CHAPTER XV
The Suppression of Malaria
Benjamin M. Baker, M.D.
From the onset of World War II, it was recognized that tropical diseasescould interfere seriously with military operations. Previous military histories1had adequately delineated this problem. What was not known, however, was theextent to which troops might be incapacitated by malaria under the conditions ofmodern warfare in the Tropics. Planners could not count on the opportunity torid hostile shores or vast hinterlands of endemic malaria by elimination ofmosquito breeding. In the long run, the effectiveness of U.S. troops in manyparts of the world depended principally on the suppression of clinical malariaby the use of new drugs and the development of techniques of chemotherapy.
Most medical officers arrived on the scene with little knowledge of malariaand even less practical experience. At first, the only sources of informationwere the few available textbooks and the directives prepared by The SurgeonGeneral, U.S. Army. One of the directives, Circular Letter No. 56, Office of theSurgeon General, dated 9 June 1941 recommended the following regarding chemical prophylaxis:
The use of quinine or Atabrine for prophylaxis is not recommended as aroutine procedure, as the available information indicates that these drugs donot prevent infection. However, they are of definite military value in that theydo prevent the appearance of the clinical symptoms of malaria so long as theyare taken, and thus they afford a means for keeping troops "on theirfeet" during periods of emergency in the field. When administered to troopsin special situations in unsanitated endemic areas, either of the drugs may beused 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) Quininesulphate 0.3 gm. (5 gr.) daily.
When in a very short time it became clear that the highmalaria rates in exposed troops constituted a serious problem, the few availabletrained experts on malaria were enlisted to direct hurried efforts to bringabout drug suppression of the disease. Such attempts were made as in September 1942in one area of high malaria incidence, when a commanddirective ordered that Atabrine (quinacrine hydrochloride) in doses of 0.2 gm. twice weekly be taken prophylactically but because ofaccumulation should be replaced after 3 months by quinine for 1 month. Withthese early efforts at suppressive drug control, malaria rates of combat troopsin the range of 1,500 to 2,000 per1,000 troops per annum were common.2
1Boyd, M. F.: An Historical Sketch of the Prevalence of Malaria in NorthAmerica. 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 SouthPacific Campaign, 1942-1945. II. Epidemiology of Insect-Borne Diseases in ArmyTroops. Am. J. Trop. Med. (supp.) 27: 69-89, May 1947.
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FACTORS IN EARLY FAILURES IN SUPPRESSION OF MALARIA
Experiences such as these soon led to the conclusion by lineofficers and most medical officers as well, that Atabrine was ineffective insuppressing clinical malaria under the conditions of combat. Quinine was inshort supply, but it was widely believed that quinine would provide effectivesuppression and that Atabrine was a necessary but poor substitute for it.Furthermore, when Atabrine was initially administered it frequently led tonausea, vomiting, and diarrhea. This was particularly likely to occur when theadministration was begun on shipboard, where anxiety and seasickness contributedto the prevalence of gastrointestinal upsets. Confusion, too, between the skindiscoloration due to Atabrine and cases of infectious hepatitis (a confusionadded to by some medical officers) increased fear of the drug. There were rumorsthat Atabrine caused impotence. In addition, soldiers soon learned that if theyacquired malaria they would be removed from combat areas to more adequatehospital facilities. Altogether, the value and safety of administration of thisdrug was not wholeheartedly accepted by the troops, and forward medical officersthemselves became lukewarm regarding it. Diminishing supplies of quinine werefrequently given by the medical staff to their fellow officers. The result ofall this was poor discipline in the use of suppressive therapy and consequentfailure in control of clinical malaria.
The change in the attitude of command and medical officersalike toward Atabrine and its role in the malaria problem was aided by animportant 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 thedetails of malaria suppressive therapy to Gen. (later General of the Army)Douglas MacArthur, Supreme Commander, Southwest Pacific Area. Here, a group ofmen, all known to be subject to recurrent malaria attacks, were gathered in aregion free of endemic malaria and given suppressive amounts of Atabrine.Various dosage schedules were employed, including 0.1 gm. daily for 6 days eachweek and 0.5 gm. on 2 days of each week. There was prompt cessation of clinicalmalaria, despite vigorous training which included a final forced march of 25miles.
This study pointed out the advantage of the twice weekly suppressive dose.Rigid supervision to insure the actual ingestion of the prescribed amount wasmore easily accomplished twice weekly than daily. Further, this dose, in allprobability larger than absolutely necessary for good suppression, provided anadditional margin of safety.
When this suppressive regimen was tried in a malarious areaduring combat, the results were even more impressive. Malaria rates as high as1,230 per 1,000 per annum had been observed in a battalion supposedly receiving
3Duncan, G. G.: QuinacrineHydrochloride as a Malaria-Suppressive Agent for Combat Troops. War Med. 8:305-318, November-December 1945.
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0.6 gm. of Atabrine weekly but obviously without adequatesupervision. When the dosage was changed to 0.5 gm. twice weekly, the attackrate dropped to zero within 24 hours, and not a single attack occurred duringthe next 2 months.
This and a number of other careful studies clearlyestablished the importance of making absolutely certain that the men actuallyswallowed and retained the prescribed dose of Atabrine. This so-called Atabrinediscipline, in default, certainly accounted for many of the failures of the drug as asuppressant early in the war.
There was, however, another factor that almost surelyaccounted for some failures even when the drug was faithfully ingested. Early inthe war, the recommended dosage was small and had to accumulate to reacheffective blood levels, as will be shown in more detail later (p. 473). Thisfact was not then recognized. Consequently, when troops began therapy shortlybefore or on the day of exposure, clinical malaria could appear before theconcentration of Atabrine in the blood was sufficient for suppression.
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The experience of 840 menin a construction group which landed on Guadalcanal in December 1942 illustrates this point well.4 The men had neverbeen exposed to malaria before, and on the day of landing, Atabrine in dosage of0.4 gm. per week was begun. It wasalleged that the drug was taken faithfully. In the third, fourth, and fifthweeks, 119 cases of clinical malariadeveloped, a rate of 1,523 per 1,000per annum. Beginning with the sixth week, and coinciding with the predicted timeof maximum blood concentration, the cases began to level off to about seven perweek. As will be shown later, 0.4 gm. of Atabrine per week never produces ablood level adequate to suppress all malaria and has very limited effect untilthe maximum concentration is obtained from the seventh week on.
EFFECTS OF ATABRINE WITHDRAWAL
In most theaters of operations, there were eithernonmalarious or relatively well sanitated base sections. When combat conditionspermitted, troops were usually moved to such rear areas for rest andrehabilitation. It was thought that after long suppressive therapy, especiallywith, in addition, the debilitating influences of forward area duty, Atabrinewould no longer effectively suppress clinical malaria. Administration ofAtabrine was usually terminated in such troops unless local conditions madefurther disease transmission likely. Withdrawal of Atabrine was made eitherabruptly or after preliminary attack therapy with various combinations ofAtabrine, quinine, or plasmoquin.5 It was hoped that troops sotreated would be freed, at least in part, of malaria and be less likely tosuffer supposed damage from the cumulative effects of long continued Atabrinetherapy. Finally, it was thought that, after a period without Atabrine, theymight be more susceptible to its suppressive effect when they had to return tohighly infective areas.
The results of this experiment were appalling. Depending uponthe degree of seeding, malaria rates in such troops rose to peaks as high as 15,000per 1,000 per annum, and sustained rates over a period ofmonths of 3,000 to 4,000 per 1,000annum were common.6 With some of the strains involved, attacks followed attacksrapidly. It was common to have men hospitalized for the treatment of clinicalmalaria stricken with a fresh attack before completing the accepted period ofconvalescence. In one group studied in the South Pacific Area, the intervalbetween attacks of malaria due to Plasmodium vivax averaged 28 days. The type of therapy that had been given had nosignificant influence upon the number of relapses or the interval between themin heavily seeded troops.
Such men, removed from suppressive therapy, were no longer fit for combatduty. The general physical fitness of the troops deteriorated; morale
4Personal communication, PaulHarper to author.
5Downs, W. G.: Results in anInfantry Regiment of Several Plans of Treatment for Vivax Malaria. Am. J. Trop. Med. 26:67-86, January 1946.
6See footnote 2, p. 465.
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suffered; adequate training was impossible; and hospitalfacilities and the few convalescent and rehabilitation camps available wereovertaxed. Many men as a consequence were evacuated to the United States, andothers had to be reassigned to limited duty.
Gradually, it was realized that suppressive therapy should becontinued during rehabilitation periods and that the only way of controlling thedisease in troops from whom suppressive medication had been withdrawn was toreinstitute such therapy. These decisions were reached after careful studies7of the results to be expected. It was found that general physical andpsychological fitness improved remarkably once current attacks of clinicalmalaria were prevented by suppression. It was furthermore found that fatigue, orexposure to cold, wet, and arduous combat conditions did not cause suppressedmalaria to "breakthrough" provided discipline in the administration ofAtabrine was good.
EFFECT OF SUPPRESSIVE THERAPY ON PARASITE SPECIES
In intensely malarious areas of the Pacific, the clinical disease that brokethrough poorly taken or otherwise inadequate suppressive medication waspredominantly due to Plasmodium falciparum. On Guadalcanal, for example, inJanuary 1943 the parasite species recovered during malaria attacks weredistributed, 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 asother 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.
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Guinea and Australia in 1943. A group of previouslyuninfected men were moved to a highly malarious area for a 44-day period. Onegroup took no suppressive therapy and served as controls. Sulfamerazine wasgiven in doses of 0.5 and 1.0 gm. daily to a second group. A third group wasgiven 0.1 gm. Atabrine daily 6 days a week. In the control group of 51 men, 26developed clinical malaria. In the group of 111 men on sulfamerazine, only twomanifested 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 areafor a further 3 months' period of observation and all drugs withdrawn. Of thegroup treated with sulfamerazine, 36 percent developed clinical malaria due to P. vivax as opposed to 30.8 percent of the group treated with Atabrine, whilenot a single case of malaria caused by P. falciparum developed during thisperiod of observation among the men who had received Atabrine. It is almostcertain that malaria due to P. falciparum had been transmitted to thempreviously as 10 cases developed in the control group of 51 men.
Further evidence was provided by another study9 carried out inAustralia. Human volunteers were subjected to numerous bites of infectedmosquitoes while on various suppressive regimens. The New Guinea strainsemployed were known to produce severe attacks of malaria due to P. falciparumand P. vivax, the latter with a high and rapid relapse tendency. Quinine sulfateproved to be greatly inferior to Atabrine as a suppressive drug. Severalsulfonamides in doses of 1.0 gm. daily suppressed and cured most P. falciparuminfections but were inferior to Atabrine in this respect. The sulfonamidesproved 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 alsofound highly effective in suppressing P. vivax infections, but when it waswithdrawn clinical malaria caused by P. vivax regularly developed. Hard physicalwork, forced marches, extreme cold, anorexia, blood loss, and injections ofinsulin or Adrenalin (epinephrine) failed to alter the suppressive action ofAtabrine.
There can be little doubt that the control of P. falciparuminfections by even suppressive doses of Atabrine was in large measureresponsible for the great rarity of cerebral malaria and blackwater fever in ourforces. Because these manifestations of malaria are responsible for a largeproportion of deaths from this disease, it is understandable why the death ratewas so extraordinarily low. This in itself was a happy consequence of theenforced use of Atabrine due to inadequate supplies of quinine.
9Fairley,N. H.: Chemotherapeutic Suppression and Prophylaxis in Malaria; An ExperimentalInvestigation Undertaken by Medical Research Teams in Australia. Tr.Roy. Soc. Trop. Med. & Hyg. 38: 311-355, May 1945.
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LONG-TERM CLINICAL EXPERIENCE WITH ATABRINE SUPPRESSION
Many examples are available of long-term observations in military units thatserved in highly malarious areas. They all illustrate in varying degree earlysuppressive failure, amazing rates of clinical malaria when suppressivemedication was withdrawn, and finally good control of malaria when suppressivemedication, under proper conditions of Atabrine discipline, was resumed.
Oneimpressive example10 ofthis frequently repeated experience was that of an infantry regiment in theSouth Pacific which landed on Guadalcanal in three echelons in December 1942 andearly in 1943 when malaria transmission was at a high level. Atabrine in dosesof 0.4 gm. per week was ordered. The malaria rates between December 1942 and May1943 varied between a low of 405 and a high of 1,296 per 1,000 per annum. In May1943, the regiment was removed to a nonmalarious island for rehabilitation andall suppressive medication was withdrawn. Various malaria treatment regimenswere instituted in an effort to eliminate some of the malaria seeding present inthe troops; nevertheless, for the next 7 months, the malaria rate varied between1,836 and 3,132 per 1,000 per annum. The highest rate occurred in the third weekin one segment of the regiment that previously had had the greatest exposure tomalaria transmission, and in this group the incidence of clinical attacksexceeded 14,000 per 1,000 per annum. The highest regimental rate, however,occurred in the sixth month, indicating no tendency for these extraordinarilyrapid relapses of malaria caused by P. vivax to diminish with time.
Rehabilitation of these troops had obviously not been accomplished. Theirworking efficiency was in fact, so severely depleted that they were returned tocarefully supervised Atabrine suppression late in November 1943. At first, 0.4gm. of Atabrine per week was given, but late in January 1944, the dose wasincreased to 0.6 gm. per week. As soon as this was done, there was a prompt andimpressive control of the malaria rate with return of the working capacity ofthe organization.
Then, after 2 months' duty on a nonmalarious island, theregiment served for less than 3 months on an island where malaria transmissionwas very slight. Next, there was 12 months' service in a nonmalarious area,making a total of 18 months' service while on Atabrine suppressive medicationwith little or no additional exposure to malaria transmission. Atabrinemedication was then terminated. Over the following 3 months' observation period,there was nothing like the increase in the attack rate that had followed initialdeatabrinization exactly 2 years previously. Approximately 400 men had remainedwith this regiment from its early exposure to malaria on Guadalcanal in 1942until the final termination of Atabrine suppressive medication in May 1945. Themalaria experience of these men is shown in chart 25.
10Baker, B. M., and Platt, D.: Vivax Relapse RatesFollowing Continued Atabrine Suppressive Medication: Observations on Malaria inan Infantry Regiment. Bull. Johns Hopkins Hosp. 81: 295-304, November 1947.
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In review then, there was in this group a period of 6 months' extremeexposure to malaria, 7 months of attempted but unsuccessful eradication ofmalaria, and a final period of 18 months' excellent suppression of malaria byAtabrine with negligible fresh transmission. Suppressive medication was thenterminated, but the latent malaria that developed during the next 3
CHART 25.-Malaria experience of aninfantry regiment carefully followed for 34months, South Pacific Area, December 1942-August 1945
months was much lower in incidence than in the earlier periodof Atabrine withdrawal. This was a unique experience in observing the effects oflong-term suppressive therapy on troops heavily seeded with malaria, and therewill probably never be an opportunity to confirm these observations. It seemslikely, however, that the relatively low attack rate when suppressive therapywas finally terminated was due to permanent elimination of a significant amountof latent P. vivax infection either by the long-term drug therapy or by agradual increase in biological resistance.
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CONCENTRATION OF ATABRINE IN THE BLOOD AT LEVELS EFFECTIVE FORSUPPRESSION
Basic understanding of optimum methods for suppression ofmalaria by Atabrine began only when field experience could be accuratelycontrolled by determinations of the concentration of Atabrine in the blood.There were four large studies relating clinical effectiveness to Atabrine bloodlevels, and it is upon these that most of the accepted concepts of suppressivetherapy depended. They were conducted in the United States,11 in theSouthwest Pacific,12 and in the South Pacific.13Such field studies yielded a reasonably precise means oftesting Atabrine discipline, made possible determination of effectivesuppressive dosage, and provided basic pharmacological information.
It was shown that when a constant dose of Atabrine is administered daily to agroup, individual blood levels vary widely, but that individuals who attainhigh, average, or low blood levels, do so regularly. Furthermore, the group meanlevel can be calculated accurately and is a function of dosage and duration ofadministration. The maximum blood level yielded by a given dose is attainedslowly over a period of 6 weeks, and then remains constant for the remainder ofthe period of drug administration. Fifty percent of the final equilibrium levelis reached at the end of the first week, and 50 percent of each remainder ineach 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 of18; and a dose of 0.7 gm. per week, a level of 21. Agroup mean level of 21 μg. perliter can be achieved either by giving a daily dose of 0.1 gm. for 6 weeks or byadministering 0.3 gm. daily for 4 days.Once the desired level has been attained, regardless of whether this is donewith small doses over a long period or by larger doses in a few days, the groupmean level can be maintained by the daily administration of the dose that wouldyield that level after 6 weeks of daily administration.
Interest naturally was strong in determining the blood levelsthat would protect working troops from primary and from relapsing attacks ofmalaria. One study addressed to this question was made in a segment of adivision heavily seeded with malaria. Without suppressive medication, the troopswere having a malaria rate that varied between 2,000 and 4,000 per 1,000 per annum. Twogroups of 600 men each were selected for the study. One group
11(1) Final Report on Investigation of the Effects ofActivity and Environment on Atabrine Therapy, Project No. 18, Armored ResearchLaboratory, 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 Basisfor 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 toBreakthrough of Previously Contracted Vivax Malaria. Bull. Johns Hopkins Hosp.78: 265-281, May 1946.
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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 otherhalf 0.05 gm. daily. The second group of 600 men had no medicationand served as controls. During 4 weeks of observation, 157 of thecontrols but only 14 of the group on suppressive treatment developed clinicalmalaria. It was of interest that the Atabrine blood levels of these 14 treatedmen were all considerably lower than those of the treated group that remainedfree of clinical disease. In order to investigate the relationship of Atabrineblood levels to the probability of breakthrough of malaria, plans were made toexpand 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, first0.4 gm. Atabrine per week and later 0.6 gm. per week, continuing on thelatter dose when transferred to the rehabilitation area. Results of the studywere as follows:
1. Preliminary Atabrine serum levels.-Of the nineinfantry companies, 1,021 men had serum determinations made as soon aspossible after reaching the rehabilitation area. Suppressive Atabrine wasordered, but as yet no special effort has been made to improve Atabrinediscipline. 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. perliter whereas the arithmetic means in the various companies varied between 9 and20 μg. per liter. Obviously, some officers were enforcing more rigidAtabrine discipline than others. To confirm this conclusion, a large group ofmen were assured protection from disciplinary action and confidentiallyquestioned regarding their actual intake of the ordered medication. Of those whoclaimed to have taken the suppressive doses faithfully, only 27 percenthad acquired malaria, whereas 50 percent of those who admitted to poordiscipline had the disease. Furthermore, relapses had been four times morefrequent in those who admitted to disobeying orders as to Atabrine intake.
When this information was presented to command, extraordinary precautionswere taken to see that all men who were offered six Atabrine tablets a weekactually swallowed them. The arithmetic mean of the serum Atabrine levels of onecompany rose in 4 weeks from 11 to 20 μg. per liter with a sharpconcomitant reduction in that company's malaria rate.
2. Atabrine levels at time of breakthrough.-SerumAtabrinelevels were determined in 410 soldiers at times when they developedclinical malaria. Of these men, 97.4 percent had Atabrine levels of 10 μg. per liter or below with an arithmetic mean in this group of5 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 themean level of 20 μg. per liter achieved in the best disciplined company,which had no clinical malaria during the study period.
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3. Controls.-In this same division, 404men belonging to one company were removed from allsuppressive medication at the beginning of the study. This control group had amalaria rate of 1,340 per 1,000 perannum as compared with the rate of 212 per1,000 per annum in the group given suppressive treatment.
A roughly similar study14 wasconducted in an intensely malarious area at a time when an epidemic of malariadue to P. falciparum developed in an infantry regiment in combat. Again it wasdemonstrated that the Atabrine blood levels in "protected" troops weresignificantly higher than those in men who developed clinical malaria, thisdifference presumably being a result of better discipline in the former. Therewas suggestive evidence in this study that it took a higher blood level ofAtabrine to suppress primary malaria caused by P. falciparum during combat thanto suppress relapsing malaria due to P. vivax in a rear area. This impression,however, was not confirmed beyond question, although another study15 inanother area also suggested this conclusion.
This last was a further important study of the plasma levels of Atabrine ineffective suppression, conducted in the Southwest Pacific. Again, it wasdemonstrated that there is no definite concentration in the plasma that dividesprotected individuals from those that break through suppressive therapy.However, it was pointed out that such plasma levels were obtained after thesymptoms had started and might well have been quite different from those thatprevailed at the time parasite multiplication began. Further, it was observedthat the plasma level of Atabrine varied considerably during a 24-hourperiod depending upon the time the dose was given.
From this study, the conclusion was drawn that success of any suppressiveprogram was related in part to the actual efficiency of Atabrine administrationbut that failure of suppression, even with low Atabrine plasma levels, was notalways a result of failure to take the drug.
At the same time, it was realized, however, that during suppression there wasno way to tell how much malaria was actually present though latent in troops.In the absence of this information, evaluation of any suppressive program couldnever be more than approximate. A study in the Southwest Pacific provided someinformation upon this important point.16
A previous study17 had demonstrated that after the termination ofattacks of clinical malaria by therapeutic doses of Atabrine a few parasitescould
14Final Report on an Investigation ofthe Blood Serum Level of Atabrine at Which Malaria Develops in a HyperendemicArea. Special Report to The Surgeon General by Lt. Col. A. J. Schaffer, MC, andCapt. 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. AnEvaluation 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. TheEpidemiological 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, January1947.
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often be found in the blood. These numbered usually less thanone parasite per 500 leukocytes and always less than four per 500 leukocytes.Similar parasite studies were now conducted upon troops under suppression andnot infrequently, even in the absence of symptoms and in the presence ofadequate Atabrine plasma levels, there were positive blood smears. This wasparticularly 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 500leukocytes, careful inquiry and determination of plasma Atabrine levels usuallydisclosed that insufficient Atabrine had been ingested to prevent parasitemultiplication.
When this method of study was applied to a group in whichmalaria was believed to be heavily seeded but well suppressed, parasites werefound in the blood smears of 14 percent of the men. The degree of seeding of thegroup was subsequently shown by withdrawing suppression and observing that 80percent of the entire group developed clinical malaria within an 8-week period.
Parasite surveys of this sort were correlated with malaria rates undersuppression, 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 thoughengaged in combat in a highly malarious area.
An important result of Atabrine suppressive therapy notgenerally appreciated goes more fundamentally beyond postponing the evil day ofclinical attacks until suppression is withdrawn. Atabrine in suppressive dosesfaithfully taken not only kills the gametocytes of P. vivax but prevents thedevelopment of P. vivax and P. falciparum gametocytes.18 Epidemicsof malaria result from the availability of nonimmune susceptibles, anophelesmosquitoes, and gametocyte carriers. The latter can be controlled by Atabrinesuppression and the relation of this control to outbreaks of malaria in troopswas clearly demonstrated by observations in the Southwest Pacific.
UNDESIRABLE EFFECTS OF ATABRINE
Staining of the skin was a distinct detriment to the use ofAtabrine as a suppressive agent. The sickly yellow hue of most soldiers who tookthe drug was unsightly, imposed an appearance of lack of vigor, and undoubtedlyplayed a part in poor Atabrine discipline.
Gastrointestinal upsets resulting from Atabrine were notinfrequent, particularly when the drug was first started and more particularlywhen loading doses were required. These initial intolerances almost invariably
18Bang, B.F., and Hairston, N. G.: Studies on Atabrine (Quinacrine) Suppression ofMalaria. III. TheEpidemiological Significance of Atabrine Suppression. Am. J. Trop. Med.27: 31-38, January 1947.
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subsided in time but they turned men from the drug in the beginning and someof them never accepted it willingly.
More serious reactions occurred in numbers that are not exactly known. Itwas demonstrated beyond question that Atabrine in doses employed in thetreatment of clinical malaria caused some psychoses.19 It seems probable that even in suppressive doses the drug made a contribution to less seriouspsychiatric disorders, but accurate information on this is not available.
A peculiar form of lichen planus was clearly related toAtabrine in suppressive doses.20 A few cases of exfoliativedermatitis21 were related causally but how much contributionsuppressive Atabrine made to ordinary dermatological disorders cannot bedetermined.22
The subject of Atabrine toxicity is discussed more fully elsewhere in thishistory (p. 538). The attendant discomforts, and the small risk of more seriouspotential dangers, does not detract from the enormous contribution thatsuppressive therapy made to the maintenance of the effectiveness of troopsthroughout the war.
19Newell, H. W., and Lidz, T.: The Toxicity ofAtabrine to the Central Nervous System. Am. J. Psychiat. 102: 805-818, May 1946.
20Livingood, C. S., and Dieuaide, F. R.: Untoward Reactions Attributable toAtabrine. 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. PermanentAnhidrosis, Anhidrotic Asthenia and Prolonged Dermatitis Following AtabrineDermatitis. J. Invest. Dermat. 21: 279-292, November1953.
