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Chapter XV

Contents

CHAPTER XV

The Suppression of Malaria

Benjamin M. Baker, M.D.

From the onset of World War II, it was recognized that tropical diseases could interfere seriously with military operations. Previous military histories1 had adequately delineated this problem. What was not known, however, was the extent to which troops might be incapacitated by malaria under the conditions of modern warfare in the Tropics. Planners could not count on the opportunity to rid hostile shores or vast hinterlands of endemic malaria by elimination of mosquito breeding. In the long run, the effectiveness of U.S. troops in many parts of the world depended principally on the suppression of clinical malaria by the use of new drugs and the development of techniques of chemotherapy.

Most medical officers arrived on the scene with little knowledge of malaria and even less practical experience. At first, the only sources of information were the few available textbooks and the directives prepared by The Surgeon General, U.S. Army. One of the directives, Circular Letter No. 56, Office of the Surgeon General, dated 9 June 1941 recommended the following regarding chemical prophylaxis:

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, and thus they afford a means for keeping troops "on their feet" during periods of emergency in the field. When administered to troops in special situations in unsanitated endemic areas, either of the drugs may be used under the personal supervision of a responsible officer, as follows: (1) Atabrine 0.2 gm. (3 gr.) twice a week (every 3 or 4 days) or (2) Quinine sulphate 0.3 gm. (5 gr.) daily.

When in a very short time it became clear that the high malaria rates in exposed troops constituted a serious problem, the few available trained experts on malaria were enlisted to direct hurried efforts to bring about drug suppression of the disease. Such attempts were made as in September 1942 in one area of high malaria incidence, when a command directive ordered that Atabrine (quinacrine hydrochloride) in doses of 0.2 gm. twice weekly be taken prophylactically but because of accumulation should be replaced after 3 months by quinine for 1 month. With these early efforts at suppressive drug control, malaria rates of combat troops in the range of 1,500 to 2,000 per 1,000 troops per annum were common.2

1Boyd, M. F.: An Historical Sketch of the Prevalence of Malaria in North America. Am. J. Trop. Med. 21: 223-244, March 1941.
2Downs, W. G., Harper, P. A., and Lisansky, E. T.: Malaria and Other Insect-Borne Diseases in the South Pacific Campaign, 1942-1945. II. Epidemiology of Insect-Borne Diseases in Army Troops. Am. J. Trop. Med. (supp.) 27: 69-89, May 1947.


466

FACTORS IN EARLY FAILURES IN SUPPRESSION OF MALARIA

Experiences such as these soon led to the conclusion by line officers and most medical officers as well, that Atabrine was ineffective in suppressing clinical malaria under the conditions of combat. Quinine was in short supply, but it was widely believed that quinine would provide effective suppression and that Atabrine was a necessary but poor substitute for it. Furthermore, when Atabrine was initially administered it frequently led to nausea, vomiting, and diarrhea. This was particularly likely to occur when the administration was begun on shipboard, where anxiety and seasickness contributed to the prevalence of gastrointestinal upsets. Confusion, too, between the skin discoloration due to Atabrine and cases of infectious hepatitis (a confusion added to by some medical officers) increased fear of the drug. There were rumors that Atabrine caused impotence. In addition, soldiers soon learned that if they acquired malaria they would be removed from combat areas to more adequate hospital facilities. Altogether, the value and safety of administration of this drug was not wholeheartedly accepted by the troops, and forward medical officers themselves became lukewarm regarding it. Diminishing supplies of quinine were frequently given by the medical staff to their fellow officers. The result of all this was poor discipline in the use of suppressive therapy and consequent failure in control of clinical malaria.

The change in the attitude of command and medical officers alike toward Atabrine and its role in the malaria problem was aided by an important study3 in an Army medical center located in Australia. This study was conducted by Lt. Col. (later Col.) Garfield G. Duncan, MC, Consultant in Medicine, Sixth U.S. Army, shown in figure 59, explaining the details of malaria suppressive therapy to Gen. (later General of the Army) Douglas MacArthur, Supreme Commander, Southwest Pacific Area. Here, a group of men, all known to be subject to recurrent malaria attacks, were gathered in a region free of endemic malaria and given suppressive amounts of Atabrine. Various dosage schedules were employed, including 0.1 gm. daily for 6 days each week and 0.5 gm. on 2 days of each week. There was prompt cessation of clinical malaria, despite vigorous training which included a final forced march of 25 miles.

This study pointed out the advantage of the twice weekly suppressive dose. Rigid supervision to insure the actual ingestion of the prescribed amount was more easily accomplished twice weekly than daily. Further, this dose, in all probability larger than absolutely necessary for good suppression, provided an additional margin of safety.

When this suppressive regimen was tried in a malarious area during combat, the results were even more impressive. Malaria rates as high as 1,230 per 1,000 per annum had been observed in a battalion supposedly receiving

3Duncan, G. G.: Quinacrine Hydrochloride as a Malaria-Suppressive Agent for Combat Troops. War Med. 8: 305-318, November-December 1945.


467

0.6 gm. of Atabrine weekly but obviously without adequate supervision. When the dosage was changed to 0.5 gm. twice weekly, the attack rate dropped to zero within 24 hours, and not a single attack occurred during the next 2 months.

This and a number of other careful studies clearly established the importance of making absolutely certain that the men actually swallowed and retained the prescribed dose of Atabrine. This so-called Atabrine discipline, in default, certainly accounted for many of the failures of the drug as a suppressant early in the war.

FIGURE 59.-Lt. Col. Garfield G. Duncan, MC, explaining the malaria suppressive therapy charts to Gen. Douglas MacArthur at the 101st Station Hospital, Rockhampton, Queensland, Australia, 26 November 1943. Left to right: Colonel Duncan; two officers in doorway unidentified; Lt. Col. Wallace A. Dunton, Sixth U.S. Army Training Center; Lt. Col. C. H. Morehouse, Aide-de-Camp to General MacArthur; Lt. Gen. Herbert Lunsden, British Army Liaison Officer; Lt. Gen. Robert L. Eichelberger, Commanding General, I Corps; Col. Frank LaRue, Commanding Officer, Sixth U.S. Army Training Center; and General MacArthur.

There was, however, another factor that almost surely accounted for some failures even when the drug was faithfully ingested. Early in the war, the recommended dosage was small and had to accumulate to reach effective blood levels, as will be shown in more detail later (p. 473). This fact was not then recognized. Consequently, when troops began therapy shortly before or on the day of exposure, clinical malaria could appear before the concentration of Atabrine in the blood was sufficient for suppression.


468

The experience of 840 men in a construction group which landed on Guadalcanal in December 1942 illustrates this point well.4 The men had never been exposed to malaria before, and on the day of landing, Atabrine in dosage of 0.4 gm. per week was begun. It was alleged that the drug was taken faithfully. In the third, fourth, and fifth weeks, 119 cases of clinical malaria developed, a rate of 1,523 per 1,000 per annum. Beginning with the sixth week, and coinciding with the predicted time of maximum blood concentration, the cases began to level off to about seven per week. As will be shown later, 0.4 gm. of Atabrine per week never produces a blood level adequate to suppress all malaria and has very limited effect until the maximum concentration is obtained from the seventh week on.

EFFECTS OF ATABRINE WITHDRAWAL

In most theaters of operations, there were either nonmalarious or relatively well sanitated base sections. When combat conditions permitted, troops were usually moved to such rear areas for rest and rehabilitation. It was thought that after long suppressive therapy, especially with, in addition, the debilitating influences of forward area duty, Atabrine would no longer effectively suppress clinical malaria. Administration of Atabrine was usually terminated in such troops unless local conditions made further disease transmission likely. Withdrawal of Atabrine was made either abruptly or after preliminary attack therapy with various combinations of Atabrine, quinine, or plasmoquin.5 It was hoped that troops so treated would be freed, at least in part, of malaria and be less likely to suffer supposed damage from the cumulative effects of long continued Atabrine therapy. Finally, it was thought that, after a period without Atabrine, they might be more susceptible to its suppressive effect when they had to return to highly infective areas.

The results of this experiment were appalling. Depending upon the degree of seeding, malaria rates in such troops rose to peaks as high as 15,000 per 1,000 per annum, and sustained rates over a period of months of 3,000 to 4,000 per 1,000 annum were common.6 With some of the strains involved, attacks followed attacks rapidly. It was common to have men hospitalized for the treatment of clinical malaria stricken with a fresh attack before completing the accepted period of convalescence. In one group studied in the South Pacific Area, the interval between attacks of malaria due to Plasmodium vivax averaged 28 days. The type of therapy that had been given had no significant influence upon the number of relapses or the interval between them in heavily seeded troops.

Such men, removed from suppressive therapy, were no longer fit for combat duty. The general physical fitness of the troops deteriorated; morale

4Personal communication, Paul Harper to author.
5Downs, W. G.: Results in an Infantry Regiment of Several Plans of Treatment for Vivax Malaria. Am. J. Trop. Med. 26: 67-86, January 1946.
6See footnote 2, p. 465.


469

suffered; adequate training was impossible; and hospital facilities and the few convalescent and rehabilitation camps available were overtaxed. Many men as a consequence were evacuated to the United States, and others had to be reassigned to limited duty.

Gradually, it was realized that suppressive therapy should be continued during rehabilitation periods and that the only way of controlling the disease in troops from whom suppressive medication had been withdrawn was to reinstitute such therapy. These decisions were reached after careful studies7 of the results to be expected. It was found that general physical and psychological fitness improved remarkably once current attacks of clinical malaria were prevented by suppression. It was furthermore found that fatigue, or exposure to cold, wet, and arduous combat conditions did not cause suppressed malaria to "breakthrough" provided discipline in the administration of Atabrine was good.

EFFECT OF SUPPRESSIVE THERAPY ON PARASITE SPECIES

In intensely malarious areas of the Pacific, the clinical disease that broke through poorly taken or otherwise inadequate suppressive medication was predominantly due to Plasmodium falciparum. On Guadalcanal, for example, in January 1943 the parasite species recovered during malaria attacks were distributed, as follows:8

 

Percent

Plasmodium falciparum 

55

Plasmodium vivax

24

Unidentified

19


When troops were removed to nonmalarious areas and suppressive therapy withdrawn, there was a progressive shift with time in this species distribution. For example, the same troops found to be infected on Guadalcanal with the parasites previously listed were found 5 months later to have clinical malaria from which micro-organisms were recovered, as follows:

 

Percent

Plasmodium falciparum 

0

Plasmodium vivax

99

Unidentified

1


Such observations from all parts of the world confirmed the view that all late relapsing malaria was caused by P. vivax, in accordance with the long-recognized tendency of this species to produce the most stubborn form of relapsing malaria. Gradually, it became apparent that Atabrine, even in suppressive doses, was curative for malaria due to P. falciparum.

A study by Col. Maurice C. Pincoffs, MC, which pointed out this, as well as other facts about Atabrine suppression, was carried out in New

7See footnote 3, p. 466.
8Levine, N. D., and Harper, P.: Malaria and Other Insect-Borne Diseases in the South Pacific Campaign, 1942-1945. IV. Parasitological Observations on Malaria in Natives and Troops, and on Filariasis in Natives. Am. J. Trop. Med. (supp.) 27: 119-128, May 1947.


470

Guinea and Australia in 1943. A group of previously uninfected men were moved to a highly malarious area for a 44-day period. One group took no suppressive therapy and served as controls. Sulfamerazine was given in doses of 0.5 and 1.0 gm. daily to a second group. A third group was given 0.1 gm. Atabrine daily 6 days a week. In the control group of 51 men, 26 developed clinical malaria. In the group of 111 men on sulfamerazine, only two manifested this disease. None of the 107 men on Atabrine fell ill with malaria.

Following this 44-day period, all groups were removed to a nonmalarious area for a further 3 months' period of observation and all drugs withdrawn. Of the group treated with sulfamerazine, 36 percent developed clinical malaria due to P. vivax as opposed to 30.8 percent of the group treated with Atabrine, while not a single case of malaria caused by P. falciparum developed during this period of observation among the men who had received Atabrine. It is almost certain that malaria due to P. falciparum had been transmitted to them previously as 10 cases developed in the control group of 51 men.

Further evidence was provided by another study9 carried out in Australia. Human volunteers were subjected to numerous bites of infected mosquitoes while on various suppressive regimens. The New Guinea strains employed were known to produce severe attacks of malaria due to P. falciparum and P. vivax, the latter with a high and rapid relapse tendency. Quinine sulfate proved to be greatly inferior to Atabrine as a suppressive drug. Several sulfonamides in doses of 1.0 gm. daily suppressed and cured most P. falciparum infections but were inferior to Atabrine in this respect. The sulfonamides proved very poor in their suppressive action on malaria due to P. vivax.

Atabrine was conclusively shown both to suppress and to cure all P. falciparum infections under the conditions of the experiment. This drug was also found highly effective in suppressing P. vivax infections, but when it was withdrawn clinical malaria caused by P. vivax regularly developed. Hard physical work, forced marches, extreme cold, anorexia, blood loss, and injections of insulin or Adrenalin (epinephrine) failed to alter the suppressive action of Atabrine.

There can be little doubt that the control of P. falciparum infections by even suppressive doses of Atabrine was in large measure responsible for the great rarity of cerebral malaria and blackwater fever in our forces. Because these manifestations of malaria are responsible for a large proportion of deaths from this disease, it is understandable why the death rate was so extraordinarily low. This in itself was a happy consequence of the enforced use of Atabrine due to inadequate supplies of quinine.

9Fairley, N. H.: Chemotherapeutic Suppression and Prophylaxis in Malaria; An Experimental Investigation Undertaken by Medical Research Teams in Australia. Tr. Roy. Soc. Trop. Med. & Hyg. 38: 311-355, May 1945.


471

LONG-TERM CLINICAL EXPERIENCE WITH ATABRINE SUPPRESSION

Many examples are available of long-term observations in military units that served in highly malarious areas. They all illustrate in varying degree early suppressive failure, amazing rates of clinical malaria when suppressive medication was withdrawn, and finally good control of malaria when suppressive medication, under proper conditions of Atabrine discipline, was resumed. 

One impressive example10 of this frequently repeated experience was that of an infantry regiment in the South Pacific which landed on Guadalcanal in three echelons in December 1942 and early in 1943 when malaria transmission was at a high level. Atabrine in doses of 0.4 gm. per week was ordered. The malaria rates between December 1942 and May 1943 varied between a low of 405 and a high of 1,296 per 1,000 per annum. In May 1943, the regiment was removed to a nonmalarious island for rehabilitation and all suppressive medication was withdrawn. Various malaria treatment regimens were instituted in an effort to eliminate some of the malaria seeding present in the troops; nevertheless, for the next 7 months, the malaria rate varied between 1,836 and 3,132 per 1,000 per annum. The highest rate occurred in the third week in one segment of the regiment that previously had had the greatest exposure to malaria transmission, and in this group the incidence of clinical attacks exceeded 14,000 per 1,000 per annum. The highest regimental rate, however, occurred in the sixth month, indicating no tendency for these extraordinarily rapid relapses of malaria caused by P. vivax to diminish with time. 

Rehabilitation of these troops had obviously not been accomplished. Their working efficiency was in fact, so severely depleted that they were returned to carefully supervised Atabrine suppression late in November 1943. At first, 0.4 gm. of Atabrine per week was given, but late in January 1944, the dose was increased to 0.6 gm. per week. As soon as this was done, there was a prompt and impressive control of the malaria rate with return of the working capacity of the organization.

Then, after 2 months' duty on a nonmalarious island, the regiment served for less than 3 months on an island where malaria transmission was very slight. Next, there was 12 months' service in a nonmalarious area, making a total of 18 months' service while on Atabrine suppressive medication with little or no additional exposure to malaria transmission. Atabrine medication was then terminated. Over the following 3 months' observation period, there was nothing like the increase in the attack rate that had followed initial deatabrinization exactly 2 years previously. Approximately 400 men had remained with this regiment from its early exposure to malaria on Guadalcanal in 1942 until the final termination of Atabrine suppressive medication in May 1945. The malaria experience of these men is shown in chart 25.

10Baker, B. M., and Platt, D.: Vivax Relapse Rates Following Continued Atabrine Suppressive Medication: Observations on Malaria in an Infantry Regiment. Bull. Johns Hopkins Hosp. 81: 295-304, November 1947.


472

In review then, there was in this group a period of 6 months' extreme exposure to malaria, 7 months of attempted but unsuccessful eradication of malaria, and a final period of 18 months' excellent suppression of malaria by Atabrine with negligible fresh transmission. Suppressive medication was then terminated, but the latent malaria that developed during the next 3

CHART 25.-Malaria experience of an infantry regiment carefully followed for 34 months, South Pacific Area, December 1942-August 1945

months was much lower in incidence than in the earlier period of Atabrine withdrawal. This was a unique experience in observing the effects of long-term suppressive therapy on troops heavily seeded with malaria, and there will probably never be an opportunity to confirm these observations. It seems likely, however, that the relatively low attack rate when suppressive therapy was finally terminated was due to permanent elimination of a significant amount of latent P. vivax infection either by the long-term drug therapy or by a gradual increase in biological resistance.


473

CONCENTRATION OF ATABRINE IN THE BLOOD AT LEVELS EFFECTIVE FOR SUPPRESSION

Basic understanding of optimum methods for suppression of malaria by Atabrine began only when field experience could be accurately controlled by determinations of the concentration of Atabrine in the blood. There were four large studies relating clinical effectiveness to Atabrine blood levels, and it is upon these that most of the accepted concepts of suppressive therapy depended. They were conducted in the United States,11 in the Southwest Pacific,12 and in the South Pacific.13 Such field studies yielded a reasonably precise means of testing Atabrine discipline, made possible determination of effective suppressive dosage, and provided basic pharmacological information.

It was shown that when a constant dose of Atabrine is administered daily to a group, individual blood levels vary widely, but that individuals who attain high, average, or low blood levels, do so regularly. Furthermore, the group mean level can be calculated accurately and is a function of dosage and duration of administration. The maximum blood level yielded by a given dose is attained slowly over a period of 6 weeks, and then remains constant for the remainder of the period of drug administration. Fifty percent of the final equilibrium level is reached at the end of the first week, and 50 percent of each remainder in each of the 5 succeeding weeks. A dose of 0.4 gm. of Atabrine per week produces a group mean level at the end of 6 weeks of 12 μg. per liter; a dose of 0.6 gm. per week, a level of 18; and a dose of 0.7 gm. per week, a level of 21. A group mean level of 21 μg. per liter can be achieved either by giving a daily dose of 0.1 gm. for 6 weeks or by administering 0.3 gm. daily for 4 days. Once the desired level has been attained, regardless of whether this is done with small doses over a long period or by larger doses in a few days, the group mean level can be maintained by the daily administration of the dose that would yield that level after 6 weeks of daily administration.

Interest naturally was strong in determining the blood levels that would protect working troops from primary and from relapsing attacks of malaria. One study addressed to this question was made in a segment of a division heavily seeded with malaria. Without suppressive medication, the troops were having a malaria rate that varied between 2,000 and 4,000 per 1,000 per annum. Two groups of 600 men each were selected for the study. One group

11(1) Final Report on Investigation of the Effects of Activity and Environment on Atabrine Therapy, Project No. 18, Armored Research Laboratory, Fort Knox, Ky., 23 Dec. 1943. (2) Shannon, J. A., Earle, D. P., Jr., Brodie, B. B., Taggart, J. V., and Berliner, R. W.: The Pharmacological Basis for the Rational Use of Atabrine in the Treatment of Malaria. J. Pharmacol. & Exper. Therap. 81: 307-330, August 1944.
12Bang, F. M., Hairston, N. G., Maier, J., and Trager, W.: Studies on Atabrine (Quinacrine) Suppression of Malaria. I. A Consideration of the Individual Failures of Suppression. Am. J. Trop. Med. 26: 649-661, September 1946.
13Schaffer, A. J., and Lewis, R. A.: Atabrine Studies in the Field. I. The Relation of Serum Atabrine Level to Breakthrough of Previously Contracted Vivax Malaria. Bull. Johns Hopkins Hosp. 78: 265-281, May 1946.


474

was given 0.1 gm. of Atabrine three times daily for 1 week (yielding a group mean Atabrine level in excess of 21 μg. per liter). Half of this experimental group then took 0.1 gm. Atabrine daily and the other half 0.05 gm. daily. The second group of 600 men had no medication and served as controls. During 4 weeks of observation, 157 of the controls but only 14 of the group on suppressive treatment developed clinical malaria. It was of interest that the Atabrine blood levels of these 14 treated men were all considerably lower than those of the treated group that remained free of clinical disease. In order to investigate the relationship of Atabrine blood levels to the probability of breakthrough of malaria, plans were made to expand the study with larger numbers of subjects.

A moderately seeded infantry division in a malaria-free area was selected. For longer than 10 months, these troops had had suppressive medication, first 0.4 gm. Atabrine per week and later 0.6 gm. per week, continuing on the latter dose when transferred to the rehabilitation area. Results of the study were as follows:

1. Preliminary Atabrine serum levels.-Of the nine infantry companies, 1,021 men had serum determinations made as soon as possible after reaching the rehabilitation area. Suppressive Atabrine was ordered, but as yet no special effort has been made to improve Atabrine discipline. Of this group, 65 percent had Atabrine levels of 19 μg. per liter or less. The arithmetic mean level of the entire group was 13 μg. per liter whereas the arithmetic means in the various companies varied between 9 and 20 μg. per liter. Obviously, some officers were enforcing more rigid Atabrine discipline than others. To confirm this conclusion, a large group of men were assured protection from disciplinary action and confidentially questioned regarding their actual intake of the ordered medication. Of those who claimed to have taken the suppressive doses faithfully, only 27 percent had acquired malaria, whereas 50 percent of those who admitted to poor discipline had the disease. Furthermore, relapses had been four times more frequent in those who admitted to disobeying orders as to Atabrine intake.

When this information was presented to command, extraordinary precautions were taken to see that all men who were offered six Atabrine tablets a week actually swallowed them. The arithmetic mean of the serum Atabrine levels of one company rose in 4 weeks from 11 to 20 μg. per liter with a sharp concomitant reduction in that company's malaria rate.

2. Atabrine levels at time of breakthrough.-Serum Atabrine levels were determined in 410 soldiers at times when they developed clinical malaria. Of these men, 97.4 percent had Atabrine levels of 10 μg. per liter or below with an arithmetic mean in this group of 5 μg. per liter. This figure should be compared both with the arithmetic mean of 13 μg. per liter of the "suppressed" group just discussed, and with the mean level of 20 μg. per liter achieved in the best disciplined company, which had no clinical malaria during the study period.


475

3. Controls.-In this same division, 404 men belonging to one company were removed from all suppressive medication at the beginning of the study. This control group had a malaria rate of 1,340 per 1,000 per annum as compared with the rate of 212 per 1,000 per annum in the group given suppressive treatment.

A roughly similar study14 was conducted in an intensely malarious area at a time when an epidemic of malaria due to P. falciparum developed in an infantry regiment in combat. Again it was demonstrated that the Atabrine blood levels in "protected" troops were significantly higher than those in men who developed clinical malaria, this difference presumably being a result of better discipline in the former. There was suggestive evidence in this study that it took a higher blood level of Atabrine to suppress primary malaria caused by P. falciparum during combat than to suppress relapsing malaria due to P. vivax in a rear area. This impression, however, was not confirmed beyond question, although another study15 in another area also suggested this conclusion.

This last was a further important study of the plasma levels of Atabrine in effective suppression, conducted in the Southwest Pacific. Again, it was demonstrated that there is no definite concentration in the plasma that divides protected individuals from those that break through suppressive therapy. However, it was pointed out that such plasma levels were obtained after the symptoms had started and might well have been quite different from those that prevailed at the time parasite multiplication began. Further, it was observed that the plasma level of Atabrine varied considerably during a 24-hour period depending upon the time the dose was given.

From this study, the conclusion was drawn that success of any suppressive program was related in part to the actual efficiency of Atabrine administration but that failure of suppression, even with low Atabrine plasma levels, was not always a result of failure to take the drug.

At the same time, it was realized, however, that during suppression there was no way to tell how much malaria was actually present though latent in troops. In the absence of this information, evaluation of any suppressive program could never be more than approximate. A study in the Southwest Pacific provided some information upon this important point.16

A previous study17 had demonstrated that after the termination of attacks of clinical malaria by therapeutic doses of Atabrine a few parasites could

14Final Report on an Investigation of the Blood Serum Level of Atabrine at Which Malaria Develops in a Hyperendemic Area. Special Report to The Surgeon General by Lt. Col. A. J. Schaffer, MC, and Capt. R. A. Lewis, MC, 3 July 1944.
15Bang, F. B., Hairston, N. G., Maier, J., and Trager, W.: Studies on Atabrine Suppression of Malaria. II. An Evaluation of Atabrine Suppression in the Field. Am. J. Trop. Med. 26: 753-759, November 1946.
16Bang, F. B., and Hairston, N. G.: Studies on Atabrine (Quinacrine) Suppression of Malaria. III. The Epidemiological Significance of Atabrine Suppression. Am. J. Trop. Med. 27: 31-38, January 1947.
17Bang, F. B., Hairston, N. G., Trager, W., and Maier, J.: Treatment of Acute Attacks of Vivax and Falciparum Malaria. Bull. U.S. Army M. Dept. 7: 75-89, January 1947.


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often be found in the blood. These numbered usually less than one parasite per 500 leukocytes and always less than four per 500 leukocytes. Similar parasite studies were now conducted upon troops under suppression and not infrequently, even in the absence of symptoms and in the presence of adequate Atabrine plasma levels, there were positive blood smears. This was particularly true when the troops had previously had little clinical malaria. The more attacks they had had the less likely they were to have positive smears. When in such surveys the number of parasites found exceeded four per 500 leukocytes, careful inquiry and determination of plasma Atabrine levels usually disclosed that insufficient Atabrine had been ingested to prevent parasite multiplication.

When this method of study was applied to a group in which malaria was believed to be heavily seeded but well suppressed, parasites were found in the blood smears of 14 percent of the men. The degree of seeding of the group was subsequently shown by withdrawing suppression and observing that 80 percent of the entire group developed clinical malaria within an 8-week period.

Parasite surveys of this sort were correlated with malaria rates under suppression, Atabrine discipline and determination of Atabrine plasma levels. The conclusion drawn was that when the suppressive dose of Atabrine is 0.5 gm. twice weekly, protection is afforded roughly 98 percent of troops even though engaged in combat in a highly malarious area.

An important result of Atabrine suppressive therapy not generally appreciated goes more fundamentally beyond postponing the evil day of clinical attacks until suppression is withdrawn. Atabrine in suppressive doses faithfully taken not only kills the gametocytes of P. vivax but prevents the development of P. vivax and P. falciparum gametocytes.18 Epidemics of malaria result from the availability of nonimmune susceptibles, anopheles mosquitoes, and gametocyte carriers. The latter can be controlled by Atabrine suppression and the relation of this control to outbreaks of malaria in troops was clearly demonstrated by observations in the Southwest Pacific.

UNDESIRABLE EFFECTS OF ATABRINE

Staining of the skin was a distinct detriment to the use of Atabrine as a suppressive agent. The sickly yellow hue of most soldiers who took the drug was unsightly, imposed an appearance of lack of vigor, and undoubtedly played a part in poor Atabrine discipline.

Gastrointestinal upsets resulting from Atabrine were not infrequent, particularly when the drug was first started and more particularly when loading doses were required. These initial intolerances almost invariably

18Bang, B. F., and Hairston, N. G.: Studies on Atabrine (Quinacrine) Suppression of Malaria. III. The Epidemiological Significance of Atabrine Suppression. Am. J. Trop. Med. 27: 31-38, January 1947.


477

subsided in time but they turned men from the drug in the beginning and some of them never accepted it willingly.

More serious reactions occurred in numbers that are not exactly known. It was demonstrated beyond question that Atabrine in doses employed in the treatment of clinical malaria caused some psychoses.19 It seems probable that even in suppressive doses the drug made a contribution to less serious psychiatric disorders, but accurate information on this is not available.

A peculiar form of lichen planus was clearly related to Atabrine in suppressive doses.20 A few cases of exfoliative dermatitis21 were related causally but how much contribution suppressive Atabrine made to ordinary dermatological disorders cannot be determined.22

The subject of Atabrine toxicity is discussed more fully elsewhere in this history (p. 538). The attendant discomforts, and the small risk of more serious potential dangers, does not detract from the enormous contribution that suppressive therapy made to the maintenance of the effectiveness of troops throughout the war.

19Newell, H. W., and Lidz, T.: The Toxicity of Atabrine to the Central Nervous System. Am. J. Psychiat. 102: 805-818, May 1946.
20Livingood, C. S., and Dieuaide, F. R.: Untoward Reactions Attributable to Atabrine. J.A.M.A. 129: 1091-1093, 15 Dec. 1945.
21Agress, C. M.: Atabrine as a Cause of Fatal Exfoliative Dermatitis and Hepatitis. J.A.M.A. 131: 14-21, 4 May 1946.
22Schamberg, I. L.: Studies on Post-Atabrine Dermatitis. II. Permanent Anhidrosis, Anhidrotic Asthenia and Prolonged Dermatitis Following Atabrine Dermatitis. J. Invest. Dermat. 21: 279-292, November 1953.

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