Chapter 11, Part III
CLINICAL DISORDERS: MALARIA
Malaria: Introduction and Background
Brigadier General Andre J. Ognibene, MC, USA, and Colonel O Neill Barrett, Jr., MC, USA (Ret.)
The battle between man and the pathogenic organisms with which he shares this planet has been a seesaw affair. Finding himself for years essentially defenseless against a disease, man has sometimes, by dint of hard work and a bit of luck, slowly turned the tide. With apparent victory in his grasp, his complacency has more often than not been abruptly interrupted by a vicious counter-thrust from the enemy and he has found himself in battle newly joined. This has been the story of man and penicillin against the staphylococcus, man and sulfadiazine against meningococcus and, more recently, man and the synthetic antimalarials against the Plasmodium falciparum [McCabe 1966].
Although American involvement in the war in Vietnam has ended, the battle against malaria throughout the world continues. The success of military campaigns since history has been recorded has often hinged on the presence of this disease rather than on tactics or military strength. The influence of malaria on military expeditions requires reemphasis early in any future operation to avoid those catastrophes of history so indelibly recorded on the pages of reports from ill-advised campaigns.
In the American Civil War, the armies of the North recorded 1,163,814 cases of "pure malarial fevers" among whites, of which 8,140 were fatal (Smart 1888, p.79). C. H. Melville (1910) chronicled the disastrous French Campaign in Madagascar in 1895 in which there were only 13 deaths in action and more than 4,000 deaths directly attributable to malaria.??
The Macedonian campaign in World War I was immobilized for 3 years by malaria. Among an average of 124,000 British troops per year in Macedonia, malaria accounted for 162,152 hospital admissions from 1916 to 1918 and an estimated 2 million man-days lost in 1918. The French Army fared no better; once, when ordered to attack, the French commanding general replied, "Regret that my Army is in hospital with malaria" (MacDonald 1923; Russell, West, and Manwell 1946).
After World War I, as soldiers returned to their homelands, serious epidemics developed throughout Europe. The Russian epidemic of 1922 was the largest in modern times in Europe, reaching as far north as Archangel within the Arctic Circle and causing millions of deaths among a population greatly weakened by famine and war (Boyd 1949, pp. 725, 731).
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Successful therapy for malaria dates back to the first half of the 17th century. It was first recorded in a chronicle of the Order of St. Augustine, written by a monk of that order named Calancha and published in 1639. In this book appeared a paragraph describing the "fever tree" (arbol de calenturas) found in the country of Loya (now the province of Loja, Ecuador), whose cinnamon-colored bark, when made into a powdered beverage, cured the fevers and "tertianas." Reference was made to miraculous results in Lima, Peru. Brother Calancha had announced a cure for the most widespread disease in the world. The tree was subsequently referred to as the Chincona tree, after the Countess of Chincon, who according to legend was cured of the "tertian fever" by its bark and then distributed it to the people of Lima, so that they might also be cured (Duran Reynals 1946, pp. 20-32).
In 1776, the American Continental Congress purchased Peruvian bark for use by the Continental Army, probably representing the first involvement of the U.S. Army in treatment of this disease (Hume 1943, p.160). Two centuries after its discovery, the active principle, quinine, was isolated and, in 1945, its chemical structure was defined.
The search for synthetic antimalarials began actively after the First World War when quinine was denied to the Germans by Dutch and British control of the East Indies. When the supply was once more cut off by the Japanese con quest of these islands in World War II, research was intensified, largely by investigators in the United Kingdom and the United States (Bruce-Chwatt 1964; Powell 1966; Duran-Reynals 1946, pp. 210-49).
World War II proved no exception to the established patterns of history. About 500,000 cases of malaria were reported in the U.S. Army alone (MD-PM6, pp. 116, 513). The experience of American troops in the Southwest Pacific in late 1942 and 1943 was particularly tragic. The impact of malaria on military operations there was vividly expressed in MacArthur`s famous comment, "This will be a long war, if for every division I have facing the enemy, I must count on a second division in the hospital with malaria, and a third division convalescing from this debilitating disease" (Russell, West, and Manwell 1946). Both medical and line officers lacked adequate training and education about malaria control. For instance, despite the fact that anopheline mosquitos are night biters, large concentrations of troops were allowed to attend open-air night movies. Not until malaria discipline became a command interest was control achieved. Sir Neil Cantlie, Director General of British Medical Services, called it "Health Discipline" and 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" (MD-PM6, pp. 5-6).
Interest in antimalarials had been focused on the 8-aminoquinolines before World War II. German scientists made the first breakthrough in 1926 when they synthesized pamaquine, an 8-aminoquinoline which proved effective although too toxic for clinical use. Five years later, they synthesized quinacrine (Atabrine), a 9-aminoacridine. The secrets of its manufacture were soon discovered by the Allies, and it became the most important malaria suppressant used
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during World War II. At that time it was repeatedly observed that quinacrine cured falciparum malaria. In early to mid-1943, with attention to prevention and the initiation of daily doses of this drug, the admission rates for malaria in the U.S Army in the Pacific diminished greatly (Bruce-Chwatt 1964; Powell 1966; MD-PM6, pp. 513, 568).
The intensive research carried out in the United States from 1941 to 1945 led to the screening of some 16,000 compounds, of which about 80 were selected for testing on human malaria. The advent of quinacrine as both a suppressant and a schizonticidal agent against erythrocytic forms of malaria was followed by the development of a less toxic drug, chloroquine. Field trials with chloroquine late in the war demonstrated its effectiveness as a suppressant against the New Guinea strains of Plasmodium vivax and P. falciparum and other strains from the South Pacific associated with a high incidence of relapse or recurrence. Chloroquine in a dose of 1.5 g over a 3-day period emerged as an effective regimen capable of clinically curing several strains of vivax and falciparum malaria (Bruce-Chwatt 1964; Powell 1966; MD-IM2, pp. 572-74).
Other drugs that emerged from this period were amodiaquine, a 4-aminoquinoline; sontoquine, which had been used successfully by the French in North Africa; chlorguanide (proguanil), a biguanide discovered by British investigators; and pentaquine, another 8-aminoquinoline. Subsequently, pyrimethamine, a diaminopyrimidine and antifolate structurally related to the active metabolite of chlorguanide, was discovered by a joint British and American effort in 1950. However, resistance to pyrimethamine occurred readily when it was used against falciparum strains in tropical Africa and later in the United States against P. vivax and P. malariae strains in neurosyphilis patients (BruceChwatt 1964).
The development of these new drugs, as Tigertt (1966) observed, fostered complacency about malaria control. The development of eradication programs by epidemiologists, sanitarians, and health technicians under the auspices of the World Health Organization, the Rockefeller Foundation, and the national health agencies of many countries increased the sense of security.
With the opening of hostilities in Korea in 1950, malaria again became a focus of interest. Chloroquine had been field tested in nonimmune volunteers in Panama with excellent results (Elmendorf 1947; Boldt and Goodwine 1949). However, malaria relapse (predominantly in vivax strains) had been established as due to an exoerythrocytic stage, primarily in liver parenchymal cells (Shortt and Garnham 1948); the parasite in this stage is not vulnerable to schizonticidal drugs, such as chloroquine and quinacrine. Fortunately, investigators during World War II had been developing safe, effective drugs to prevent vivax (benign tertian) malaria. Primaquine, a 6-methoxy-8-aminoquinoline, the least toxic and most effective 8-aminoquinoline, was recognized for its value in preventing relapses and curing vivax malaria (Powell 1966; Alving, Arnold, and Robinson 1952; Edgcomb et al. 1950).
At the time of the Korean conflict, volunteer studies established the superiority of primaquine against the early and late tissue phase of the Chesson strain of P. vivax. The efficacy of this drug was further demonstrated by Alving
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and associates (1953) in large-scale clinical trials. These researchers studied 975 U.S. soldiers with Korean vivax malaria who were treated at the station hospitals in Fort Knox, Ky., and Fort Benning, Ga. One group received the standard 3-day chloroquine regimen (total dose of 1.5 g); a second group received, in addition, 27 mg of pamaquine base daily for 14 days; and the third group received chloroquine plus 15 mg primaquine base daily for 14 days. The results are shown in table 37 and indicate the relapse rate after 2 years.
TABLE 37.-Comparative incidence of relapse in treatment of Korean vivax malaria, 1951-52
Based on preliminary results of this study, The Surgeon General of the Army approved the use of primaquine as terminal prophylaxis for 14 days in all U.S. troops returning from Korea. A team headed by Dr. Alf Alving was dis patched to the Far East Command in August 1951 to determine the practicability of this program and on 16 December 1951 it was initiated (FEC-AR).
Archambeault (1954) reviewed the incidence of malaria, based upon the number of troops transported by sea from the Far East between January 1951 and June 1953, and demonstrated a considerable reduction in the attack rate of vivax malaria as reported in the United States. Despite the availability of drugs and the medical effort, the U.S. Army suffered over 30,000 cases of malaria during the Korean conflict (McCabe 1966, p.314).
In the ensuing years, a 3-day chloroquine, 14-day primaquine base regimen became the standard treatment for malaria throughout the world. Alving and his group were aware of the toxicity of a dose of 30 mg primaquine base daily (twice the amount needed to effect a radical cure of vivax malaria) (Arnold et al. 1954); they noted that approximately 10 to 15 percent of healthy American blacks developed a severe but self-limited hemolytic anemia when given a daily dose of primaquine. On the basis of additional clinical trials, Alving et al. (1960) predicted and then demonstrated that a single 45-mg dose of primaquine base per week plus the standard 300 mg of chloroquine would be an effective radical cure for naturally acquired vivax infection. Clinically demonstrable hemolysis was not produced by this dose of primaquine in adult males with glucose-6-phosphate dehydrogenase deficiency who were sensitive to the drug. This regimen was considered superior to the 14-day primaquine course.
In 1960, U.S. military and civilian personnel stationed in Korea were placed on weekly C-P (chloroquine-primaquine) tablets in a large-scale field trial involving more than 50,000 adults (Vivona et al. 1961). The results were so successful that the C-P tablet became the standard Army regimen by 1962 (DA-Circ).
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Malariologists became complacent; some even believed significant drug resistance was unlikely to occur.
The basis for this contentment was a true sense of pride in the accomplishments of the preceding decade. This was the period of "smug satisfaction," characterized by comments such as one which appeared in the 1961 World Health Organization Bulletin indicating that the clinician had at his disposal a complete series of effective drugs for the treatment of all stages of the disease (Tigertt 1972). The efficacy of chloroquine and the 8-aminoquinolines essentially erased malaria from consciousness in the minds of military planners. Concomitant developments in insecticides led in 1955 to the World Health Organization global eradication effort (WHO), which was aimed at interrupting the transmission cycle by spraying infected areas twice yearly for several years, with a follow up case-finding period.
At the dawning of the Vietnam war, progress in malaria control and therapy had apparently relegated the disease to historical interest and eliminated it as a threat to the modern field army (chart 12). The following chapters will attest to the error of this judgment. The ability of the malarial parasite to repeatedly meet the challenge of manmade chemical assault demands continued skepticism toward any claim to the development of a "final chapter" in the history of malaria.
The story of malaria in Vietnam before American involvement has been briefly summarized by Kiel (1968). The disease had apparently been known for thousands of years and was ascribed to evil spirits in the mountainous regions, which lived near the water and attacked men during sleep. Persons with malaria were described by the popular phrase mat bung, da chi or "pallor of the face with slate like tint."
One of the earliest stories describing the importance of what was probably malaria in Vietnamese history concerns the Mongolian ruler, Kublai Khan. To secure trade routes to India and Persia, he sent his son Togan in 1285 to conquer the Red River Valley in what is now Vietnam. After several months of success, many of the invaders fell ill from "the climate" and Togan was driven from the country (Kiel 1968, p.2).
The French experience began in 1858, and malaria was soon the most serious medical problem. Laveran reported that between 1890 and 1896, 25 percent of the European troops stationed in Vietnam died of malaria. During the period 1945 to 1954, a total of 293,814 cases were recorded, though only 620 deaths occurred. The incidence of the disease showed a progressive decline during that period, however. In 1946, the incidence was 40 per 1,000 troops per year; it had dropped to 9 per 1,000 per year by 1954 (Kiel 1968, pp. 2-5).
Although precise statistical data are difficult to obtain, malaria had always been a serious problem for the Vietnamese. Data concerning deaths from infectious diseases in the period 1955-65 confirm its importance (table 38). The disease is hyperendemic in the Central Highlands. A study by Pham Trong indicated that in this area, at less than 1,000 meter altitudes, the splenic index is 50 to 80 percent and malaria parasites are found in 49 to 100 percent of groups studied. Above 1,000 meters, the splenic index falls to 3 percent or less, and
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CHART 12.-Cases of malaria reported in the United States, 1935-60
parasites are found in zero to 6 percent. The disease is common among the Montagnards and North Vietnamese refugees, especially the former. Pham Trong found that 473 of 1,834 Montagnard slides examined were positive, while only 13 of 512 refugee slides were positive (Kiel 1968, p.3).
Along the littoral and in Saigon, the disease is far less common. Le Van Long studied malaria in children in the Saigon area and found that positive smears varied from 0.43 to 3.47 percent in different precincts. P. vivax was the predominant species, while in the highlands there was a higher incidence of P. falciparum (Kiel 1968, p.4).
Data concerning malaria in Vietcong troops have been difficult to obtain, but 80 to 100 percent were reported to have contracted malaria despite the use
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TABLE 38.- Deaths from infectious diseases in South Vietnam, 1955-65
of Paludrine prophylaxis (Kiel 1968, p.9). Joseph Alsop (1967) reported that malaria rates of 50 to 75 percent were common. In his column he quoted a captured Vietcong battalion report: "General health in 10 days from Aug. 8 to 18-Malaria 60 percent, beri beri 10 percent, other diseases 20 percent."
Malaria was to have an impressive impact on American troops in Vietnam as well. The average annual rate of admission to hospital and assignment to quarters for this disease (26.7 per 1,000 per year) was low compared to those of the Southwest Pacific Area (70.3 per 1,000 per year) and the China-Burma-India theater (101 per 1,000 per year) during World War II. However, the debilitating impact of malaria on American troop strength was not reflected in overall rates. In December 1965, the overall rate in Vietnam reached a peak of 98.4 per 1,000 per year, while certain units operating in the Ia Drang valley experienced rates up to 600 per 1,000 per year and at least two maneuver battalions were rendered ineffective by malaria (Neel 1973, pp. 37-38).
REFERENCES
Alsop, J. 1967. Matter of fact. The bind on the VC. Washington Post, 22 Mar. 67, p. A-21.
Alving, A. S.; Arnold, J.; and Robinson, D. H. 1952. Status of primaquine. I. Mass therapy of subclinical vivax malaria with primaquine. J.A.M.A. 149:1558-62.
Alving, A. S.; Hankey, D. D.; Coatney, G. R.; Jones, R., Jr.; Coker, W. G.; Garrison, P. L.; and Donovan, W. N. 1953. Korean vivax malaria. II. Curative treatment with pamaquine and primaquine. Am. J. Trop. Med 2: 970-76.
Alving, A. S.; Johnson, C. F.; Tarlov, A. R.; Brewer, G. J.; Kellermeyer, R.W.; and Carlson,P.E.1960. Mitigation of the haemolytic effect of primaquine and enhancement of its action against exoerythrocytic forms of the Chesson strain of Plasmodium vivax by intermittent regimens of drug administration. Bull, World Health Organ. 22:621-31.
Archambeault, C. P. 1954. Massantimalarial therapy in veterans returning from Korea. J.A.M.A. 154:1411-15.
Arnold, J.; Alving, A. S.; Hockwald, R. S.; Clayman, C. B.; Dern, R. J.; Beutler, E.; and Jeffery, G. M. 1954. The effects of continuous and intermittent primaquine therapy on the relapse rate of Chesson strain vivax malaria. J. Lab. & Clin. Med 44: 429-38.
Boldt, T. H., and Goodwine, C. H.1949. A second year`s field trail with chloroquine suppression of high endemic malaria in a Panamanian village. J.Nat. Malaria Soc. 8: 238-46.
Boyd, M. F., ed. 1949. Malariology. Vols. I and II. Philadelphia: W. B. Saunders Co.
Bruce-Chwatt, L. J. 1964. Changing tides of chemotherapy of malaria. Brit. M. J. 1: 581-86. Communicable diseases: Malaria, Preventive Medicine in World War II. See MD-PM6.
DA-Circ-Department of the Army Circular No. 40-16. 4 Dec. 1962.
Department of the Army Circular. See DA-Circ.
Duran-Reynals, M. L. 1946. The fever bark tree. New York: Doubleday & Co.
Edgcomb, J. H.; Arnold, J.; Young, E.H., Jr.; Alving, A. S.; and Eichelberger, L.1950.Primaquine, SN 13272, a new curative agent in vivax malaria; a preliminary report. J. Nat. Malaria Soc. 9: 285-92.
Elmendorf, J. E., Jr. 1947.Preliminary report on field experiments to demonstrate effectiveness of various methods of malaria control. Am. J. Trop. Med. 27: 135-45.
Far East Command, Annual Report, Medical Service Activities. See FEC-AR.
FEC-AR-Medical Section, General Headquarters, Far East Command. 1951. Annual Report, Medical Service Activities, 1 Jan.-31 Dec. 51. On file at U.S. Army Center of Military History. Hume, E. E. 1943. Victories of Army medicine. Philadelphia: J.B. Lippincott Co.
Infectious diseases, Internal Medicine in World War II. See MD-IM2.
Kiel, F. W.1968. Malaria in Vietnam. In Pathology Annual, ed. S. C. Sommers, pp. 1-27. New York: Appleton-Century-Crofts.
MacDonald, A. G. 1923. Prevention of malaria. In History of the Great War based on official documents, ed. W. G. Macpherson, W. H. Horrocks, and W. W. O. Beveridge, vol. II, pp. 189-238. London: His Majesty`s Stationery Office.
McCabe, M. E. 1966. Malaria-A military medical problem yet with us. M. Serv. J. Canada 22:313-32.
MD-IM2-Medical Department, U.S. Army.1963. Infectious diseases. Internal Medicine in World War II, vol. II. Washington: Government Printing Office.
MD-PM6-Medical Department, U.S. Army.1963. Communicable diseases: Malaria. Preventive Medicine in World War II, vol. VI. Washington: Government Printing Office.
Melville, C. H. 1910. Prevention of malaria in war. In The prevention of malaria, ed. R. Ross.2d ed. London: John Murray.
Neel, S. 1973. Medical support of the U.S. Army in Vietnam, 1965-1970. Vietnam Studies. Washington: Government Printing Office.
Neva, F. A. 1967. Malaria-recent progress and problems. New England J. Med 277: 1241-52.
Powell, R. D. 1966. The chemotherapy of malaria. Clin. Pharmacol.& Therap. 7: 48-76.
Russell, P. F.; West, L. S.; and Manwell, R.D. 1946. Practical malariology. Philadelphia: W.B. Saunders Co.
Shortt, H. E., and Garnham, P.C. C. 1948. Pre-erythrocytic stage in mammalian malaria parasites. Nature 161: 126.
Smart, C.1888. The medical and surgical history of the War of the Rebellion. Part III. Vol. I. Medical History. Washington: Government Printing Office.
Tigertt, W. D. 1966. Present and potential malaria problems. Mil. Med. 131 (supp.): 853-56.
_____1972. The malaria problem, past, present, and future. Arch. Int. Med. 129: 604-6.
Vivona, S.; Brewer, G. J.; Conrad, M.; and Alving, A. S. 1961. The concurrent weekly administration of chloroquine and primaquine for the prevention of Korean vivax malaria. Bull. World Health Organ. 25: 267-69.
WHO-World Health Organization Expert Committee on Malaria. 1957. 6th report. Technical Report Series No. 123. Geneva.
World Health Organization Expert Committee on Malaria. See WHO.
