CHAPTER XVII
Treatment of Malaria
Perrin H. Long, M.D.
INTRODUCTION
An interesting commentary on the state of health of the people of the UnitedStates at the beginning of World War II was that the majority of physiciansentering the Armed Forces had had practically no experience in the diagnosis ortreatment of malaria. To be sure, in the medical school courses of clinicalmicroscopy, each had studied stained slides showing malarial parasites, or ifthere happened to be a patient in the ward who had malaria inoculata, thickfresh films of blood might have been examined. Occasionally in seaports, sailorssuffering from malaria were seen on the medical services, treated with quinine,and then discharged shortly after their fever had subsided. As far as malariainoculata was concerned, the problem was often to keep the infection from dyingout rather than to arrest it by treatment. The average younger Americanphysician, except in certain rural areas in the Southern United States, hardlygave a thought to malaria and was unconcerned about his lack of knowledge ofthis disease.
When it became evident in May 1940 that the Armed Forces of the United Stateswere going to be sharply augmented, the Surgeons General of the Army and theNavy requested Dr. Lewis H. Weed, then Chairman of the Division of MedicalSciences of the National Research Council, to set up certain consultative andadvisory committees. One of the earliest of the groups formed by Dr. Weed wasthat which, under the chairmanship of Dr. Henry E. Meleney, devoted itself toproblems of tropical diseases. Of course, malaria immediately became a primesubject for discussion by this group. Out of the work of this subcommittee camethe initial recommendation for the suppression and treatment of malaria withquinine. Obviously in 1940 and during the first half of 1941, there was nopositive indication that the Axis Powers would seize Indonesia, the main sourceof the world's supply of quinine. Although Atabrine (quinacrine hydrochloride)and certain other suppressive and therapeutic agents were carefully considered,their use for suppressive or therapeutic purposes at that time was alwaysthought of as secondary to the use of quinine.
The military events that occurred late in 1941 and early in 1942 brought arude awakening to all concerned with malaria in this country. With relativelysmall supplies of quinine on hand, the Japanese move into Indonesia and Malaya,which cut off the major source of quinine, brought the Subcommittee on TropicalDiseases, National Research Council, to the recom-
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mendation that the military forces of the United States must rely on Atabrinefor the suppressive and the specific therapy of malaria. At that time, there wasrelatively little in the U.S. medical literature concerning the properties ofAtabrine, and very few American physicians had used it or, for that matter, evenheard of it. Very little was known about its pharmacological or toxicproperties. Schemes of therapy, either suppressive or definitive, were based onempirical observations or even guesswork. This was the status of affairs whenthe Office of Scientific Research and Development initiated its large-scaleresearch project on Atabrine in 1942. One of the earliest applied projects wastesting the drug in normal human beings over a period of weeks to determine itspossible toxic effects when it was used for suppressive therapy over a longperiod. The dosage schedule employed was 0.1 gm. twice a week. Various socialgroups, such as students, reform-school inmates, and prisoners in penalinstitutions, were employed as test subjects in these early trials. One of theresults of these trials was extraordinarily significant. But how significant itwas, unfortunately, was not recognized until, at least in the North African(later Mediterranean) Theater of Operations, U.S. Army, serious, if notpermanent, damage had been done to the minds of the military relative to the useof Atabrine for the suppression of malaria. It was noted that in the testsubjects there were sharp, prostrating gastrointestinal attacks characterized bynausea, vomiting, and diarrhea following the third dose of the suppressivemedication. This occurred very frequently in the student group, very much lessfrequently in the reformatory inmates, and least of all in the inmates of theState prisons. It was also observed that, if the therapy was continued, therewere very few individuals who had to discontinue the Atabrine because ofgastrointestinal disturbances following subsequent doses of Atabrine. It wasfurther noted that, if the drug was given in dosages of 0.1 gm. per day,gastrointestinal disturbances were minimal.
In the North African and Mediterranean theaters, where everything having todo with malaria was a joint command and professional project between the Britishand Americans, and for a considerable period with the French and Italian forces,the author was a member of the Malaria Committee of Allied Force Headquarters.In January 1943, this committee began its discussion which led to a jointcommand directive regarding the use of Atabrine for the suppression of malaria.The author, remembering the gastrointestinal disturbances that occurred afterthe third dose in the trials in the United States, held out for a dailysuppressive dose of Atabrine. The British and French members of the committeeresolutely opposed this method of suppression. To make a long story short, theauthor was outvoted and, under the operational rules of Allied ForceHeadquarters, had to accept the committee's decision. On 22 April 1943,suppressive therapy was begun on a biweekly (Monday and Thursday) basis, 0.1 gm.of Atabrine per dose. No troubles were encountered after the administration ofthe first two doses. The third dose was administered to all troops at theevening meal on Thurs-
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day, 29 April 1943. Within 4 or 5 hours, sharply definedtoxic reactions characterized by varying degrees of nausea, vomiting, anddiarrhea made their appearance. Curiously enough, military personnel stationedto the rear of combat elements suffered far more than the fighting men. Infantryunits of the II Corps in combat in Tunisia had about 5 percent toxic reactions;whereas, in certain hospitals and headquarters units in the rear, more than 75percent of the personnel were affected. As one of our British colleaguesremarked the next day, "it had been a shaking experience."
Understandably, as reports of toxic reactions piled into Allied ForceHeadquarters from all over the North African theater, consternation prevailed,and there was an immediate demand that suppressive therapy be discontinued. Calmwas eventually restored, faith in the use of Atabrine was reaffirmed officially,and suppressive therapy was continued. However, as can well be imagined, thedamage was done, and it can be said that throughout the rest of the war,discipline relative to suppressive therapy was poor in many units throughout thetheater. Then, to compound confusion, the first great seasonal epidemic ofinfectious hepatitis occurred in American troops beginning in August 1943, andin many quarters this epidemic was at first thought related to the use ofAtabrine for the suppression of malaria. The author cannot determine, from thereports available to him, whether similar incidents occurred during theinitiation of suppressive therapy with Atabrine in other theaters of operations.However, it appears that, in all areas in which there was fighting and malariawas epidemic, the discipline required to carry out successful campaigns for thesuppression of malaria by the use of Atabrine was difficult to enforce and theterrific toll of ineffective military personnel resulting from malarial attackswas directly related to this lack of discipline. Command was not convinced ofthe value of suppressive therapy with Atabrine and did not, except in a fewareas, take the steps necessary to make the suppressive program effective.
EXPERIENCE IN THE PACIFIC
Our military forces first felt the impact of malaria on their ability to wagewar effectively in the South Pacific Area. The experiences with malaria in thatarea were so rich and varied, and such careful, large-scale studies were carriedout on its nature and the suppressive and therapeutic problems it posed, thereader is referred to other volumes in the history of the Medical Department inWorld War II for statistical and other details.1The substance of these observations is in part summarized here, for theirbearing on treatment.
1(1) Medical Department, United States Army. Internal Medicine in World War II. Volume I. Medical Consultants. Washington: U.S. Government Printing Office, 1961, pp. 603-618. (2) Medical Department, United States Army. Preventive Medicine in World War II. Volume VI. Communicable Diseases: Malaria. [In press.]
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In this as in other theaters, most medical officers early in the war hadlittle practical knowledge of malaria. Some few had had clinical experience,mostly in the southeastern part of the United States, and they were disposed toascribe "properties to quinine that it did not possess." Such"malaria experts" scattered through many medical units "werebelieved to have done much harm, for most of them preached quinine withevangelical zeal and blamed" everything, particularly the very difficultproblem of controlling relapsing malaria, "on the enforced use of Atabrine."Quinine, in short supply, was limited by command to cases intolerant to Atabrine,and the problem of controlling relapse was not solved until experience hadtaught the proper use of Atabrine.
According to Col. Benjamin M. Baker, MC, Senior Consultant in Medicine,Office of the Surgeon, South Pacific Area, there were few cases of cerebralmalaria (46), fewer still of severe anemia (14), blackwater fever (13), andsplenic rupture (6). However, based on sample tabulations of individual medicalrecords, there were no admissions for blackwater fever in the Central and SouthPacific Areas during 1942-45. As in the Army as a whole, there were few deaths;in this theater, only 24 were attributed directly to malaria between 3 October1942 and 1 September 1944. The more virulent infections caused by Plasmodiumfalciparum predominated during epidemics. Infections with the less virulentbut stubbornly relapsing Plasmodium vivax appeared in increasingly higherpercentages of cases when troops were removed from malarious to nonmalariousislands and suppressive Atabrine therapy gradually withdrawn. It was apparentthat Atabrine, even in suppressive dosage, cured malaria due to P. falciparum.To this specific action of the drug has been ascribed the low death rate and thecomparatively low incidence of malignant malaria in the Pacific areas. The mostpressing concern of the U.S. Army was the very high relapse rate of vivax infections,immobilizing whole regiments of men.
The 147th Infantry Regiment met the enemy, both human and plasmodial, inGuadalcanal (1942-43), armed against the latter with suppressive doses ofquinine for a short period, and Atabrine later. In May 1943, the entire regimentwas sent to Samoa, a nonmalarious island. Here, Atabrine therapy was graduallywithdrawn, and the men were given no further specific treatment until theydeveloped fresh attacks, with the hope that their malaria would "burnitself out." The actual result was the development of chronic malaria withrepeated relapses in the overwhelming majority. It was apparent that thesuppressive therapy on Guadalcanal had cured few, if any, cases of malaria dueto P. vivax. Massive therapy was also ineffective in curing latent vivaxinfections. Before the regiment could be returned to active duty,suppressive medication with Atabrine had to be reinstituted. This therapyeffectively reduced the malaria rate, and the physical fitness of the regimentwas restored.
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Similar results followed a similar attempt to "demalarialize" theAmerical Division on the Fiji Islands. Troops heavily seeded with malaria werenot well enough to return to combat after many months of "demalarialization."Many patients were evacuated to the Zone of Interior, but many remained in thetheater, relapsing repeatedly. The only reasonable course was to resumesuppressive therapy with the hope, but as yet no certainty, that continued usewould materially reduce the staggering noneffective rate.
An experiment was set up on the Fiji Islands with combat units engaged inmaneuvers under conditions simulating those of jungle warfare. One group wasgiven no suppressive therapy; the other, sufficient Atabrine to establish theblood levels that had been found to be effective. In the control group, therelapses continued to occur at about the same rate as during previous months; inthe treated group, malaria was practically eliminated. The cases that diddevelop were in men who, like some others observed previously, exhibitedconsistently low Atabrine blood levels.
Subsequent to this study, troops were kept on suppressive medication whetherthey remained in malarious areas or were sent to nonmalarious regions for restand recreation. First to come under the new policy was the 25th InfantryDivision, which had become heavily seeded with malaria on Guadalcanal and wasnow removed to malaria-free New Zealand, where suppressive therapy wascontinued. After Atabrine discipline was tightened, the results were excellent.
Having proved feasible, the control of malaria by continued suppressivemedication was required by military necessity. Experience had shown thatAtabrine in suitable dosage (0.1 gm. a day) was an effective suppressive formost if not all primary malaria and, if continued, for recurrent attacks.Nevertheless, many questions remained in medical minds. Some feared that relapsewas only being postponed to the day when Atabrine would finally be withdrawn.Some thought the parasite would acquire tolerance to the drug. Suchconsiderations had an important bearing on plans for reemployment of highlymalarialized troops, and on treatment of troops in malarious areas.
To provide answers to many questions, a large number of menof the 147th Infantry were followed from Guadalcanal (November 1942) to Iwo Jima(August 1945). Their medical history "included heavy exposure, lightexposure, atabrinization, de-atabrinization, long-continued suppressivemedication, and terminal de-atabrinization." The observations, made on thesame experimental group and covering this not inconsiderable expanse of time,space, and experience, appeared to justify the conclusion that long-continuedsuppressive Atabrine therapy does, in fact, ultimately destroy a large amount ofinfection due to P. vivax. After 17 months of continuous suppression, allantimalarial therapy was discontinued, in the nonmalarious environment of IwoJima, 20 months after the last significant exposure to infection. During theensuing 3 months, there was only a slight increase in the malaria rate incontrast to the violent outbreaks that had followed the initial deatabrini-
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zation. It was, unfortunately, not possible to continue followup observationsbeyond this 3-month period.
In another comprehensive study, no serious aftereffects ofmalaria were found in soldiers who had been through many clinical attacks. Toxicreactions to Atabrine were not troublesome in the South Pacific Area. Signs ofintolerance in the central nervous system appeared in a small group of cases andwere carefully studied; they subsided when dosage was decreased. In comparativestudies, other drugs (Plasmochin naphthoate (pamaquine naphthoate), thesulfonamides, totaquine) appeared to be generally inferior or not superior toAtabrine.
In the Southwest Pacific Area, important studies were carriedout on suppressive treatment, such as those in Australia by Lt. Col. (laterCol.) Garfield G. Duncan, MC, of the American Army and by Brigadier N. HamiltonFairley of the British, and those by Lt. Col. (later Col.) Maurice C. Pincoffs,MC, and others in New Guinea. The observations made early in the war on thatisland were probably the first to demonstrate clinically that malaria caused by P.falciparum could be cured by Atabrine in suppressive dosage.2Subsequent studies by Bang and others showed that a certain concentration of thedrug in the blood was necessary for protection against clinical attacks and thatequilibrium could be achieved by giving 0.1 gm. daily for 6 weeks, or 0.3 gm.daily for 4 days, and could be maintained by continuing suppressive doses. Itwas shown that this treatment resulted in control of gametocyte carriers andthis, in turn, prevented epidemic outbreaks of malaria when troops were exposedagain to infection.
EXPERIENCE IN THE INDIA-BURMA THEATER
Malaria as constituting a major medical problem in theIndia-Burma theater has been presented in another volume in the history of theMedical Department in World War II, from which the following summary has beenlargely drawn.3 It is obvious that in many instances information willoverlap. In India, U.S. troops were exposed to malaria, most of them for thefirst time, in a vast region where the incidence was something like 4,000 per1,000 per annum in the population. An overnight journey by train was likely toresult in clinical malaria in 80 percent or more of the troops making the trip.The highest percentage of patients with malignant tertian malaria was seen inthis theater; cerebral malaria was the principal clinical problem. Medicalofficers came from the United States unprepared for the multiform manifestationsof the disease and were often, particularly at first, uncertain in diagnosis. Asto treatment, there was much individual experimentation. This may have been due,in part, to the proximity of the Indian Medical Service and its methods oftherapy; in part, to delays in receiving
2Baker, B. M., and Platt, D.: The Effect of Long-Continued Suppressive Atabrine Medication on Relapses of Vivax Malaria. Tr. Am. Clin. & Climatol. A. 58: 145-152, 1946.
3See footnote 1, p. 495.
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information from the Surgeon General's Office on newermethods of treatment; and in part, perhaps, to the presence in Army hospitals ofhighly individualistic, research-minded medical officers.
The overall percentage of cases of malaria classified as cerebral, in thethree hospitals where most of them were seen, was 1.9 percent. At the 20thGeneral Hospital, the incidence was 2.3 percent for all patients with malariaand was 2.2 percent for Americans alone. At the 73d Evacuation Hospital, duringa 6-month period, there were 57 cases of cerebral malaria with 27 fatalities,only 1 an American. At the 48th Evacuation Hospital, treating chiefly Chinesesoldiers, between April 1944 and March 1945, the mortality was 43 percent, withno deaths in Americans. From September 1943 to May 1945, the 14th EvacuationHospital had 121 cases with 33 deaths, all the fatalities occurring in Chinesepatients.
P. falciparum was recognized as the causative agent in most cerebralcases; some few were ascribed to P. vivax. In the majority of allAmerican patients with malaria, P. vivax predominated; in the majority ofChinese, P. falciparum predominated. Col. Francis C. Wood, MC, ofthe 20th General Hospital thought that an observation made there threw lightupon this. Some Chinese patients were given no treatment for several dayspreparatory to testing with a new drug, at the request of Chinese medicalofficers. This was Fraxine, a preparation of unknown composition and, in theevent, of no proved value. Of these patients, those with infections due to P.vivax became symptom free in 4 days without treatment; the infections with P.falciparum did not subside during this period. It appeared probable thatChinese soldiers infected with P. vivax recovered spontaneously and wereusually not seen at hospitals.
The India-Burma theater was established in October 1944 whenU.S. Army Forces, China-Burma-India, was divided into two separate theaters-theChina Theater and the India-Burma Theater. What seems to have been the firstpublication in the theater on the treatment of malaria appeared in the openingissue of the Field Medical Bulletin, Headquarters, Services of Supply,U.S. Army Forces in China-Burma-India (August 1942). This was a summary of apamphlet issued by the British War Office recommending treatment different fromthat advised in Circular Letter No. 56, Office of the Surgeon General, U.S.Army, 9 June 1941, entitled "A Note on the Treatment and Control of CertainTropical Diseases." In the November 1942 issue of the Field MedicalBulletin, Maj. Sydney P. Waud, MC, and Maj. Robert S. Crew, MC, of the 159thStation Hospital, presented "several changes in the treatment ofmalaria," derived from the School of Tropical Medicine, Calcutta, India.Finally, the Bulletin in its January 1943 issue reprinted Circular LetterNo. 135, Office of the Surgeon General, U.S. Army, dated 21 October 1942 andentitled "The Treatment and Clinical Prophylaxis of Malaria," but inthe issue of February 1943, Lt. Col. Gordon S. Seagrave,
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MC, expressed doubt concerning the efficacy of Atabrine and presented his ownviews on therapy including liquor arsenicalis and neoarsphenamine.
The theateras a whole continued to use the plan of treatment outlined in Circular LettersNos. 135 and 33, the latter dated 2 February 1943 and entitled "Treatmentand Control of Certain Tropical Diseases." Circular Letter No. 33 wasreplaced by Circular Letter No. 153, Office of the Surgeon General, U.S. Army,19 August 1943, entitled "The Drug Treatment of Malaria, Suppressive andClinical." By the end of 1943, installations in heavily infested areas hadreached their own conclusions on the basis of experience. The view expressed ina special report on malaria in the annual report of the 73d Evacuation Hospitalwas that all methods in use there were about equally effective in their endresults but that quinine and Atabrine used in combination reduced temperaturemore rapidly than the officially recommended therapy. At the 48th EvacuationHospital, Lt. Col. (later Col.) Herman A. Lawson, MC, and Maj. John A. Dillon,MC, treated a group of Chinese patients with a somewhat larger total dose ofAtabrine than was recommended, but could find no certain advantage. Theexperience of the theater with the treatment described in Circular Letter No.153 was summarized in the Essential Technical Medical Data reported to TheSurgeon General for June 1944. The general opinion was that only in very sickpatients was it necessary to supplement Atabrine with quinine, usually given byinjection. Patients with cerebral malaria were sometimes unable to take oralmedication. In such cases, before parenteral Atabrine was available, quinine wasgiven intravenously.
During the period covered by Circular Letters Nos. 135, 33, and 153, whichincluded all of 1943 and most of the malarial season of 1944, occasionalinvestigations were made, particularly at the 20th General Hospital, on theeffectiveness of drugs or combinations of drugs other than those recommended,and also on the side effects and usefulness of commonly used drugs.
The treatment of relapse in benign tertian malaria with a combination ofAtabrine and Mapharsen (oxophenarsine hydrochloride) was studied by Maj. CalvinF. Kay, MC. Relapses occurred in the group so treated as frequently as in thosetreated with Atabrine alone.
Fraxine, a preparation used by Chinese medical officers and tested at theirrequest, proved of no value in malignant tertian malaria, and its effectivenessin benign tertian malaria was extremely doubtful in view of the apparenttendency of Chinese troops to recover spontaneously.
A special problem with Chinese patients was to keep them inthe hospital. As soon as they felt better they left or were taken out by theircommanding officers. To circumvent this, Maj. Thomas E. Machella, MC, sought todevise a safe and effective method of giving the total dose of Atabrine within24 hours. A group of 80 Chinese patients given 0.3 gm. of Atabrine every 3 hoursfor eight doses, did as well or even better, as regards duration of fever andparasitemia, as compared with patients treated according to Circular Letter No.153. Because 2 of the 80 patients showed signs of stimulation of the centralnervous system, the dosage was reduced to 0.2 gm. every 3 hours for eight doses.
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An experimental study by Major Machella failed to demonstrateany effect of a single intravenous infusion of an antimalarial (Atabrine or SN6,911) upon the ability of the liver to excrete bromsulphalein before, during,and after an attack of malaria. Some patients with cerebral malaria were treatedwith a single intravenous infusion of Atabrine, the dose varying from 0.6 gm. to1.0 gm. The patients who received the infusion too rapidly hadbrief psychotic episodes. Although the number of cases was small, Major Machellafelt that Atabrine was at least as effective as quinine, and that 0.8 gm.Atabrine given by slow intravenous drip was an effective method of clearing theblood of parasites.
All three drugs commonly used in the treatment of malaria produced reactions.Plasmochin proved to be particularly toxic in Negroes. Many Negro patients fromunits working along the Ledo-Burma road were seen at the 73d Evacuation and 20thGeneral Hospitals. A severe type of hemolytic reaction to Plasmochin occurred inapproximately 30 patients. One patient was Chinese and the rest were Negroes.All of them developed a moderately severe anemia; in six, the erythrocyte countfell below two million. Because of the frequency and severity of thesereactions, administration of this drug was stopped in all hospitals in theAssam-Burma region, and eventually in the theater.
Quinine had long been known to produce toxic effects. Used intravenously incases of cerebral malaria prior to the advent of parenteral Atabrine, it wasgenerally considered a lifesaving procedure. At the 48th Evacuation Hospital,however, eight Chinese patients died in convulsions shortly after injection ofquinine. Although admittedly a cause and effect relationship could not beproved, the clinical impression was so strong that at this hospital anyreasonable alternative was regarded as preferable.
All the reactions commonly attributed to Atabrine were seen in this theater,including atypical lichen planus and various other skin reactions, toxicpsychoses, and the usual gastrointestinal disturbances. When suppressivetreatment with Atabrine was instituted in February 1945, many medical officerswere still apprehensive of its supposed toxic potentialities. Many symptoms wereattributed to Atabrine without good evidence of a causal relationship, others ona more plausible basis. The Air Transport Command's division surgeon, Col.Edward A. Abbey, MC, and the chief of preventive medicine, Maj. Edgar A.Lawrence, MC, reported on the effects of continued doses (0.1 gm. daily) on thevisual acuity of airplane pilots, concluding there was no adverse effect exceptin rare, highly sensitive individuals. In these, withdrawal of Atabrineresulted in relief of symptoms; readministration of the drug was followed byrecurrence, which in turn was relieved by cessation of suppressive therapy.
Various nonspecific therapeutic measures were employed, particularly at the20th General Hospital, with variable benefit. Transfusions of whole blood werethought to be lifesaving in some cases, especially in those with pulmonaryedema. At this hospital an initial spinal tap was considered advisable in allcases. At the 73d Evacuation
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Hospital, on the contrary, the reduction of spinal-fluidpressure by lumbar puncture was thought to be appreciably effective only in rarecases. At both hospitals intravenous Adrenalin (epinephrine) was considered ofvalue in some cases, but was not in routine use because of untoward reactions.Sedatives were universally used for excited or convulsive patients, usuallyAmytal Sodium or paraldehyde given intravenously. Various other measures weretried without any striking benefit. These included oxygen therapy, Benzedrine (racemicdesoxy-nor-ephedrine), ephedrine, aminophylline by intravenous and byintracarotid injection, and injection of nitroglycerine into the carotid.
EXPERIENCE IN THE MEDITERRANEAN (FORMERLY NORTH AFRICAN)
THEATER OF OPERATIONS
Lt. Col. Harold H. Golz, MC, 182d Station Hospital, and Maj.Phillip B. Bleecker, MC, 225th Station Hospital, collected and compiledextensive data on the epidemiology, clinical and laboratory diagnosis, clinicalcourse, and treatment of malaria in U.S. Army troops in countries bordering theMediterranean. What follows is in large part taken from the final report onmalaria written by Colonel Golz.4
Throughout recorded history, malaria played its part in theinsidious defeat of armies, and here, in this theater in World War II, itrapidly became the foremost medical problem. The vast majority of Americantroops who moved into these highly malarious regions had never been exposed tothe disease, and the great majority of medical officers had had no experiencewith it. At that time, the possibilities of drug prophylaxis and suppressionwere only in process of being elucidated, and mechanical protection frominfection in amphibious operations could at best be only a feeble effort.Fortunately, the initial landings were made at a season when the incidence ofprimary infections was low.
The disease occurred throughout the theater, more intensively in certainregions. In North Africa, the most highly malarious areas were in theneighborhood of Rabat and Port Lyautey in Morocco, the Constantine area inAlgeria, and the Tunis-Bizerte-Ferryville area in Tunisia. Sicily had a highrate on the Catania plain and on the southern coastal plain. The entire easterncoastal plain of Corsica was highly malarious, and the malaria rate in civiliansof Sardinia was the third highest in the world. A survey of 802 children inSardinia before World War II showed that 34.2 percent had positive smears, ofwhich 51.4 percent were P. falciparum and 43.1 percent were P. vivax.
The worst malarial areas in Italy were in the region of Salerno and Paestum,along the Volturno and Garigliano Rivers, about the Pontine Marshes, and aroundthe river mouths on the eastern coast. There was little malaria in southernFrance, and urban centers such as Florence were free of malaria, although it didapproach the municipal limits of Rome and Naples.
4Golz, Harold H.: Human Malaria in the North African and MediterraneanTheaters of Operations, U.S. Army. [Official record.]
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Incidence
Based on sample tabulations of individual medical records,there were approximately 81,000 cases (attacks) of known malaria in the U.S.Army in the Mediterranean theater during 1942-45. These cases consisted of newadmissions and readmissions as well as admissions for other causes, but in whichmalaria existed concurrently or developed subsequently (table 54, ch. XIV).There were approximately 28,000 cases of FUO (fever of undetermined origin)recorded on individual medical records in the Mediterranean theater during thewar period, and of these, between 5 and 10 percent were probably malaria.Assuming that 7.5 percent, or 2,100 cases, of FUO's were malaria, this number,when added to the approximate 81,000 known malaria cases, produced about 83,000probable cases of malaria in the Mediterranean theater during 1942-45. By year,this meant that there were less than 1,000 cases in 1942, about 34,000 in 1943,40,000 in 1944, and 8,000 cases in 1945.
The data on malaria, by month, in the Mediterranean theater for 1942-45 areshown in table 66. The 1942-43 data are based on tabulations of individualmedical records and consist of new cases admitted for malaria and new cases inwhich malaria appeared as a secondary diagnosis. The 1944-45 data are from thestatistical health reports and are in terms of total malaria
[Data based on tabulations of individual medical records (1942-43) and statistical health reports (1944-45)]
[Rate expressed as number of cases per annum per 1,000 average strength]
Month | 19422 |
| 1944 | 1945 | ||||
Number of cases | Rate |
| Rate | Number of cases | Rate | Number of cases | Rate | |
January | --- | --- | 517 | 24.95 | 1,392 | 29.11 | 759 | 19.95 |
February | --- | --- | 214 | 10.28 | 2,214 | 46.61 | 636 | 15.98 |
March | --- | --- | 60 | 2.24 | 4,498 | 72.11 | 988 | 20.60 |
April | --- | --- | 86 | 2.89 | 4,222 | 80.24 | 1,077 | 28.23 |
May | --- | --- | 180 | 4.85 | 3,022 | 56.67 | 1,139 | 31.20 |
June | --- | --- | 1,847 | 47.82 | 4,691 | 69.75 | 1,002 | 25.81 |
July | --- | --- | 4,806 | 112.00 | 4,341 | 81.26 | 639 | 23.67 |
August | --- | --- | 8,516 | 191.50 | 4,897 | 90.78 | 392 | 15.32 |
September | --- | --- | 6,047 | 129.78 | 4,870 | 73.88 | 111 | 7.90 |
October | --- | --- | 6,235 | 122.93 | 3,270 | 60.96 | 32 | 2.96 |
November | 67 | 8.58 | 2,550 | 53.24 | 2,030 | 38.04 | 21 | 2.41 |
December | 664 | 43.92 | 1,753 | 34.85 | 1,235 | 25.48 | 4 | .88 |
|
| 731 | 31.89 | 32,811 | 71.84 | 40,682 | 61.67 | 6,800 | 20.52 |
1The 1942-43 data represent incidence; it consists of newcases admitted for malaria and cases in which malaria appeared as a secondarydiagnosis. The 1944-45 data are in terms of total malaria attacks, which iscomprised of cases readmitted for malaria as well as new primary and secondarycases.
2No troop strength present in the theater before November 1942.
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attacks which include readmissions as well as new cases. Thestatistics enumerate the malaria attacks as they were diagnosed and reportedcurrently and regularly on the statistical health report and may includetentative diagnoses. Such data therefore do not tally identically with thosederived from statistical tabulations of individual medical records which arebased on final diagnoses. However, they do provide a general basis forepidemiological description of malaria in the Mediterranean theater during WorldWar II. The average length of hospitalization for this disease in 1943 was afraction less than 17 days, representing a total of about 425,000 man-days lostduring the year or the equivalent of the effectiveness of an entire divisionlost for a month. In 1944 the average period of hospitalization was reduced to11.8 days but the number of man-days lost for the year was 519,000. In theaverage hospital, malaria represented 4 to 5 percent of all hospital admissions.
The geographic distribution of the cases broken down intoclinical types is shown in table 67. This table shows only 22,936 cases andrepresents the total experience of 32 hospitals of all types during their entireperiod of operation in NATOUSA (North African Theater of Operations, U.S. Army)to August 1944. Table 68 shows the incidence of clinical types for the remainderof 1944 and about half of 1945, when the bulk of our troops were in Italy.
In the Sicilian campaign (9 July to 17 August 1943), the lossin fighting effectiveness in the Allied armies was equivalent to two infantrydivisions and exceeded the total number of battle casualties by 20 percent. Alarge number of men also developed the disease while in training in areas oftroop concentration in North Africa and were unable to participate in theinvasion. The number of troops thus affected was well over a thousand.
The malaria of Sicilian origin made its appearance in theSeventh U.S. Army and British Eighth Army after 7 August 1943 and reached apeak a week later. The rates for these two armies were 425.43 and 420.39, respec-
Area | Vivax (tertian) malaria | Falciparum (estivo- | Malariae (quartan) malaria | Mixed-type malaria | Unclassified malaria | Clinical malaria | Total | Percent |
Africa | 7,068 | 1,221 | 94 | 15 | 505 | 983 | 9,886 | 43.1 |
Italy | 7,737 | 507 | 19 | 5 | 449 | 1,329 | 10,046 | 43.8 |
Sicily | 2,428 | 340 | --- | 32 | 17 | --- | 2,817 | 12.3 |
Other areas1 | 174 | 11 | 2 | --- | --- | --- | 187 | .8 |
|
| 17,407 | 2,079 | 115 | 52 | 971 | 2,312 | 22,936 | 100.0 |
Percent of total | 75.9 | 9.1 | 0.5 | 0.2 | 4.2 | 10.1 |
| 100.0 |
1Pantelleria, France, Corsica, and Sardinia.
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Period | Vivax | Falciparum malaria | Quartan |
| Clinical | Total | |||||
| Old | New | Old | New | Old | New | Old | New | Old | ||
15 Sept.-27 Oct. | 1,541 | 762 | 76 | 8 | 1 | 2 | 63 | 37 | 112 | 28 | 2,630 |
28 Oct.-8 Dec. | 1,042 | 824 | 448 | 5 | 2 | --- | 18 | 15 | 152 | 56 | 2,162 |
9 Dec.-12 Jan. | 414 | 551 | 15 | 7 | --- | --- | 3 | 8 | 75 | 46 | 1,119 |
13 Jan.-2 Feb. | 185 | 304 | 4 | 4 | --- | --- | --- | 9 | 12 | 23 | 541 |
3 Feb.-2 Mar. | 190 | 444 | 1 | 3 | 1 | 1 | 1 | 7 | 22 | 22 | 692 |
3 Mar.-30 Mar. | 257 | 442 | 2 | 2 | --- | --- | 3 | 4 | 18 | 25 | 753 |
31 Mar.-27 Apr. | 329 | 434 | 2 | --- | 2 | 1 | 4 | 5 | 53 | 51 | 881 |
28 Apr.-11 May | 256 | 281 | 1 | --- | --- | --- | 6 | 6 | 14 | 23 | 587 |
|
| 4,214 | 4,042 | 149 | 29 | 6 | 4 | 98 | 91 | 458 | 274 |
|
|
| 178 | 10 | 189 | 732 | 9,365 | |||||
Percent of total | 88.2 | 1.9 | 0.1 | 2.0 | 7.8 | 100.0 | |||||
tively, although in some divisions they were much higher. The incidence inthe entire campaign would approximate 400 per 1,000 per annum. Later, strictcontrol measures were adopted. The rates dropped steadily, but it was not somuch the control measures that were responsible for the drop in the malarialrates in Sicily in the fall of 1943 as it was the removal of troops fromhypermalarious areas and the fact that it was fall of the year.
Several explanatory remarks should be made in referring to table 66: In 1943,the highest rates occurred during the summer months when they were expected. InOctober 1943, when the bulk of U.S. troops were in North Africa, there was arise in the rate which was also expected because of the September rains, butthis rise did not appear in 1944 when the greater part of U.S. troops were inItaly. The increase in malaria noted in 1943 cannot be attributed to conditionsin North Africa. It resulted from conditions existing on the Salerno beachheadduring September and had its origin in the sharp increase in cases of malaria inthe Fifth U.S. Army during that period. The rates in the winter of 1943 and 1944were relatively high during the season when few if any primary cases occur andare explained by the relapses of primary infections incurred during the summerand early fall of 1943. The withdrawal of Atabrine suppressive treatment fromNovember 1943 to May 1944 undoubtedly played an important role in these rates.In 1943, the FUO rate was twice as high as that in 1944 because, for variousreasons, the effort to make laboratory diagnoses in that year was not as great.
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In the summer of 1944, the FUO rate was noticeably high. Thiscan be accounted for in part by the high incidence of pappataci fever from Julythrough September. Many medical officers were unfamiliar with this disease anddiagnosed such cases as fever of undetermined origin.
The relatively high rate in August and September 1944,however, has another explanation. For several months prior to the invasion ofsouthern France (15 August), three divisions that had been withdrawn from theFifth U.S. Army and assigned to the Seventh U.S. Army were staged and trained ina malarial area near Naples. These divisions, classed as noncombat troops, hadmalarial rates of 130 to 140 per 1,000 per annum while in training.
Hospitalization
Medical battalions-Through the usual channels of evacuation, a sick soldier reached the clearing station by way of the battalion aid station and the collecting station. At each of these, the need for hospitalization and treatment was evaluated. When the need was recognized, the patient was evacuated to the next medical echelon. Thus, he usually reached the evacuation hospital from the clearing station. At the collecting and clearing stations, facilities for making the diagnosis of malaria on other than clinical grounds were not often available so that the patient ordinarily left the clearing station with a diagnosis of fever of undetermined origin or, occasionally, suspected malaria, without having had specific treatment. Under exceptional circumstances when the military requirement for manpower was pressing, a diagnosis of clinical malaria might be made by the surgeon at the collecting station on the basis of a recent previous attack of malaria, a typical history, and a palpable spleen. If the soldier was only mildly ill, the surgeon might return him to his unit with instructions to remain at rest in his tent for several days, and standard Atabrine treatment was administered under the close supervision of a company aidman. Although this method of management left much to be desired, it resulted in the saving of many man-days that would ordinarily have been lost through evacuation, hospitalization, and the process of return to unit.
Evacuation hospitals-Thistype of hospital was the firststop in the chain of evacuation where adequate facilities existed for making alaboratory diagnosis of malaria. These hospitals used the same diagnosticmethods as employed in the fixed hospitals of rear echelons-namely, repeatedthick smears. (The 15th Evacuation Hospital took three thick and thin smears forroutine examination and if these were negative, a fourth was taken 2 hours afterthe subcutaneous injection of 0.5 cc. of Adrenalin 1: 1,000. If the smearfollowing Adrenalin was negative, the diagnosis of clinical malaria was madeonly if there was a history of recent malaria, a typical clinical picture, and apalpable spleen.) As a result of such careful methods of examination, often doneunder highly adverse conditions, the diagnosis of clinical malaria was not oftenmade in evacuation hospitals.
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Evacuation policies varied widely from time to time and were influenced by(1) the anticipated need for beds, (2) the experience of the corps, army, orbase section surgeon, and (3) the professional intelligence of the medicalofficer who was directly responsible for the administrative phases ofevacuation. During the Sicilian campaign of 1943, hundreds of patients sufferingfrom malaria were evacuated from the II Corps area to North Africa becausesufficient beds for their care were not available, owing to the fact that theSeventh U.S. Army broke away from its prepared plan of providing hospitalizationand did not call for all of their large evacuation hospitals until after thecampaign was over. In the fall and early winter of 1943, hundreds of patientsill with malaria were evacuated to hospitals in the Peninsular Base Sectionbecause beds for their care were not considered to be available in the FifthU.S. Army area, although data on the bed status during that period show thatrarely after 1 November were there less than 1,500 usable beds in the Fifth U.S.Army area and that generally the figure for empty beds was much greater. Withexperience, fewer and fewer malarial patients were evacuated. Much unnecessaryevacuation of malarial patients with a resultant loss of manpower occurred-bothin forward and in rear areas-because many administrative officers in charge ofevacuation looked upon patients as "bodies" occupying space withoutreference to their disease and their ability to return to their units promptly.
When patients were evacuated, they were moved by air, rail, ship, orambulance to the next echelon hospital, usually the general hospital, althoughin certain instances they might be sent to a station hospital.
General hospitals-By the time the malarial patient reached the generalhospital, diagnosis had usually been made and treatment started. When the courseof treatment was completed, the patient was given such reconditioning as hemight require and was then returned to his unit by way of the replacement depot.Most general hospitals made the diagnosis of clinical malaria only in veryexceptional circumstances, although they concurred in such a transfer diagnosiswhen the patient had already been under treatment. When this diagnosis was madeinitially in these hospitals, it was usually in cases in which, although thicksmears were negative, the patient's condition required prompt treatment and hisresponse to specific treatment was typical.
Under certain circumstances, general hospitals received patients directlyfrom command by way of a dispensary. When malaria was suspected in these cases,every effort was expended to make a laboratory diagnosis. At the 12th GeneralHospital, when the combination of leukopenia, qualitative changes in thelymphocytes of the peripheral blood, and reticulocytosis was found, repeatedthick smears were taken without further request from the ward officer.
Another source of admission was in transfers from station hospitals fromwhich the patients were sent as problems in disposition.
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It was only in the last half of 1944 that hospitals in this theaterreclassified soldiers to limited assignment because of malaria. Thisreclassification, made but rarely, was usually applied to a combat individualwho had been relatively noneffective because of repeated hospitalizationswithout, however, meeting the criteria for evacuation to the Zone of Interior.Frequently, letters from unit medical officers requesting reclassificationaccompanied the soldier to the hospital. The purpose was to permit the combatunit to get a more effective replacement and to move the patient to anenvironment where he was less likely to relapse and could still be of some useto the service.
The theater policy for reclassification to class C (return tothe United States) for malarial patients was set forth in Circular Letter No.21, Office of the Surgeon, Headquarters, NATOUSA, dated 3 April 1944. Thecriteria for this classification were cachexia, repeated attacks with persistentsplenomegaly, refractory anemia, repeated attacks of cerebral malaria, andblackwater fever. This policy did not envisage evacuation to the Zone ofInterior for repeated attacks per se. Approximately 1 percent of patients withmalaria eventually were sent to the United States for this cause. A review ofthe records of several general hospitals revealed the following additionalcauses for C classification:
1. Chronic cachexia with or without persistent splenomegalyand anemia in a patient who had lost 3 months or more from duty in 1 yearbecause of malaria.
2. Proved intolerance to both Atabrine and quinine.
3. Treatment-resistant parasitemia.
4. Psychosis following falciparum infections.
5. Repeated attacks of falciparum malaria.
Station hospitals-These hospitals were not normally in the chain ofevacuation and for the most part received their patients directly from commandby way of dispensaries, although during periods of peak evacuation, the stationhospital might supplement the bed capacity of general hospitals. Many cases hada laboratory diagnosis made in the referring dispensary, and when the report ofthe smear accompanied the patient it was accepted without verification. Othercases arrived with the diagnosis of fever of undetermined origin. Diagnosticmethods then employed were the same as those used in the general hospitals, anda diagnosis of clinical malaria was rarely made. For example, in one stationhospital, it was resorted to only seven times in more than 800 malariaadmissions, and in 6 of these cases, it was the transfer diagnosis of patientsalready under specific treatment. Treatment methods and criteria forreclassification to limited assignment were the same as those employed ingeneral hospitals. When it was felt that a malaria patient should be evacuatedto the Zone of Interior, he was transferred to a general hospital fordisposition.
Duration of hospitalization-From the Machine Records Unit, Allied ForceHeadquarters, it was determined that the overall average period of
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hospitalization for 6,078 cases of malaria in the 8-monthperiod between September 1944 and May 1945 was 14.5 days. This average appliedonly to cases discharged to general military duty and did not includereclassified cases or cases disposed of by transfer to other hospitals. Whencalculated for type of hospital the following averages were obtained: (1) Fieldand evacuation hospitals, 10.4 days; (2) station hospitals, 13.9 days; and (3)general hospitals, 22.6 days.
Laboratory procedures-In the early days of this theater, the diagnosis"clinical malaria" was made more often than was necessary. Clinicianshad no hesitancy in ascribing responsibility for this to the inexperience oflaboratory technicians which was undoubtedly a factor, but clinicians shouldnot forget that their own unfamiliarity with the disease was as large a factor,if not larger. After more than 2 years of rich experience with malaria, mosthospital clinicians and technicians had become thoroughly acquainted with it.These two groups were mutually helpful in the quest for knowledge of thisdisease, and certainly much credit for this happy state of affairs can beascribed to those officers in high echelons of the theater who waged arelentless war against the diagnosis of "clinical malaria."Subsequently, hospital medical officers almost without exception proudly claimedthat they rarely if ever made the unsupported diagnosis and they staunchlydefended their own technicians as experts in parasite identification. And,indeed, the rank and file of laboratory technicians in the theater had becomehighly efficient parasitologists; for this, due credit must be given to thetraining courses for technicians conducted by the malariologists.
A note on technique may not be amiss. All hospitals agreed that a thick-dropblood film was indispensible. In 17 of 20 hospitals visited, thick-dropexamination was routine, and several of these hospitals had dispensed with thethin smear entirely, maintaining they could identify the species satisfactorilyon the thick drop. In the other three hospitals, the thin smear was examinedfirst, and if negative, the thick drop was examined. The purpose was to savetime in diagnosis, but in Italy, where the ratio of P. vivax to P. falciparumwas about 46:1, perhaps such urgency was unwarranted.
For routine work, more than one-third of the hospitalspreferred Field's stain, prepared fresh each week, kept cold, and filtered atleast twice weekly. Other hospitals invariably used Giemsa stain in preferenceto Wright's stain.
Many studies were carried out in the laboratories of Army hospitals, whichhave been described in detail elsewhere (p. 489). Here it may be noted, thatcertain characteristics formerly though to be limited to falciparum infectionswere not uncommonly found with P. vivax; in particular, double-cell infections,double-chromatin dots, and marginal rings.
Treatment
Theater directives-The history of the treatment of malaria in this theater properly begins with Circular Letter No. 6, Office of the Surgeon,
510
Headquarters, NATOUSA, dated 10 April 1943, in which the QAP (quinine-Atabrine-Plasmochin)treatment is recommended; that is, quinine 0.67 gm. three times a day for 2 or 3days to control parasitemia, followed by Atabrine 0.1 gm. three times a day for5 days followed by a 2-day rest period, and then 0.1 gm. of Plasmochin two orthree times a day for 5 days. Circular Letter No. 32, Office of the Surgeon,Headquarters, NATOUSA, 3 September 1943, amended Circular Letter No. 6,eliminating Plasmochin from the schedule and also recommending, as analternative, Atabrine alone, 0.2 gm. three times a day for 5 days. Finally, on14 September 1943, Circular Letter No. 34, Office of the Surgeon, Headquarters,NATOUSA, advocated the Atabrine schedule: 0.2 gm. of the drug every 6 hours forfive doses followed by 0.1 gm. three times a day for 6 days. Circular Letter No.10, Office of the Surgeon, Headquarters, NATOUSA, dated 15 February 1944,recommended that for third and subsequent relapses quinine be used in a dosageof 1.0 gm. three times a day for 3 days and then 0.3 gm. three times a day for10 days. Circular Letter No. 41, Office of the Surgeon, Headquarters, NATOUSA,dated 29 July 1944, rescinded Circular Letter No. 10 in view of the fact thatthe use of quinine in the therapy of relapsing malaria had shown no advantagesover the use of Atabrine.
Atabrine-This therapeutic Atabrine dosage scheme was found to be safe,effective, and productive of results equally as good as those obtained withquinine. Formerly, it had been observed that Atabrine did not effect atemperature drop as promptly as did quinine. At that time, it was not thepractice to administer loading doses of Atabrine during the first day or two oftreatment. This objection was largely eliminated after it was found that theplasma concentration of the drug was a measure of its therapeutic effectivenessand that effective levels were more rapidly attained when larger doses weregiven at the start of a therapeutic regimen.
It was the experience of all the medical officers of the Mediterraneantheater that many soldiers said they were intolerant of Atabrine, but when thedrug was given in either suppressive or therapeutic doses, no such intolerancewas demonstrated. Toxic reactions from therapeutic Atabrine were extremely rare.There were probably few if any medical officers in this theater who were notfinally convinced that Atabrine was at least as effective and safe as quinine.This attitude represented a complete reversal of opinion within 2 years and, assuch, was an eloquent testimonial to the value of the drug. When Atabrine wasintroduced as a suppressant in doses of 0.2 gm. twice weekly 2 years before,there was such an explosive outbreak of gastrointestinal symptoms that the drugfell into some measure of disrepute. Medical officers were wary and suspiciousof it, and only its continued use at the insistence of higher authority servedto dispel these fears. A few officers still remained somewhat reluctant toaccept Atabrine as the drug of choice. They were mainly physicians who hadbecome thoroughly indoctrinated with the virtues of quinine when it was the onlyefficient antimalarial available.
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The chief remaining differences of opinion regarding theeffectiveness of the two drugs were concerned with the speed of action inbringing the temperature into the normal zone. When Atabrine was given asdirected in Circular Letter No. 34 and quinine as directed in Circular LetterNo. 10, many officers thought that quinine brought the temperature to normal 24to 48 hours sooner than did Atabrine and that in most cases patients did nothave another chill after quinine was started, whereas most had one additionalparoxysm after Atabrine. A smaller group of officers could observe no differencein this respect between the two drugs, and a small minority thought thatAtabrine produced faster results. Obviously, these differences of opinion werelargely due to the fact that they were based upon clinical impressions. The onlyfactual data on the subject were gathered by Capt. (later Maj.) Franklin K.Paddock, MC, of the 33d General Hospital on 28 cases treated with quinine and 24cases treated with Atabrine, in such dosage as has been described. His resultsare summarized in table 69 and show that there was little difference between thetwo drugs.
Duration of fever (days) |
| Atabrine | ||
| Percent | Number | Percent | |
1 | 14 | 85.7 | 24 | 100.0 |
2 | 21 | 75.0 | 22 | 91.7 |
3 | 13 | 46.4 | 7 | 29.2 |
4 | 2 | 7.1 | 2 | 8.3 |
In many hospitals, 0.4 gm. Atabrine by intramuscularinjection was substituted for the initial dose of 0.2 gm. Atabrine givenorally. Officers who used this modification of the routine plan wereenthusiastic over the results. There were no toxic effects; temperatures fell tonormal within 24 hours; there was no secondary rise in temperature and noadditional paroxysms; and convalescence was quicker. Several other hospitalsinitiated treatment with 0.2 gm. given intramuscularly. The results were not asgood as with the larger dose. The 118th Station Hospital gave 0.4 gm. Atabrineorally in one dose and followed it with 0.1 gm. three times daily. Results weresaid to be comparable with those obtained from the larger of the doses givenintramuscularly.
Plasmochin-The drug was dropped from the therapeuticarmamentarium early because no peculiarly beneficial effect was ascribed to itand because of the narrow margin of safety between therapeutic and toxic doses.
Quinine-For reasons of supply, its use was limited. Patients wereoccasionally seen who failed to respond to quinine given orally and in whom no
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trace of the drug could be found in the urine. In certain types of cases, itwas freely used intravenously, in all instances well diluted and given slowly.Circular letters directed that quinine should be administered in at least 300cc. of normal saline or glucose and saline. Reactions other than mild cinchonismwere not seen. In cerebral malaria, this was the routine method of treatment. Itwas usually given in infections with P. falciparum when patients werevomiting. One hospital gave at least one dose of quinine intravenously in all falciparum infections. The dose employed was almost invariably 10 gr., and itwas repeated at 6- to 8-hour intervals when necessary.
Sulfonamides.-Occasionally,a misdiagnosed case of malaria was treated with one of the sulfonamidedrugs. It was observed that the drug, usually sulfadiazine, did suppressclinical symptoms and parasitemia. A few reports were received indicating thatsulfadiazine in full therapeutic doses might possess some merit in the treatmentof falciparum gametocytemia resistant to Atabrine and quinine.
Sontoquine-A limited supply of Sontoquine bisulfate and Sontoquinenaphtholate was received in the theater and divided between the 225th and 182dStation Hospitals. It was planned that each hospital should treat equal numbersof malaria cases with each of the two drugs and that a third group should betreated with Atabrine for comparison. Unfortunately, the experiments wereundertaken at a season when the malaria rate was the lowest in theater history,and during the period of study both hospitals were moved to other locations inItaly. Consequently, a total of only 14 cases were studied in the two hospitals.Of these, eight patients received Sontoquine and six patients received Atabrine.The dose of all three drugs was 0.2 gm. every 6 hours for five doses and then0.1 gm. three times a day for 6 days. There was no difference noted between thetwo salts of Sontoquine and no difference between these drugs and Atabrine.Temperatures returned to normal and blood smears were negative within 48 hoursin the patients treated with Sontoquine and in all but one of the patientstreated with Atabrine. This one patient had fever and positive smears until thefifth day of treatment. No sign or symptom of intolerance to Sontoquine wasnoted, and repeated blood counts and urinalyses failed to show any ill effectswhatsoever. It was planned to continue this study.
Iron.-Routine use of iron in all cases of malaria in some hospitals wasthought to speed convalescence.
Other measures-Intravenous glucose and saline were freely used to combatdehydration. In vivax cases with vomiting, the fluids often seemed to allay thissymptom so that patients could retain oral therapy. One hospital reported that asingle dose of morphine had a similar effect.
In patients gravely ill with falciparum infections, repeatedinfusions of plasma and whole blood were frequently employed. Several medicalofficers felt that these measures were frequently lifesaving.
513
Treatment To Reduce Relapse Rate
Throughout the entire history of the theater, officers were searching for atherapeutic regimen that would reduce the relapse rate in vivax infections. The7th Station Hospital reported that relapse after Atabrine treatment appeared tobe considerably delayed and that recurrence frequently followed quininetreatment within a matter of days or weeks.
Many different dosage schedules and combinations of Atabrine, quinine, andPlasmochin were used in the various hospitals and some of these programsrequired weeks of hospitalization. The criticism common to all of these studieswas that they were done in only a very small series of cases; they were notcontrolled, and followup studies were either inadequate or completely lacking.It is perhaps significant that not a single officer was found who had any faithwhatsoever in any of these or other plans of treatment designed to preventrelapses. For the sake of interest and completeness, several of these plans willbe noted.
One hospital supplemented routine Atabrine or quinine treatment with amodified Ascoli treatment plan. Adrenalin was given intravenously in graduateddoses beginning with 0.01 mg. and increasing to 0.1 mg. or to tolerance. Eightpatients received this treatment daily for 15 days and four received it twicedaily for 10 days.
Another hospital gave quinine intravenously with Adrenalin three times dailyfor 7 days. Another hospital gave 0.2 gm. Atabrine every 6 hoursintramuscularly followed by 0.2 gm. twice daily by the same route for 6 days.The local effects were said to have been disagreeable.
Still another hospital gave a routine course of quininefollowed by a routine course of Atabrine followed by four weekly doses ofMapharsen. Another hospital gave a routine course of Atabrine, followed by aroutine course of quinine, followed by a routine course of Atabrine. On thefirst day of treatment the patient received 0.4 gm. bismuth subsalicylate,intramuscularly, and on the 7th, 14th, and 21st days, 0.2 gm. In addition hereceived 60 mg. of Mapharsen twice weekly for six doses.
In many of the above instances patients relapsed within a month or two aftercompletion of treatment.
Capt. (later Maj.) John C. Ransmeier, MC, of the300thGeneral Hospital treated three cases of relapsing vivax malaria with Fuadin(stibophen) (one with quinine as well, two with Fuadin only) reasoning that itspenetration into the cells of the reticuloendothelial system might beeffective. One patient received 6 daily doses of 5 cc. intramuscularly, another10 cc. doses daily, and the third 10 doses of 5 cc. each at 24-to 48-hourintervals. The patient who received quinine as well was followed for only 1month, during which he was well. In the second patient, the temperaturebecame normal within 48 hours and parasites disappeared from the peripheralblood within 96 hours. He relapsed on the 13th day after completing treatment.The third patient became afebrile within 72 hours. At the conclusion oftreatment parasites were absent from the peripheral blood for only 72 hours.Clinical relapse occurred in the ninth posttreatment day. Mild neutropenia wasobserved in all three cases.
As a result of experiences such as those cited, few medical officers in thistheater believed that current methods of treatment could do more than suppresssymptoms and parasitemia in vivax malaria. In another theater, prolongedexperience suggested that Atabrine therapy not only was effective in
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suppressing relapsing malaria but, if continued long enough,might ultimately cure it (p. 497). There is no indication in Colonel Golz'sreport that such consistently long-sustained therapy was ever carried through inthe Mediterranean theater where, indeed, conditions were lacking for suchcontinuous observations on identical groups of men as were possible in thePacific area. The desideratum was a method of treatment that would obviaterelapses. The British thought they had achieved this goal, or come near it, bytheir use of Plasmochin in conjunction with quinine. U.S. Army medical officershad early discarded Plasmochin, finding it of no particular merit as used bythem, and very toxic, especially in Negro troops. Our achievement was rather inthe increasingly more efficient use of Atabrine. Both lines of thought werefruitful and, during and since World War II, have been carried to more effectivetherapy and new drugs.
Results of Treatment
Mortality-One measure of the effectiveness of treatment is the deathrate which in the Mediterranean, as in all theaters, was extraordinarily low. Inthe entire history of the theater, there were approximately 62,000 definitelydiagnosed new cases of malaria in U.S. Army troops. According to individualmedical records for 1942-45, there were 57 deaths due to malaria among casesoriginating in the Mediterranean theater. There were 3 deaths in 1942, 40 in1943, 13 in 1944, and 1 in 1945. After an extensive search, Colonel Golzdiscovered only 11 deaths that actually occurred in the Mediterranean theater.Of 8 deaths ascribed to malaria on clinical grounds in official records for1944, post mortem studies showed that death was due to other causes in 5 (1Hodgkin's disease, 1 brain tumor, 1 infectious hepatitis, 1 hemorrhagicbronchopneumonia, and 1 "cause undetermined but not malaria"). By anycalculation, the mortality was surprisingly low.
There are several reasons for this. Table 67 shows that in Italy theincidence of infection caused by P. falciparum was low. Other factors wereAtabrine suppressive treatment (curing many falciparum infections) and theexcellent distribution and the high caliber of medical care available to U.S.troops.
Morbidity-The malaria relapse rate was 28 percent in the Mediterraneantheater and 23 percent in the Pacific areas. These figures are gross figures inthat they have not been adjusted to take into account evacuation, death, ortransfer of cases. The figures merely reflect a ratio of readmissions to newadmissions.
Several attempts were made to assay the dimensions of the problem by indirectmeans. Colonel Golz, on the basis of data shown in tables 70 and 71, concludedby one line of reasoning that, of any group of primary malaria cases, 30.6percent might be expected to relapse at least once, with the average number ofrelapses being 2.08 for the group. He also cited Lt. Col. (later
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Col.) James B. McLester, MC, of the 17th General Hospital who, using the samedata and some of his own, made a somewhat different approach. Of a group ofcases followed from 1 to 10 months, 30.5 percent relapsed. Over one-half of therelapses during the first 9 months occurred in the first 2 months and anotherquarter, in the next 2 months. Since after 6 months, the monthly rate remainedbetween 1 and 2 percent, it seemed probable that the relapse rate would be foundto be between 50 and 60 percent if the followup were more complete and continuedlonger. Other data, more extensive numerically, derived from 27 hospitals byquestionnaire by the malariologist of NATOUSA, suggested, by several lines ofreasoning, a relapse rate of about 50 to 55 percent.
Number and type of hospitals reporting |
| Relapses | Total | ||
| Percent | Number | Percent | ||
1 field | 33 | 11.3 | 258 | 88.7 | 291 |
1 evacuation | 1,525 | 83.5 | 301 | 16.5 | 1,826 |
2 convalescent | 55 | 34.0 | 107 | 66.0 | 162 |
16 station | 5,467 | 61.1 | 3,479 | 38.9 | 8,946 |
7 general | 1,492 | 49.6 | 1,516 | 50.4 | 3,008 |
|
| 8,572 | 60.2 | 5,661 | 39.8 | 14,233 |
Number and types of hospitals reporting1 |
| Total cases | ||||||||||
1 | 2 |
| 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | ||
1 evacuation | 184 | 36 | 28 | 29 | 9 | 4 | 7 | 0 | 2 | 2 | 0 | 301 |
1 convalescent | 14 | 15 | 14 | 4 | 3 | 0 | 1 | 2 | 0 | 0 | 0 | 53 |
10 station | 934 | 496 | 267 | 137 | 69 | 32 | 21 | 15 | 6 | 3 | 4 | 1,984 |
6 general | 553 | 230 | 126 | 97 | 57 | 43 | 40 | 14 | 8 | 2 | 4 | 1,174 |
|
| 1,685 | 777 | 435 | 267 | 138 | 79 | 69 | 31 | 16 | 7 | 8 | 3,512 |
Percent of total | 48.0 | 22.1 | 12.4 | 7.6 | 3.9 | 2.2 | 2.0 | 0.9 | 0.5 | 0.2 | 0.2 | 100 |
1Data not available from field hospitals.
Colonel McLester stressed the obstacles to statistical accuracy. In theMediterranean theater, the number and composition of troops were constantlychanging with the tactical situation, and the population at the time of recurrence might be very different in size from the population at the time of pri-
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mary attack. Fresh troops might come in who had notpreviously been exposed to malaria and might have time for only one attack.Soldiers who had had a primary attack might be evacuated, or killed, ortransferred to another theater before relapse could develop. Furthermore, in anattempted followup of patients who had been treated in the 17th GeneralHospital, gross errors were found in their medical histories. Also, the recordwas regarded with suspicion when a patient, known to have had an attack with P.falciparum, was reported as having relapse with P. vivax.5
Table 72 will show that the percentage of cases transferred to the Zone ofInterior is not a valid figure for the malaria question as a whole. Many of theadmissions to general hospitals were transferred from other hospitals, and withfew exceptions only general hospitals had the power to transfer cases to theZone of Interior.
Many of the cases found in general hospitals had beentransferred there by other hospitals specifically for Zone of Interiordisposition because of repeated recurrences. Nevertheless, a study wasundertaken at the 182d Station Hospital to determine the final disposition ofits malaria cases: 757 cases were investigated, of which 437 were recurrent and320 were primary. Of these, 103 cases were transferred to other hospitals forreasons other than malaria and could not be traced as to disposition. Of theremaining 654, those who were transferred were satisfactorily traced. The resultof this study showed that 641 went to general military service, 5 went tolimited assignment, and 8 (1.22 percent) were recommended for evacuation to theZone of Interior by a general hospital.
| Total cases | Number evacuated | Percent |
18 station | 10,604 | 28 | 0.26 |
7 general | 3,185 | 250 | 7.85 |
|
| 13,789 | 278 | 2.02 |
5Although complete and accurate statistics on the incidenceof relapse are not available from any theater, similar relapse rates forMediterranean strains (approximately 30 percent) were found elsewhere inthis theater and also in the Zone of Interior during periods of 120 daysfollowing treatment with various antimalarials. Relapse rates were much higherwith Pacific strains during like observation periods of 120 days, beingapproximately 80 percent in one study and 80 to 90 percent in another. It shouldbe noted, however, that a very much higher percentage of relapses of Pacificorigin will fall within the 120-day period (75 percent occurring within thefirst 60 days in one study). With the Mediterranean strains, there is a longeraverage interval to the first relapse (150 to 200 days). Even when this is takeninto account, the estimated rate of 50 to 60 percent remains appreciably lowerfor the Mediterranean strains of P. vivax.
Modifications of relapse rates by the treatment preceding the observationperiods were not such as to invalidate these calculations, except whenPlasmochin was used in conjunction with quinine. In extensive comparisons, themajority of relapses occurred within the first month after treatment withquinine or totaquine and within 3 months after quinacrine or chloroquine; thatis, well within the span of 120 days.-P. H. L.
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Machine records data concerning cases sent to the Zone ofInterior are available for the period 15 September 1944 to 6 April 1945. Duringthis time, 8,055 cases of malaria were disposed of and, of these, 90 cases (1.1percent) were returned to the Zone of Interior for this cause. An additional 36cases were found with a secondary diagnosis and the available records were notclear as to which diagnosis was responsible for the evacuation. If these twogroups are combined, the total number of cases is 126 or 1.6 percent.
Case Histories
In the 13 case histories6 which follow, examples ofparticular problems-most of them exceptional, some moretypical-are describedbriefly. Included are eight fatalities.
Skin lesions
Herpes labialis occurred in some cases, and occasionallyurticaria, which was usually transitory. Urticaria had been seen more often inthe early days of the theater, when quinine therapy was still popular. ColonelGolz reported an interesting case, summarized in case 1. Four hospitalsreported seven cases of purpura simplex, beginning shortly after orconcomitantly with the clinical onset, and clearing completely soon after thestart of antimalarial treatment; in four cases this was associated with vivaxinfections, in three, with falciparum infections. One hospital reported 10cases of erythema multiforme.
Case 1- In one unusual case, the maturation of each cycleof parasites was accompanied by a severe attack of generalized urticaria andangioneurotic edema of about 12 hours' duration. These attacks occurred threetimes at 48-hour intervals without any sign or symptom to suggest malaria. Therewas no elevation of temperature. With the fourth such attack the patient had hisfirst chill and rise in temperature. P. vivax was found in his blood. Atabrinetreatment resulted in prompt cessation of his hives and he had no further chillor fever. During the 4 months following his discharge from the 182d StationHospital he had five relapses for which he was admitted to other hospitals, andin each relapse the same train of events occurred. He was then evacuated to theZone of Interior.
Blackwater fever
Four cases were reported in the Mediterranean theater. Caseabstracts of two of these patients are appended, one of whom died. Availabledata on the third patient were so meager as to raise the question of diagnosticaccuracy. Records of the fourth were not available.
Case 2.-The soldier was admitted to the 33d General Hospital with a historyof chills, jaundice, and dark urine for 4 days. The record did not state whetherhe had previously had malaria. Prior to admission he had no treatment. On theday of admission he was stuporous and icteric but malaria smears were negativeand the leukocyte count
6In another theater, however, under more favorable conditions forprolongedobservations on the same body of men, there was shown a reversal of speciesincidence from 55 percent P. falciparum, 24 percent P. vivax during an epidemicin a malarious environment, to zero percent P. falciparum, 99 percent P.vivax,after the troops were removed to a nonmalarious environment.-P. H. L.
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was 4,700. On the second hospital day trophozoites of P.falciparum were found in the blood. The urine was negative except for a trace ofalbumin. On the second and third days he was given 2.7 gm. of quinine orally and1.3 gm. intravenously. On the third day the red blood cell count was 4,330,000,the hemoglobin 13.0 gm., and the leukocyte count 5,300. On the fourth day theurine became reddish brown in color, showed 3+ albumin and was positive to testfor occult blood. The red blood cell count had dropped to 3,060,000 and thehemoglobin to 11.5 gm. per 100 cc. Trophozoites of P. falciparum were stillpresent in the blood. The blood nonprotein nitrogen was 37.5 mg. percent and theicteric index, 9 units. Quinine treatment was stopped; Atabrine, given orally,was started cautiously; and the patient was given a transfusion of 500 cc. ofwhole blood. On the fifth day he was much improved; the urine was negative; thered blood cell count, 3,780,000; the hemoglobin, 12.0 gm. per 100 cc.; andgametocytes of P. falciparum were present on blood smear. The Atabrine dosagewas then increased. Thereafter the course on full doses of Atabrine wasuneventful. The urine remained normal although the anemia persisted at a levelof about 3,500,000 red cells per cu. mm. Gametocytes of P. falciparum were found on the smear dailyuntil the day after Atabrine was stopped.
Case 3.-A 32-year-old soldier was admitted to a station hospital in August1943 complaining of chills, fever, and general malaise for 4 days. He statedthat he had had malaria several years previously in the United States. He alsostated that he had been taking Atabrine in suppressive doses regularly. Physicalexamination revealed nothing of note. Blood smear was positive for P. falciparum.He was given 10 gr. of quinine three times daily by mouth. On the second day hisgeneral condition had deteriorated and quinine was increased to four timesdaily. Physical and X-ray signs of bronchopneumonia developed on the third day.On the fourth day the urine became dark brown and gave a strongly positive testfor blood. The hemoglobin fell from 13.0 gm. in the morning to 10.5 gm. in the afternoon. The blood nonprotein nitrogen began to rise. Hewas given a transfusion of whole blood and an intravenous infusion of sodiumbicarbonate solution. This treatment was repeated on the fifth day. The course,however, had been progressively unfavorable and he died on the fifth hospitalday with a clinical diagnosis of blackwater fever. Autopsy confirmed the causeof death as malaria.
Vague symptomatology
Every hospital representative interviewed in this theaterreported occasionally seeing patients who complained of vague symptoms offatigue, headache, and malaise; whose temperatures remained perfectly normal,and whose blood smears were positive for vivax trophozoites. Asymptomaticcarriers of falciparum gametocytes were relatively more common. Not infrequentlymet were cases of proved malaria with recent histories of one or morehospitalizations for fever of undetermined origin, with spontaneous remission.It is highly probable that these previous febrile episodes were due to malarialactivity.
Case 4-A soldier without a previous history of malaria was admitted to astation hospital with the admitting diagnosis from his dispensary as "Vaguecomplaints-nervous." The hospital history indicated that hehad had a poor appetite, general malaise, and chilly sensations at night for aweek. During the first 24 hours in the hospital his temperature remained normaland he showed what were interpreted as signs of an anxiety neurosis. On theevening of the second day in the hospital, the patient had a chill, histemperature rose sharply and he became irrational, confused, and restless.Examination of the blood showed a marked anemia, leukocytosis of 14,000 and aheavy infestation of the red blood cells with P. falciparum. In spite of 5 gr.of quinine intra-
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venously every 6 hours and four whole blood transfusions of500 cc. each, his condition gradually deteriorated. He lapsed into coma on thethird hospital day and died on the fifth.
Fever
In approximately 75 percent of vivax infections, the typicalintermittent temperature graph with quotidian or tertian paroxysms was seen. Therelatively high percentage of remittent fever (25 percent) may beascribed to the prompt institution of specific treatment. The majority of falciparum infections exhibited remittent fever without frank paroxysms.
Some cases were without fever through all or a large part of their clinicalcourse.
Case 5-A soldier was admitted to a station hospital witha history of having had chills and fever, nausea and vomiting for a week. Onadmission jaundice was observed and the liver was palpated three fingerbreadthsbelow the costal margin. He was afebrile and malaria was not suspected. Twodays after admission the patient became stuporous. His red blood cell count was2,700,000, his leukocyte count 40,000, blood nonprotein nitrogen 99 mg. percent,and his blood smear was positive for P. falciparum. Despite vigorous treatmentwith oral and parenteral quinine, the patient died on the third hospital day,having remained afebrile throughout.
Liver and spleen
Hepatomegaly of mild degree was associated with malaria inabout 15 or 20 percent of cases. Minimal scleral icterus was seenin less than 5 percent and was thought to be an expression of the blooddestructive process that accompanies malaria. Definite jaundice wasoccasionally seen concurrently with malaria and was thought to be due tocomplicating infectious hepatitis. Definite jaundice due to malaria did occur inblackwater fever and moribund cases. The term "malarial hepatitis" wasfreely and glibly used in this theater, but no evidence was adduced to show thatsuch a condition existed. Pathologists found no parenchymal lesion; liverfunction tests showed only transitory changes, and enlargement of the liver wasusually only transitory.
The spleen was often found palpably enlarged during thesecond week of the acute attack. It was usually soft and tender in the acutestages, and was firm and not tender in the chronic stages. Reports from varioushospitals in this theater varied widely as to the incidence of palpable spleens.The acute splenic tumor usually subsided rapidly after antimalarial therapy.Persistent enlargement usually signified a chronic latent infection; many of thecases that had frequent relapses had a chronic splenomegaly. In one case, aruptured spleen was found at autopsy.
Case 6-A soldier was admitted to a station hospital in amoribund condition. He was reported to have fainted shortly before admission andon recovering consciousness complained of substernal pain and vomiting. Hedenied any injury. In the emergency room he showed extreme pallor, air hunger,and restlessness. His pulse was imperceptible. The abdomen was notdistended nor tender. A blood smear showed 4 percent parasitization of the redcells with P. vivax. Plasma was administered as an emergency measure, but thepatient ceased breathing while the plasma was being given. At autopsy theperitoneal cavity was found to be filled with blood and a 4 cm. tear was notedin
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the spleen. The pathological diagnosis was splenomegaly due to vivaxinfection, and spontaneous rupture of the spleen.
Gastrointestinal symptoms
Vomiting, occurring in about 20 percent of vivax infections,was usually not severe and was associated only with the paroxysms; in falciparuminfections, it tended to be more severe and persistent and was one of thefrequent indications of the cerebral syndrome.
Abdominal pain was very common. Most frequent was an achy pain high in theleft upper quadrant, sometimes radiating to the left lower chest and oftenaggravated by respiratory excursions. Infrequent cases were seen simulatingacute surgical emergencies. Two in which laparotomy was performed are described:
Case 7-A soldier was admitted to an evacuation hospital with a historysuggestive of a ruptured abdominal viscus. There was boardlike rigidity of theabdominal muscles, and the leukocyte count was 14,000. Exploratory laparotomyrevealed nothing abnormal. Subsequently P. falciparum was discovered in theperipheral blood. Antimalarial therapy produced complete recovery.
Case 8-A soldier was admitted to a station hospital witha diagnosis of acute appendicitis, having experienced 24 hours previously theonset of generalized cramping abdominal pain, which subsequently localized inthe right lower quadrant. There was nausea but no vomiting or disturbance ofbowel habit. There was no history of malaria. The temperature was 102.8? F. andthe leukocyte count 5,900. Marked tenderness was noted in the right lowerquadrant on direct palpation and on rectal examination. Emergency appendectomywas performed but a normal appendix was removed. The postoperative course for 2weeks was complicated by intermittent fever of 100? or 102? F. exhibiting atertian periodicity. (On one occasion he had a chill and a temperature rise to105? F.) Repeated malaria smears were negative. On the 19th postoperative day P.vivax was found. Antimalarial therapy resulted in disappearance of all signs andsymptoms.
Generalized aching or cramping abdominal pain was occasionally a complaint,especially in patients with diarrhea. It was usually of mild degree,occasionally more severe, and occurred in about 10 percent of infections with P.vivax. In malignant tertian malaria, diarrhea was not more common but was often more severe, at times dysenteric. The stools in such casessometimes contained red blood cells but never pus, parasites, or pathogenicbacteria. A brief description of a fatal case follows.
Case 9.-A 24-year-old soldier was admitted to a stationhospital in October 1943 complaining of severe diarrhea of 5 days' duration. Thediarrhea was accompanied by severe abdominal cramps and grossly bloody stools.He had had one chill prior to admission. There was no previous history ofmalaria but the soldier had fought through the Sicilian campaign several monthspreviously. On examination he was found to be in shock. The pulse was almostimperceptible, blood pressure was 70 systolic and 60 diastolic, and temperature97? F. The abdomen was rigid, leukocyte count was 25,000 and the red blood cellcount was below 3 million. The stools contained dark blood and blood smears werepositive for P. falciparum. The surgical consultant felt that there was noindication for surgical intervention. On the first hospital day he was given 10gr. of quinine intravenously, a transfusion of one liter of citrated blood andapparently adequate amounts of physiological saline solution intravenously. Oralquinine therapy
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was started. On the second day he was markedly improved.Diarrhea and vomiting ceased; temperature rose to 101? F. and the systolicblood pressure to 110. Oral quinine three times daily was continued. On thethird day he suddenly went into a state of peripheral circulatory collapse andpromptly died. Autopsy showed an extensive hemorrhagic enterocolitis. Malariaparasites were found in sections of the intestinal tract and the heart showednumerous areas of focal necrosis. No notable changes were found in the brain.
The cerebral syndrome
Of the 57 deaths due to malaria in the Mediterranean theaterduring 1942-45 (p. 514), 14 were ascribed to vivax malaria, 27 to falciparummalaria, and 16 to "other or unclassified malaria" (the "othermalaria" excluding quartan malaria and mixed malaria infections). In the 11deaths reported by Colonel Golz, 10 were due to malignant tertian malaria, andof these, 8 were caused by the cerebral form of the disease. All eight casesillustrated the grave danger attendant upon failure, for whatever cause, toinitiate vigorous treatment early.
Case 10-A soldier was admitted to an evacuation hospitalwith a history of chills and fever for 4 days. There was no past history ofmalaria. On the day before admission he had a temperature of 104.4? F.with pain in the left upper quadrant, and smears were positive for P.falciparum.He was given 0.2 gm. of Atabrine every 6 hours orally. On admission histemperature was 98.8? F. and his general condition seemed to be fair. Bloodcounts showed a marked anemia and smears showed all stages of P. falciparum.Spinal fluid was negative except for increased pressure. On the second hospitalday he suddenly became stuporous, psychotic, and could not be aroused. There wasonly a slight pupillary reaction and his neck was rigid. On this day the patientreceived a total of 3.3 gm. of quinine intravenously. In spite of this hedeveloped tonic convulsions and died. Blood quinine level was 7.1 mg. per liter.
Case 11-A 45-year-old soldier was admitted to a stationhospital in the spring of 1943 in a marked state of mental confusion anddelirium. Because of his mental state no history could be obtained. Persistentvomiting was present. Red blood cell count was 2,000,000 and leukocyte count12,000. Diagnosis was made on the second day with the identification of P.falciparum in the peripheral blood. Ten grains of quinine were given orallythree times daily. However, vomiting persisted. On the fourth day 10 gr. ofquinine intravenously every 8 hours was instituted, and the patient receivedthis medication four times. He was also given two whole blood transfusions. Helapsed into coma in spite of this treatment and died on the fifth day. Autopsyreport was not available.
Case 12-A soldier was admitted to a station hospital ina comatose state. Signs of lobar pneumonia were present. There was markedanemia, and blood smears were positive for P. falciparum. In spite of treatmentwith sulfadiazine, intravenous quinine, whole blood transfusions, and oxygen,the patient died on the third hospital day. Death was ascribed clinically tocerebral malaria. Autopsy showed lobar pneumonia and numerous malaria parasitesin the brain, heart, and muscles.
The incidence of this ill-defined syndrome varied widely among the hospitalrepresentatives questioned although none declared it to be common. Restricted tocases showing one or more of such signs as coma, meningismus, convulsions,persistent delirium, and well-defined neurological signs, 144 cases werereported due to P. falciparum and 19 due to P. vivax. This did not
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represent total theater experience, since it was not possible to survey allof the hospitals in the theater.
Of the eight deaths in this theater due to cerebral malaria, all werefalciparum infections. The modern concept of the pathological physiology ofcerebral malaria permits a reasonable doubt as to its occurrence in vivax infections. In only 1 of the 19 cases so reported was the record available foranalysis, and in this case the accuracy of the diagnosis was questionable. Asummary follows.
Case 13-The patient became ill 6 October 1944 with nausea and somevomiting. Began "shaking." No further coherent story could beelicited. Temperature was 97? F., pulse 104, and respiration 24. Therewere no abnormal findings. The battalion surgeon who sent the patient to thestation hospital on 7 October, suspected malaria. Temperature was 100.2? F. attime of onset.
The patient was semicomatose on 8 October 1944. Lumbarpuncture was done on the same day. Pressure was elevated. The first tubecontained red cells; the second was crystal clear. There were 84 cells, 30polymorphonuclears, and 58 lymphocytes. The examining medical officer wasnot certain that the patient had meningitis. Lymphocytic choriomeningitis orencephalitis was considered. The patient had four generalized convulsions on 11October and was transferred on that date in deep coma to a general hospital withthe diagnosis of epilepsy. On admission considerable motor unrest was noted butno movements of right side. Examination was difficult but did show bilateralankle clonus and Babinski's and Oppenheim's signs. Abdominal reflexes wereabsent. Right side of face did not move as well as left; slight internal squint,right eye. Pendular nystagmus, on looking ahead, changed to definite slowvestibular variety on looking to right. Conjugate movements of eyes werepreserved; pupils dilated, reacted poorly to light; fundi normal. Patient gaveno response to painful stimuli. Definite meningitis neck with directBrudzinski's sign and bilateral Kernig's sign. Temperature was 102.2? F., pulse96, respiration 22, and blood pressure 126 systolic and 80 diastolic.
The picture was that of an acute meningoencephalitis. How many of the focalsigns were due to the illness per se and how many a product of thepostconvulsive state could not then be determined.
Spinal puncture yielded clear fluid; 280 mm. of water pressure; normaldynamics; 4 white blood cells (lymphocytes); sugar, 100 mg. percent; chlorides,733 mg. percent; globulin, negative. Total protein, 22 mg. percent. Kahnnegative. Gold curve, 1,111,000,000. Subsequent smear, culture, and pelliclestudies were negative.
12 October 1944: Temperature dropped to normal. Patient responded toquestions but was confused much of the time. Neurological signs persisted.
13 October 1944: Spinal fluid examination showed: 260 mm. of waterpressure; clear; pressure dropped to 70 mm. of water after removal of 30 cc. offluid; 5 white blood cells (lymphocytes); sugar, 62 mg. percent (simultaneousblood sugar, 84 mg. percent); chlorides, 759 mg. percent; globulin, negative;total protein, 24 mg. percent. Smear and subsequent culture, negative.Generalized convulsion; then Jacksonian fit of right side. "Status"aborted with intravenous Amytal Sodium.
14 October 1944: Suspect right homonymous hemianopsia (transient). Periods ofdelirium and hallucinations. Afebrile.
16 October 1944: Two attacks of furor (equivalents). Was being given luminal(phenobarbital). Bromides added.
17 October 1944: Today patient has left homonymous hemianopsia. Noastereognosis. Some tendency toward preservation. Meningeal signs persist.
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18 October to 23 October 1944: Essentially the same. Some confusion.Hemianopsia (left) persists.
24 October 1944: Temperature to 101.8? F. Malaria smear positive for tertianparasites.
25 October 1944: Temperature rose to 103.4? F. during morning. Second slidepositive for malaria (P. vivax). Quinine sulfate, 15 gr., three times a day bymouth started.
Four previous smears had been negative for malaria and he hadbeen afebrile for 10 days when the micro-organism was found. White blood counts:7 October, 12,350 (neutrophils, 80 percent; lymphocytes, 20 percent), 8 October,5,300 (neutrophils, 74 percent; lymphocytes, 26 percent), 11 October, 11,500 (neutrophils,64 percent; lymphocytes, 36 percent).
Serology: Kahn, positive, 11 October. Kahn and Wassermann, negative, 17October. All spinal Kahns negative. Blood bromide, 75 mg. percent, 25 October1944.
Spinal puncture on 25 October: Pressure 200 mm. of water; 2white blood cells (lymphocytes); sugar, 56 mg. percent; chlorides, 685 mg.percent. Total protein, 26 mg. percent. Gold curve, 1,111,000,000.
Course: Afebrile on 26 October 1944, and since. Clearedmentally. All neurological signs cleared up except the homonymous field defectwhich was still present when he was transferred.
Regardless of some diagnostic confusion, all medical officersin the theater acquired a wholehearted respect for the cerebral manifestationsof the disease. The grave prognosis of the frank cerebral syndrome and theserious implications of persistent vomiting in falciparum infections werequickly learned, and this was responsible for the early institution of vigoroustherapy in such cases.
Cachexia
As with cerebral malaria, the incidence varied widely asreported by the various hospitals because of lack of uniformity in the criteriafor diagnosis. When the discussion was limited to chronic, truly cachecticstates, 12 hospitals reported a total of only 26 cases. It is probable that thetheater experience did not greatly exceed this figure. Many medical officersnoted that the American soldier stood repeated attacks of vivax malariaremarkably well, and a study in the South Pacific confirmed their impression.
From the reports cited, it can be seen that in all theatersof operations in which command and medical officers found malaria a majorproblem their experiences were very similar, and the stages of their educationin dealing with this disease were painfully alike. Rarely has the old adage,"Experience is a hard teacher" been so well illustrated in the annalsof medico-military history. The same prejudices, the same mistakes, the samefumblings, and the same slow correction of errors in tactical and medicalthinking mark the evolution toward solution of the problem of malaria asexhibited in the reports of the consultants in medicine. Lack of foresight, onthe one hand, caught us with scant supplies of quinine; on the other hand,enterprise and ingenuity found ways to improve upon quinine. Under the pressuresof war, we learned the chapter on malaria and expanded the section on chemother-
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apy. Military medicine, like war itself and the events that lead to war, isfull of such ironies; of failures to do something relatively simple that wouldsave much trouble, and then doing something prodigious under the most tryingcircumstances; in other words, of the human capacity for getting ourselves intothe most dreadful difficulties, and then, by summoning great vigor,intelligence, and fortitude, getting ourselves out again. The great wars of ourtimes might be in general so described. The question for the future is how longthe human race can take its victories by hairsbreadth; whether, as the wheelspins, we shall always come out on top.
