly the sites of hundreds of cases of malaria in troops. The effectiveness of a drug and command enforcement were obviously not enough to prevent malaria.

Three original oral histories from individuals with different perspectives on the war against malaria were chosen as representative of views common among numerous WWII veterans interviewed. These three represent the senior command level, the level of the battalion surgeon, and the infantry officer on the front lines.

Colonel Benjamin M. Baker, Medical Corps, was a senior staff officer who wrote some of the official accounts of Atabrine. Baker entered the war in March 1942 and was Chief of the Medical Service for the Johns Hopkins Unit (18th General Hospital) in Fiji. He was later transferred to South Pacific Headquarters (commanded by Admiral William Halsey and under the Chief Surgeon Colonel Earl Maxwell) as the Consultant in Medicine. After the battle of Okinawa, Baker moved to MacArthur's theater, where he served as MacArthur's Chief Consultant of Medicine until the end of the war.

Before the war, Baker was a professor of medicine at the Johns Hopkins School of Medicine. Given this background and his position in the war, his reaction to the overwhelming presence of malaria might seem surprising: I didn't know anything about malaria, never heard of a case of malaria except from my father (all quotes from Baker were via personal communication, April 20, 1993). Unfortunately, this was a common reaction of U.S. physicians sent to the South Pacific.

Baker credited Atabrine as a lifesaver: "We had no deaths, we had no blackwater fever, which was a perfect Godsend." His own personal experience with the drug convinced Baker that this drug was effective: I took one Atabrine tablet a day for three and a half years, never missed a dose, and of course, I never had malaria." As for personal side effects: I wouldn't have known I was doing anything more than brushing my teeth."

Comprehending the reasons for the lack of compliance seemed a simple matter for Baker: Noncompliance was because they wanted to go home, and they knew if they got malaria, they wouldn't have to fight on Guadalcanal." Using simple laboratory tests, Baker determined that blood levels of Atabrine in individuals who contracted malaria were too low. His conclusion was: "When vivax malaria broke through Atabrine suppression, that's because the boys didn't take it."

The entire time that Baker was in the Pacific was a learning experience for him and for those involved with the Atabrine program. Recounting one of the real surprises of Atabrine, he recalled: "Fifteen thousand Marines were moved from Guadalcanal to Fiji. . . seventy-five thousand malaria attacks in one year. . . roughly five recurrences in one year. We didn't have any idea that Atabrine suppression would not prevent malaria when troops were moved out of a malarious area." This signified a reeducation at the command level of Atabrine's restriction to suppression, not cure, of vivax malaria, as stated in the Surgeon General's Circular Letter No. 56.

Baker's perspective on the Atabrine deployment represents a unique point of view in the war. His view was similar to that of a commanding general overlooking the entire battlefield, and as such he saw the big picture and few of the details. Dr. George Sharpe served in the South Pacific from March 1944 until November 1945. He served most of his time in the war as a battalion surgeon with the 20th Infantry Regiment, 6th Infantry Division. Sharpe had done an internship at Walter Reed and was considered knowledgeable in the ways of military and tropical medicine. He comments: "I don't know what the line people thought, cause they were relying on us. . . [wel who didn't know what we were doing" (all quotes from Sharpe were via personal communication, April 22, 1993).

Although he knew of the existence of Atabrine, his comments about Atabrine were common among battalion surgeons: "We started taking Atabrine when we first arrived at New Guinea.... couple days before the yellow started to show.... We were just told that Atabrine was a new drug, and that it would keep you from getting malaria." Official information was scarce to the battalion surgeons, even though *we pieced out that it was a suppressive somehow and that it was mostly for combat." The information about prevention of malaria and antimalarial treatment passed on to the troops was the best that they felt they had to offer: "You're taking this stuff so you don't get malaria."

The Atabrine discipline provided by the upper echelons was inconsistent. Sharpe once wrote: "At times we would have to line the men up and make certain they took their Atabrine, and one tablet each day was doled out to them."4 Later, in Manila, he wrote: "We noted an increase in the number of malaria cases diagnosed.... Advisory information from upper echelon included a recommendation that two Atabrine tablets were needed to suppress the disease manifestations. Whenever possible, supervised, mandatory ingestion of the drug was done in the chow line."4

With regard to side effects and anti-Atabrine propaganda, Sharpe commented on the confusion present even among the medical officers: "I don't remember it as a major problem. ... several people might have said, 'I hear that this will make you sterile' and we had no information to the contrary.... in those days, none of us believed that our United States government would ever give, or do, anything that would harm anyone of us" (personal communication). Shape himself was taken off Atabrine: "In January 19461 was assigned to Walter Reed to start a residency in internal medicine. My fever returned with a vengeance and the diagnosis of malaria was finally made-the Atabrine suppression therapy had interfered with the identification of parasites in my bloodstream."4

The experiences of Baker and Sharpe illustrate a few problems with the amount of information that was passed from the upper echelons to the doctor at the front. The effect this had on the soldier at the line, and the effect it had on compliance with Atabrine discipline, is illustrated by Robert Green.

Major General Robert Green was Deputy Surgeon General of the Army from 1973 to 1977. Before going to medical school, he served in WWII as a captain, Headquarter's Commandant of the 18th Infantry, 1st Infantry Division. Green's first combat experience was during the invasion of North Africa in 1942; eventually, he joined the British 78th Division near Tunis. There, from February 14 to 22, 1943, they fought the Germans at Kasserine Pass, Tunisia. gI found out later that there was malaria there. . . we had no discussion about that at all" (all quotes from Green were via personal communication, April 14,1993). Commenting on the instructions received regarding drugs they were given to take or regarding prevention of diseases found in the area, he said: 'The medical people at the time were pretty passive. I received none, except what you learned practically." During the campaign in Sicily in early 1943, Green commented that they were "Totally unprepared. . . no mention of malaria there.... August 1943, they started to release Atabrine for treatment and prophylaxis. Sicily was the first that I remember it.... I was one of the ones that got the daily dose, some people got really sick with it, and I got nauseated. But again, I don't recall any instructions ... the rumors were rampant, that it made you sterile.... people did turn yellow."

The emphasis placed on Atabrine discipline did not seem to reach the troops for whom it was meant. Green stated: "I didn't take it all the time. They didn't tell me to." Green notes that Atabrine discipline was a command function: "They were passed out by the company, not the medical officers." When asked about the command emphasis and his perception of the importance placed on Atabrine discipline, Green stated: "We turned it over mainly to our sergeants . I don't think they did [enforce compliance]." Even as a commander, Green took quinine instead of Atabrine if he took any prophylaxis at all: "Atabrine made me sick, so I didn't take it. I really didn't appreciate the importance of taking it, and maybe I could have tolerated it." With regard to the problem of stopping the administration of Atabrine, Green vividly remembers a 30-day convoy to England to prepare for the Normandy invasion: "Then, of course, they threw away the Atabrine tablets as soon as they got on the ship, and nobody said to keep it up.... therein lies the real hazard, is that nobody said to keep taking the darned Atabrine. Everybody stopped. On the way back, and I don't know how it was reported, but from what I saw, I would estimate that a third of the troops on board that convoy had malaria."

To Green at least, the idea of a soldier purposely getting malaria to avoid combat or be sent home was ludicrous: "Most of our soldiers fought to get back to the unit." With the institution of Malaria Forward Treatment Units by the British and the assignment of ever more experienced physicians forward with the Americans, it is important to note Sir William Slim's observation on this proposed practice: "If it only took them half a dozen miles from the front and brought them briskly back it was not so attractive."3

A consideration of these three views gives us a new perspective on the Atabrine experiment. It also provides us with a reeducation in a basic preventive medicine tenet: education, or good information dissemination, is the cornerstone of any program that is to succeed. Blind forced compliance with any effort or regimen is bound to fail to some extent unless education accompanies this effort.

The lessons of the malaria and Atabrine experience reveal the importance of education in any preventive medicine program. The events of WWII illustrate the evolution of these ideas, lessons that are difficult to learn and more difficult to remember. The loss of these hard-won principles can be seen in the similarities evident in one of our recent military operations.

Somalia (Operation Restore Hope) and Mefloquine

In December 1992, U.S. military personnel were deployed on a United Nations mission to Somalia called Operation Restore Hope. Almost 50 years after we first began our battle with malaria in WWII, we found ourselves in another battle against malaria in Somalia. Although this was not our military's first exposure to the disease since WWII, it is notable for having been the first in which another new, controversial antimalarial drug was used in a large-scale military operation.

U.S. Navy Commander R. Kevin Hanson, MD, was a preventive medicine physician involved in both Operation Desert Storm and Operation Restore Hope. Commander Hanson commented that "Operation Restore Hope would have ground to a halt without preventive medicine efforts. We seem to have turned the corner with Desert Storm. If this Somalia experience had come years-instead of months-after our experience in the Gulf, these preventive medicine lessons of Desert Storm might have lost their impact."5 A retrospective examination of malaria among forces in Somalia would help us to discern the validity of this statement with regard to antimalarial prophylaxis.

Somalia reports a significant level of malaria, which can be regarded as one of the country's most important diseases. Malaria is currently considered to be transmitted throughout the year in most of Somalia (moderately endemic), with seasonal increases in the frequency of transmission during the rainy season.6 More than 90% of the malaria seen in the endemic population is caused by Plasmodium falciparum, with Plasmodium malariae and Plasmodium vivax accounting for only 2 and 4% of the reported cases, respectively.7

Mefloquine is an antimalarial drug developed by the Army malarial chemotherapy program and introduced in 1985. It was considered a major advancement in the treatment of multidrug-- resistant (especially chloroquine-resistant) malaria. This drug, like Atabrine, had its problems with introduction for use as malaria prophylaxis. There were reports of Stevens-Johnson syndrome,8 seizures,9 agranulocytosis,'o and numerous neuropsychiatric side effects.ll-ls Later studies using large population surveys"6,'7 and randomized, double-blind clinical trials(18-20) showed an equal frequency of mild side effects in mefloquine users compared with users of any other current antimalarial drug. These studies came after the beginning of the use of mefloquine in Somalia, and rumors about side effects were widespread in the military by the time these results were published.

As with Atabrine in WWII, the problem of rumors of side effects that limit compliance could be solved with the recognition of commander responsibility for troop health. Commander Hanson noted that the Joint Task Force (U.S. forces) and Unified Task Force (including forces from other nations) commander in Somalia, General Robert B. Johnston, USMC, supported the preventive medicine efforts with a strong memorandum about each commander's responsibility for maintaining troop health. Hanson predicted that "Today's young officers will remember that throughout their careers."5 One battalion commander resisted this recommendation and the medical advice given to him, however, and his troops had the highest rate of malaria during the operation.

Mefloquine, like Atabrine, is suppressive for vivax malaria because of the hepatic stage of this species of the malarial parasite. Discontinued use of the antimalarial drug results in the reappearance of vivax malaria, as happened in WWII. Today, the use of terminal prophylaxis to clear the patient of the infectious organisms is accomplished with the use of primaquine.

A recommendation for the use of terminal prophylaxis is contained in a review of the infectious disease threats present in Somalia. The recommendation from infectious disease physicians at Walter Reed was that "prophylaxis with oral primaquine to eliminate persistent hepatic parasites should be given to all patients with confirmed P. vivax, except those who are pregnant and those with a glucose-6-phosphate-dehydrogenase deficiency, and it would be considered for all others on their departure from Somalia."21 These physicians were echoing recommendations made in the previous year in the Medical Letter.22 Another review states the warning for terminal prophylaxis in even clearer language: The acute impact of malaria on military and civilian humanitarian workers should be minimal if there is strict adherence to antimalaria regimens, especially the terminal 4 weeks of prophylaxis after departure from the endemic area.6 However, there was not universal agreement on a recommendation for terminal prophylaxis. One published review of disease threats in Somalia at the time fails to mention the use of terminal prophylaxis or the threat of malaria caused by P. vivax.23

In spite of command vigilance regarding its responsibility for troop health and most experts' advice to provide terminal prophylaxis, cases of malaria began to appear among deployed personnel. From December 1992 through April 1993, malaria was diagnosed in 48 military personnel in Somalia. An additional 83 military cases were diagnosed by late June 1993 after return to the United States. Of these 83 cases, 62 of them occurred in Army personnel and 21 in Marines. Even though vivax malaria accounts for only 4% of malaria in indigenous personnel, in 53 of these imported cases that were fully investigated, P. vivax was the causative organism in 77%.24 The low frequency of vivax malaria in Somalia resulted in the official policy that terminal prophylaxis was not recommended for Army personnel. On May 21, 1993, the Office of the Surgeon General of the Army reversed the original policy and mandated primaquine for terminal prophylaxis of personnel returning from Somalia. Terminal prophylaxis had been recommended for Marine and Navy personnel from the beginning of the conflict, however, yet there were 21 Marine cases.

Examinations of U.S. military personnel returning to the United States with malaria reached some conclusions regarding the failure of malarial control. One study looked at 106 U.S. Marines diagnosed with malaria after returning from Somalia. They found that P. vivax accounted for 87% of the malaria cases detected. The study concluded that "Noncompliance with personal protective measures and chemoprophylaxis contributed to the largest outbreak of imported malaria in U.S. military personnel since the Vietnam conflict. 25 A survey of Marines found that only 56% of patients complied with the chemoprophylaxis. What is imperative to note in the Somalia Marine study is that the 56% compliance was among Marines who received an appropriate regimen for both in-country and terminal prophylaxis. An additional 50% of the Marines for whom complete chemoprophylaxis data were available did not receive an appropriate regimen for both in-country and terminal prophylaxis. This study begins with known malaria cases and attempts to explain the proximate cause of the infection. Although the study concludes that prophylactic compliance among the Marines contributed to the high malaria rate, it ignores the effect of education and a proper antimalarial regimen as the principal cause.

In another, very different study, 344 military personnel deployed to Somalia on mefloquine between early December 1992 and late January 1993 were prebriefed about compliance with malaria chemoprophylaxis and personal protective methods. Immediately before return to the United States, these troops were surveyed about compliance, illnesses in-country, and potential adverse drug reactions. Full compliance with mefloquine was reported by 98% of the personnel, with only one soldier discontinuing the use of mefloquine because of bothersome side effects. With approximately 9,000 person-weeks of use, only one case of malaria (P. vivax was reported, with this occurring in an individual who missed at least one dose of chemoprophylaxis.26 The authors of this study reached a conclusion similar to that of the previously mentioned study with malaria in Marines, that noncompliance was the proximate cause of malarial infection. Conclusions The effective use of prevention medicine is a desirable goal regardless of perspective. In a cost-conscious society, it decreases the cost of our expanding and increasingly sophisticated curative medical interventions, and for the patient, it decreases the cost of morbidity and mortality. In a military situation, the use of effective preventive medicine can maintain the available fighting force and be decisive in victory or defeat.

Possibly the greatest single concept to be learned from this review of antimalarial prophylaxis is the critical contribution of education to the success of clinical preventive efforts. Both in WWII and in Somalia, the failure to address education on multiple levels contributed to ineffective or only partially effective malaria control. It was the lack of education among the policymakers that led them to ignore Atabrine and mefloquine's suppressive qualities. Unit commanders were not educated initially to recognize their responsibility as principal caretakers of their troops' health. Finally, it was the failure of the military medical community to educate the individual soldier regarding the importance of the antimalarial prophylaxis and the correct manner of administration that limited troop compliance.

The need for education of the policy-makers is evident both in WWII and Somalia. Baker was one policy-maker who was surprised when Marines were moved from Guadalcanal to Fiji and contracted malaria. This event came long after the Office of the Surgeon General's 1941 statement about Atabrine's suppressive quality. In Somalia, although numerous recommendations were made regarding the need for terminal prophylaxis to prevent vivax malaria,(6,21,21) it was not until May 21, 1993, that the Army reversed its policy not to provide terminal prophylaxis and mandated the use of primaquine.

WWII represents the dawn of recognition of command responsibility for troop health. This was continued when General Robert B. Johnston emphasized the importance of command responsibility for troop health at the very onset of action in Somalia. Still, there were documented cases of commanders who did not follow this advice, and the troops paid the price with relatively high rates of malaria.5

Little was known of the WWII soldier's point of view regarding antimalarial prophylaxis, so much of this paper's examination focused on the oral histories of three men who represent their generation's views regarding this matter. Comments from a battalion surgeon that "We were just told that Atabrine was a new drug, and that it would keep you from getting malaria" (G. Sharpe, personal communication) reflect the level of education passed to the front-line medical personnel. Remarks such as, "I didn't take it all the time. They didn't tell me to" (R. Green, personal communication) were unfortunately all too common among soldiers at the front. The situation in Somalia was no better in many ways.

These two examples illustrate the importance of education across multiple levels. On the surface, the use of Atabrine in WWII and mefloquine in Somalia represent preventive medicine programs with many strengths. Each had a recognized threat, an effective drug, adequate supplies of that drug, an identified and accessible susceptible population, and an organized delivery system. Lack of education made these efforts, with all their strengths, failures for every person who contracted malaria.

This paper supports the importance of education on multiple levels for all preventive medicine programs. Any regimen, blindly followed, is doomed to failure, at least to some degree, if education of the policy-makers and especially the end user does not accompany the effort.

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Department of Medicine, Tripler Army Medical Center, HI 96859.

This manuscript was received for review in April 1997. The revised manuscript was accepted for publication in January 1998.

Reprint & Copyright by Association of Military Surgeons of U.S., 1998.

Copyright Association of Military Surgeons of the U.S. Sep 1998
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