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Treatment of Malaria
Perrin H. Long, M.D.
An interesting commentary on the state of health of the people of the United States at the beginning of World War II was that the majority of physicians entering the Armed Forces had had practically no experience in the diagnosis or treatment of malaria. To be sure, in the medical school courses of clinical microscopy, each had studied stained slides showing malarial parasites, or if there happened to be a patient in the ward who had malaria inoculata, thick fresh films of blood might have been examined. Occasionally in seaports, sailors suffering from malaria were seen on the medical services, treated with quinine, and then discharged shortly after their fever had subsided. As far as malaria inoculata was concerned, the problem was often to keep the infection from dying out rather than to arrest it by treatment. The average younger American physician, except in certain rural areas in the Southern United States, hardly gave a thought to malaria and was unconcerned about his lack of knowledge of this disease.
When it became evident in May 1940 that the Armed Forces of the United States were going to be sharply augmented, the Surgeons General of the Army and the Navy requested Dr. Lewis H. Weed, then Chairman of the Division of Medical Sciences of the National Research Council, to set up certain consultative and advisory committees. One of the earliest of the groups formed by Dr. Weed was that which, under the chairmanship of Dr. Henry E. Meleney, devoted itself to problems of tropical diseases. Of course, malaria immediately became a prime subject for discussion by this group. Out of the work of this subcommittee came the initial recommendation for the suppression and treatment of malaria with quinine. Obviously in 1940 and during the first half of 1941, there was no positive indication that the Axis Powers would seize Indonesia, the main source of 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 always thought of as secondary to the use of quinine.
The military events that occurred late in 1941 and early in 1942 brought a rude awakening to all concerned with malaria in this country. With relatively small supplies of quinine on hand, the Japanese move into Indonesia and Malaya, which cut off the major source of quinine, brought the Subcommittee on Tropical Diseases, National Research Council, to the recom-
mendation that the military forces of the United States must rely on Atabrine for the suppressive and the specific therapy of malaria. At that time, there was relatively little in the U.S. medical literature concerning the properties of Atabrine, and very few American physicians had used it or, for that matter, even heard of it. Very little was known about its pharmacological or toxic properties. Schemes of therapy, either suppressive or definitive, were based on empirical observations or even guesswork. This was the status of affairs when the Office of Scientific Research and Development initiated its large-scale research project on Atabrine in 1942. One of the earliest applied projects was testing the drug in normal human beings over a period of weeks to determine its possible toxic effects when it was used for suppressive therapy over a long period. The dosage schedule employed was 0.1 gm. twice a week. Various social groups, such as students, reform-school inmates, and prisoners in penal institutions, were employed as test subjects in these early trials. One of the results of these trials was extraordinarily significant. But how significant it was, unfortunately, was not recognized until, at least in the North African (later Mediterranean) Theater of Operations, U.S. Army, serious, if not permanent, damage had been done to the minds of the military relative to the use of Atabrine for the suppression of malaria. It was noted that in the test subjects there were sharp, prostrating gastrointestinal attacks characterized by nausea, vomiting, and diarrhea following the third dose of the suppressive medication. This occurred very frequently in the student group, very much less frequently in the reformatory inmates, and least of all in the inmates of the State prisons. It was also observed that, if the therapy was continued, there were very few individuals who had to discontinue the Atabrine because of gastrointestinal disturbances following subsequent doses of Atabrine. It was further 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 to do with malaria was a joint command and professional project between the British and 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 joint command directive regarding the use of Atabrine for the suppression of malaria. The author, remembering the gastrointestinal disturbances that occurred after the third dose in the trials in the United States, held out for a daily suppressive dose of Atabrine. The British and French members of the committee resolutely opposed this method of suppression. To make a long story short, the author was outvoted and, under the operational rules of Allied Force Headquarters, 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 of the first two doses. The third dose was administered to all troops at the evening meal on Thurs-
day, 29 April 1943. Within 4 or 5 hours, sharply defined toxic reactions characterized by varying degrees of nausea, vomiting, and diarrhea made their appearance. Curiously enough, military personnel stationed to the rear of combat elements suffered far more than the fighting men. Infantry units 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 75 percent of the personnel were affected. As one of our British colleagues remarked the next day, "it had been a shaking experience."
Understandably, as reports of toxic reactions piled into Allied Force Headquarters from all over the North African theater, consternation prevailed, and there was an immediate demand that suppressive therapy be discontinued. Calm was eventually restored, faith in the use of Atabrine was reaffirmed officially, and suppressive therapy was continued. However, as can well be imagined, the damage 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 the theater. Then, to compound confusion, the first great seasonal epidemic of infectious hepatitis occurred in American troops beginning in August 1943, and in many quarters this epidemic was at first thought related to the use of Atabrine for the suppression of malaria. The author cannot determine, from the reports available to him, whether similar incidents occurred during the initiation of suppressive therapy with Atabrine in other theaters of operations. However, it appears that, in all areas in which there was fighting and malaria was epidemic, the discipline required to carry out successful campaigns for the suppression of malaria by the use of Atabrine was difficult to enforce and the terrific toll of ineffective military personnel resulting from malarial attacks was directly related to this lack of discipline. Command was not convinced of the value of suppressive therapy with Atabrine and did not, except in a few areas, 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 wage war effectively in the South Pacific Area. The experiences with malaria in that area were so rich and varied, and such careful, large-scale studies were carried out on its nature and the suppressive and therapeutic problems it posed, the reader is referred to other volumes in the history of the Medical Department in World War II for statistical and other details.1 The substance of these observations is in part summarized here, for their bearing 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.]
In this as in other theaters, most medical officers early in the war had little practical knowledge of malaria. Some few had had clinical experience, mostly in the southeastern part of the United States, and they were disposed to ascribe "properties to quinine that it did not possess." Such "malaria experts" scattered through many medical units "were believed to have done much harm, for most of them preached quinine with evangelical zeal and blamed" everything, particularly the very difficult problem 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 had taught 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 cerebral malaria (46), fewer still of severe anemia (14), blackwater fever (13), and splenic rupture (6). However, based on sample tabulations of individual medical records, there were no admissions for blackwater fever in the Central and South Pacific 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 October 1942 and 1 September 1944. The more virulent infections caused by Plasmodium falciparum predominated during epidemics. Infections with the less virulent but stubbornly relapsing Plasmodium vivax appeared in increasingly higher percentages of cases when troops were removed from malarious to nonmalarious islands and suppressive Atabrine therapy gradually withdrawn. It was apparent that 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 the comparatively low incidence of malignant malaria in the Pacific areas. The most pressing 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, in Guadalcanal (1942-43), armed against the latter with suppressive doses of quinine for a short period, and Atabrine later. In May 1943, the entire regiment was sent to Samoa, a nonmalarious island. Here, Atabrine therapy was gradually withdrawn, and the men were given no further specific treatment until they developed fresh attacks, with the hope that their malaria would "burn itself out." The actual result was the development of chronic malaria with repeated relapses in the overwhelming majority. It was apparent that the suppressive therapy on Guadalcanal had cured few, if any, cases of malaria due to P. vivax. Massive therapy was also ineffective in curing latent vivax infections. Before the regiment could be returned to active duty, suppressive medication with Atabrine had to be reinstituted. This therapy effectively reduced the malaria rate, and the physical fitness of the regiment was restored.
Similar results followed a similar attempt to "demalarialize" the Americal Division on the Fiji Islands. Troops heavily seeded with malaria were not well enough to return to combat after many months of "demalarialization." Many patients were evacuated to the Zone of Interior, but many remained in the theater, relapsing repeatedly. The only reasonable course was to resume suppressive therapy with the hope, but as yet no certainty, that continued use would materially reduce the staggering noneffective rate.
An experiment was set up on the Fiji Islands with combat units engaged in maneuvers under conditions simulating those of jungle warfare. One group was given no suppressive therapy; the other, sufficient Atabrine to establish the blood levels that had been found to be effective. In the control group, the relapses continued to occur at about the same rate as during previous months; in the treated group, malaria was practically eliminated. The cases that did develop were in men who, like some others observed previously, exhibited consistently low Atabrine blood levels.
Subsequent to this study, troops were kept on suppressive medication whether they remained in malarious areas or were sent to nonmalarious regions for rest and recreation. First to come under the new policy was the 25th Infantry Division, which had become heavily seeded with malaria on Guadalcanal and was now removed to malaria-free New Zealand, where suppressive therapy was continued. After Atabrine discipline was tightened, the results were excellent.
Having proved feasible, the control of malaria by continued suppressive medication was required by military necessity. Experience had shown that Atabrine in suitable dosage (0.1 gm. a day) was an effective suppressive for most if not all primary malaria and, if continued, for recurrent attacks. Nevertheless, many questions remained in medical minds. Some feared that relapse was only being postponed to the day when Atabrine would finally be withdrawn. Some thought the parasite would acquire tolerance to the drug. Such considerations had an important bearing on plans for reemployment of highly malarialized troops, and on treatment of troops in malarious areas.
To provide answers to many questions, a large number of men of the 147th Infantry were followed from Guadalcanal (November 1942) to Iwo Jima (August 1945). Their medical history "included heavy exposure, light exposure, atabrinization, de-atabrinization, long-continued suppressive medication, and terminal de-atabrinization." The observations, made on the same experimental group and covering this not inconsiderable expanse of time, space, and experience, appeared to justify the conclusion that long-continued suppressive Atabrine therapy does, in fact, ultimately destroy a large amount of infection due to P. vivax. After 17 months of continuous suppression, all antimalarial therapy was discontinued, in the nonmalarious environment of Iwo Jima, 20 months after the last significant exposure to infection. During the ensuing 3 months, there was only a slight increase in the malaria rate in contrast to the violent outbreaks that had followed the initial deatabrini-
zation. It was, unfortunately, not possible to continue followup observations beyond this 3-month period.
In another comprehensive study, no serious aftereffects of malaria were found in soldiers who had been through many clinical attacks. Toxic reactions to Atabrine were not troublesome in the South Pacific Area. Signs of intolerance in the central nervous system appeared in a small group of cases and were carefully studied; they subsided when dosage was decreased. In comparative studies, other drugs (Plasmochin naphthoate (pamaquine naphthoate), the sulfonamides, totaquine) appeared to be generally inferior or not superior to Atabrine.
In the Southwest Pacific Area, important studies were carried out on suppressive treatment, such as those in Australia by Lt. Col. (later Col.) Garfield G. Duncan, MC, of the American Army and by Brigadier N. Hamilton Fairley 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 that island were probably the first to demonstrate clinically that malaria caused by P. falciparum could be cured by Atabrine in suppressive dosage.2 Subsequent studies by Bang and others showed that a certain concentration of the drug in the blood was necessary for protection against clinical attacks and that equilibrium 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. It was shown that this treatment resulted in control of gametocyte carriers and this, in turn, prevented epidemic outbreaks of malaria when troops were exposed again to infection.
EXPERIENCE IN THE INDIA-BURMA THEATER
Malaria as constituting a major medical problem in the India-Burma theater has been presented in another volume in the history of the Medical Department in World War II, from which the following summary has been largely drawn.3 It is obvious that in many instances information will overlap. In India, U.S. troops were exposed to malaria, most of them for the first time, in a vast region where the incidence was something like 4,000 per 1,000 per annum in the population. An overnight journey by train was likely to result 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 in this theater; cerebral malaria was the principal clinical problem. Medical officers came from the United States unprepared for the multiform manifestations of the disease and were often, particularly at first, uncertain in diagnosis. As to treatment, there was much individual experimentation. This may have been due, in part, to the proximity of the Indian Medical Service and its methods of therapy; 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.
information from the Surgeon General's Office on newer methods of treatment; and in part, perhaps, to the presence in Army hospitals of highly individualistic, research-minded medical officers.
The overall percentage of cases of malaria classified as cerebral, in the three hospitals where most of them were seen, was 1.9 percent. At the 20th General Hospital, the incidence was 2.3 percent for all patients with malaria and was 2.2 percent for Americans alone. At the 73d Evacuation Hospital, during a 6-month period, there were 57 cases of cerebral malaria with 27 fatalities, only 1 an American. At the 48th Evacuation Hospital, treating chiefly Chinese soldiers, between April 1944 and March 1945, the mortality was 43 percent, with no deaths in Americans. From September 1943 to May 1945, the 14th Evacuation Hospital had 121 cases with 33 deaths, all the fatalities occurring in Chinese patients.
P. falciparum was recognized as the causative agent in most cerebral cases; some few were ascribed to P. vivax. In the majority of all American patients with malaria, P. vivax predominated; in the majority of Chinese, P. falciparum predominated. Col. Francis C. Wood, MC, of the 20th General Hospital thought that an observation made there threw light upon this. Some Chinese patients were given no treatment for several days preparatory to testing with a new drug, at the request of Chinese medical officers. This was Fraxine, a preparation of unknown composition and, in the event, 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 that Chinese soldiers infected with P. vivax recovered spontaneously and were usually not seen at hospitals.
The India-Burma theater was established in October 1944 when U.S. Army Forces, China-Burma-India, was divided into two separate theaters-the China Theater and the India-Burma Theater. What seems to have been the first publication in the theater on the treatment of malaria appeared in the opening issue of the Field Medical Bulletin, Headquarters, Services of Supply, U.S. Army Forces in China-Burma-India (August 1942). This was a summary of a pamphlet issued by the British War Office recommending treatment different from that 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 Certain Tropical Diseases." In the November 1942 issue of the Field Medical Bulletin, Maj. Sydney P. Waud, MC, and Maj. Robert S. Crew, MC, of the 159th Station Hospital, presented "several changes in the treatment of malaria," derived from the School of Tropical Medicine, Calcutta, India. Finally, the Bulletin in its January 1943 issue reprinted Circular Letter No. 135, Office of the Surgeon General, U.S. Army, dated 21 October 1942 and entitled "The Treatment and Clinical Prophylaxis of Malaria," but in the issue of February 1943, Lt. Col. Gordon S. Seagrave,
MC, expressed doubt concerning the efficacy of Atabrine and presented his own views on therapy including liquor arsenicalis and neoarsphenamine.
The theater as a whole continued to use the plan of treatment outlined in Circular Letters Nos. 135 and 33, the latter dated 2 February 1943 and entitled "Treatment and Control of Certain Tropical Diseases." Circular Letter No. 33 was replaced by Circular Letter No. 153, Office of the Surgeon General, U.S. Army, 19 August 1943, entitled "The Drug Treatment of Malaria, Suppressive and Clinical." By the end of 1943, installations in heavily infested areas had reached their own conclusions on the basis of experience. The view expressed in a special report on malaria in the annual report of the 73d Evacuation Hospital was that all methods in use there were about equally effective in their end results but that quinine and Atabrine used in combination reduced temperature more rapidly than the officially recommended therapy. At the 48th Evacuation Hospital, 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 of Atabrine than was recommended, but could find no certain advantage. The experience of the theater with the treatment described in Circular Letter No. 153 was summarized in the Essential Technical Medical Data reported to The Surgeon General for June 1944. The general opinion was that only in very sick patients was it necessary to supplement Atabrine with quinine, usually given by injection. Patients with cerebral malaria were sometimes unable to take oral medication. In such cases, before parenteral Atabrine was available, quinine was given intravenously.
During the period covered by Circular Letters Nos. 135, 33, and 153, which included all of 1943 and most of the malarial season of 1944, occasional investigations were made, particularly at the 20th General Hospital, on the effectiveness 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 of Atabrine and Mapharsen (oxophenarsine hydrochloride) was studied by Maj. Calvin F. Kay, MC. Relapses occurred in the group so treated as frequently as in those treated with Atabrine alone.
Fraxine, a preparation used by Chinese medical officers and tested at their request, proved of no value in malignant tertian malaria, and its effectiveness in benign tertian malaria was extremely doubtful in view of the apparent tendency of Chinese troops to recover spontaneously.
A special problem with Chinese patients was to keep them in the hospital. As soon as they felt better they left or were taken out by their commanding officers. To circumvent this, Maj. Thomas E. Machella, MC, sought to devise a safe and effective method of giving the total dose of Atabrine within 24 hours. A group of 80 Chinese patients given 0.3 gm. of Atabrine every 3 hours for eight doses, did as well or even better, as regards duration of fever and parasitemia, as compared with patients treated according to Circular Letter No. 153. Because 2 of the 80 patients showed signs of stimulation of the central nervous system, the dosage was reduced to 0.2 gm. every 3 hours for eight doses.
An experimental study by Major Machella failed to demonstrate any effect of a single intravenous infusion of an antimalarial (Atabrine or SN 6,911) upon the ability of the liver to excrete bromsulphalein before, during, and after an attack of malaria. Some patients with cerebral malaria were treated with a single intravenous infusion of Atabrine, the dose varying from 0.6 gm. to 1.0 gm. The patients who received the infusion too rapidly had brief psychotic episodes. Although the number of cases was small, Major Machella felt 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 the blood 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 from units working along the Ledo-Burma road were seen at the 73d Evacuation and 20th General Hospitals. A severe type of hemolytic reaction to Plasmochin occurred in approximately 30 patients. One patient was Chinese and the rest were Negroes. All of them developed a moderately severe anemia; in six, the erythrocyte count fell below two million. Because of the frequency and severity of these reactions, administration of this drug was stopped in all hospitals in the Assam-Burma region, and eventually in the theater.
Quinine had long been known to produce toxic effects. Used intravenously in cases of cerebral malaria prior to the advent of parenteral Atabrine, it was generally considered a lifesaving procedure. At the 48th Evacuation Hospital, however, eight Chinese patients died in convulsions shortly after injection of quinine. Although admittedly a cause and effect relationship could not be proved, the clinical impression was so strong that at this hospital any reasonable 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, toxic psychoses, and the usual gastrointestinal disturbances. When suppressive treatment with Atabrine was instituted in February 1945, many medical officers were still apprehensive of its supposed toxic potentialities. Many symptoms were attributed to Atabrine without good evidence of a causal relationship, others on a 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 the visual acuity of airplane pilots, concluding there was no adverse effect except in rare, highly sensitive individuals. In these, withdrawal of Atabrine resulted in relief of symptoms; readministration of the drug was followed by recurrence, which in turn was relieved by cessation of suppressive therapy.
Various nonspecific therapeutic measures were employed, particularly at the 20th General Hospital, with variable benefit. Transfusions of whole blood were thought to be lifesaving in some cases, especially in those with pulmonary edema. At this hospital an initial spinal tap was considered advisable in all cases. At the 73d Evacuation
Hospital, on the contrary, the reduction of spinal-fluid pressure by lumbar puncture was thought to be appreciably effective only in rare cases. At both hospitals intravenous Adrenalin (epinephrine) was considered of value in some cases, but was not in routine use because of untoward reactions. Sedatives were universally used for excited or convulsive patients, usually Amytal Sodium or paraldehyde given intravenously. Various other measures were tried without any striking benefit. These included oxygen therapy, Benzedrine (racemic desoxy-nor-ephedrine), ephedrine, aminophylline by intravenous and by intracarotid injection, and injection of nitroglycerine into the carotid.
EXPERIENCE IN THE MEDITERRANEAN (FORMERLY NORTH AFRICAN)
Lt. Col. Harold H. Golz, MC, 182d Station Hospital, and Maj. Phillip B. Bleecker, MC, 225th Station Hospital, collected and compiled extensive data on the epidemiology, clinical and laboratory diagnosis, clinical course, and treatment of malaria in U.S. Army troops in countries bordering the Mediterranean. What follows is in large part taken from the final report on malaria written by Colonel Golz.4
Throughout recorded history, malaria played its part in the insidious defeat of armies, and here, in this theater in World War II, it rapidly became the foremost medical problem. The vast majority of American troops who moved into these highly malarious regions had never been exposed to the disease, and the great majority of medical officers had had no experience with it. At that time, the possibilities of drug prophylaxis and suppression were only in process of being elucidated, and mechanical protection from infection in amphibious operations could at best be only a feeble effort. Fortunately, the initial landings were made at a season when the incidence of primary infections was low.
The disease occurred throughout the theater, more intensively in certain regions. In North Africa, the most highly malarious areas were in the neighborhood of Rabat and Port Lyautey in Morocco, the Constantine area in Algeria, and the Tunis-Bizerte-Ferryville area in Tunisia. Sicily had a high rate on the Catania plain and on the southern coastal plain. The entire eastern coastal plain of Corsica was highly malarious, and the malaria rate in civilians of Sardinia was the third highest in the world. A survey of 802 children in Sardinia before World War II showed that 34.2 percent had positive smears, of which 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 around the river mouths on the eastern coast. There was little malaria in southern France, and urban centers such as Florence were free of malaria, although it did approach the municipal limits of Rome and Naples.
4Golz, Harold H.: Human Malaria in the North African and Mediterranean Theaters of Operations, U.S. Army. [Official record.]
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 new admissions and readmissions as well as admissions for other causes, but in which malaria 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 the war 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 83,000 probable 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 are shown in table 66. The 1942-43 data are based on tabulations of individual medical records and consist of new cases admitted for malaria and new cases in which malaria appeared as a secondary diagnosis. The 1944-45 data are from the statistical 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)]
1The 1942-43 data represent incidence; it consists of new
cases admitted for malaria and cases in which malaria appeared as a secondary
diagnosis. The 1944-45 data are in terms of total malaria attacks, which is
comprised of cases readmitted for malaria as well as new primary and secondary
attacks which include readmissions as well as new cases. The statistics enumerate the malaria attacks as they were diagnosed and reported currently and regularly on the statistical health report and may include tentative diagnoses. Such data therefore do not tally identically with those derived from statistical tabulations of individual medical records which are based on final diagnoses. However, they do provide a general basis for epidemiological description of malaria in the Mediterranean theater during World War II. The average length of hospitalization for this disease in 1943 was a fraction less than 17 days, representing a total of about 425,000 man-days lost during the year or the equivalent of the effectiveness of an entire division lost for a month. In 1944 the average period of hospitalization was reduced to 11.8 days but the number of man-days lost for the year was 519,000. In the average hospital, malaria represented 4 to 5 percent of all hospital admissions.
The geographic distribution of the cases broken down into clinical types is shown in table 67. This table shows only 22,936 cases and represents the total experience of 32 hospitals of all types during their entire period 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 remainder of 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 loss in fighting effectiveness in the Allied armies was equivalent to two infantry divisions and exceeded the total number of battle casualties by 20 percent. A large number of men also developed the disease while in training in areas of troop concentration in North Africa and were unable to participate in the invasion. The number of troops thus affected was well over a thousand.
The malaria of Sicilian origin made its appearance in the Seventh U.S. Army and British Eighth Army after 7 August 1943 and reached a peak a week later. The rates for these two armies were 425.43 and 420.39, respec-
1Pantelleria, France, Corsica, and Sardinia.
tively, although in some divisions they were much higher. The incidence in the entire campaign would approximate 400 per 1,000 per annum. Later, strict control measures were adopted. The rates dropped steadily, but it was not so much the control measures that were responsible for the drop in the malarial rates in Sicily in the fall of 1943 as it was the removal of troops from hypermalarious 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. In October 1943, when the bulk of U.S. troops were in North Africa, there was a rise in the rate which was also expected because of the September rains, but this rise did not appear in 1944 when the greater part of U.S. troops were in Italy. The increase in malaria noted in 1943 cannot be attributed to conditions in North Africa. It resulted from conditions existing on the Salerno beachhead during September and had its origin in the sharp increase in cases of malaria in the Fifth U.S. Army during that period. The rates in the winter of 1943 and 1944 were relatively high during the season when few if any primary cases occur and are explained by the relapses of primary infections incurred during the summer and early fall of 1943. The withdrawal of Atabrine suppressive treatment from November 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 various reasons, the effort to make laboratory diagnoses in that year was not as great.
In the summer of 1944, the FUO rate was noticeably high. This can be accounted for in part by the high incidence of pappataci fever from July through September. Many medical officers were unfamiliar with this disease and diagnosed 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 of southern France (15 August), three divisions that had been withdrawn from the Fifth U.S. Army and assigned to the Seventh U.S. Army were staged and trained in a malarial area near Naples. These divisions, classed as noncombat troops, had malarial rates of 130 to 140 per 1,000 per annum while in training.
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-This type of hospital was the first stop in the chain of evacuation where adequate facilities existed for making a laboratory diagnosis of malaria. These hospitals used the same diagnostic methods as employed in the fixed hospitals of rear echelons-namely, repeated thick smears. (The 15th Evacuation Hospital took three thick and thin smears for routine examination and if these were negative, a fourth was taken 2 hours after the subcutaneous injection of 0.5 cc. of Adrenalin 1: 1,000. If the smear following Adrenalin was negative, the diagnosis of clinical malaria was made only if there was a history of recent malaria, a typical clinical picture, and a palpable spleen.) As a result of such careful methods of examination, often done under highly adverse conditions, the diagnosis of clinical malaria was not often made in evacuation hospitals.
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, or base section surgeon, and (3) the professional intelligence of the medical officer who was directly responsible for the administrative phases of evacuation. During the Sicilian campaign of 1943, hundreds of patients suffering from malaria were evacuated from the II Corps area to North Africa because sufficient beds for their care were not available, owing to the fact that the Seventh U.S. Army broke away from its prepared plan of providing hospitalization and did not call for all of their large evacuation hospitals until after the campaign was over. In the fall and early winter of 1943, hundreds of patients ill with malaria were evacuated to hospitals in the Peninsular Base Section because beds for their care were not considered to be available in the Fifth U.S. Army area, although data on the bed status during that period show that rarely 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. With experience, fewer and fewer malarial patients were evacuated. Much unnecessary evacuation of malarial patients with a resultant loss of manpower occurred-both in forward and in rear areas-because many administrative officers in charge of evacuation looked upon patients as "bodies" occupying space without reference to their disease and their ability to return to their units promptly.
When patients were evacuated, they were moved by air, rail, ship, or ambulance to the next echelon hospital, usually the general hospital, although in certain instances they might be sent to a station hospital.
General hospitals-By the time the malarial patient reached the general hospital, diagnosis had usually been made and treatment started. When the course of treatment was completed, the patient was given such reconditioning as he might 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 very exceptional circumstances, although they concurred in such a transfer diagnosis when the patient had already been under treatment. When this diagnosis was made initially in these hospitals, it was usually in cases in which, although thick smears were negative, the patient's condition required prompt treatment and his response to specific treatment was typical.
Under certain circumstances, general hospitals received patients directly from 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 General Hospital, when the combination of leukopenia, qualitative changes in the lymphocytes of the peripheral blood, and reticulocytosis was found, repeated thick smears were taken without further request from the ward officer.
Another source of admission was in transfers from station hospitals from which the patients were sent as problems in disposition.
It was only in the last half of 1944 that hospitals in this theater reclassified soldiers to limited assignment because of malaria. This reclassification, made but rarely, was usually applied to a combat individual who had been relatively noneffective because of repeated hospitalizations without, however, meeting the criteria for evacuation to the Zone of Interior. Frequently, letters from unit medical officers requesting reclassification accompanied the soldier to the hospital. The purpose was to permit the combat unit to get a more effective replacement and to move the patient to an environment where he was less likely to relapse and could still be of some use to the service.
The theater policy for reclassification to class C (return to the United States) for malarial patients was set forth in Circular Letter No. 21, Office of the Surgeon, Headquarters, NATOUSA, dated 3 April 1944. The criteria for this classification were cachexia, repeated attacks with persistent splenomegaly, refractory anemia, repeated attacks of cerebral malaria, and blackwater fever. This policy did not envisage evacuation to the Zone of Interior for repeated attacks per se. Approximately 1 percent of patients with malaria eventually were sent to the United States for this cause. A review of the records of several general hospitals revealed the following additional causes for C classification:
1. Chronic cachexia with or without persistent splenomegaly and anemia in a patient who had lost 3 months or more from duty in 1 year because 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 of evacuation and for the most part received their patients directly from command by way of dispensaries, although during periods of peak evacuation, the station hospital might supplement the bed capacity of general hospitals. Many cases had a laboratory diagnosis made in the referring dispensary, and when the report of the smear accompanied the patient it was accepted without verification. Other cases arrived with the diagnosis of fever of undetermined origin. Diagnostic methods then employed were the same as those used in the general hospitals, and a diagnosis of clinical malaria was rarely made. For example, in one station hospital, it was resorted to only seven times in more than 800 malaria admissions, and in 6 of these cases, it was the transfer diagnosis of patients already under specific treatment. Treatment methods and criteria for reclassification to limited assignment were the same as those employed in general hospitals. When it was felt that a malaria patient should be evacuated to the Zone of Interior, he was transferred to a general hospital for disposition.
Duration of hospitalization-From the Machine Records Unit, Allied Force Headquarters, it was determined that the overall average period of
hospitalization for 6,078 cases of malaria in the 8-month period between September 1944 and May 1945 was 14.5 days. This average applied only to cases discharged to general military duty and did not include reclassified cases or cases disposed of by transfer to other hospitals. When calculated for type of hospital the following averages were obtained: (1) Field and 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. Clinicians had no hesitancy in ascribing responsibility for this to the inexperience of laboratory technicians which was undoubtedly a factor, but clinicians should not 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, most hospital clinicians and technicians had become thoroughly acquainted with it. These two groups were mutually helpful in the quest for knowledge of this disease, and certainly much credit for this happy state of affairs can be ascribed to those officers in high echelons of the theater who waged a relentless war against the diagnosis of "clinical malaria." Subsequently, hospital medical officers almost without exception proudly claimed that they rarely if ever made the unsupported diagnosis and they staunchly defended their own technicians as experts in parasite identification. And, indeed, the rank and file of laboratory technicians in the theater had become highly efficient parasitologists; for this, due credit must be given to the training courses for technicians conducted by the malariologists.
A note on technique may not be amiss. All hospitals agreed that a thick-drop blood film was indispensible. In 17 of 20 hospitals visited, thick-drop examination was routine, and several of these hospitals had dispensed with the thin smear entirely, maintaining they could identify the species satisfactorily on the thick drop. In the other three hospitals, the thin smear was examined first, and if negative, the thick drop was examined. The purpose was to save time in diagnosis, but in Italy, where the ratio of P. vivax to P. falciparum was about 46:1, perhaps such urgency was unwarranted.
For routine work, more than one-third of the hospitals preferred Field's stain, prepared fresh each week, kept cold, and filtered at least twice weekly. Other hospitals invariably used Giemsa stain in preference to Wright's stain.
Many studies were carried out in the laboratories of Army hospitals, which have been described in detail elsewhere (p. 489). Here it may be noted, that certain characteristics formerly though to be limited to falciparum infections were not uncommonly found with P. vivax; in particular, double-cell infections, double-chromatin dots, and marginal rings.
Theater directives-The history of the treatment of malaria in this theater properly begins with Circular Letter No. 6, Office of the Surgeon,
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 3 days to control parasitemia, followed by Atabrine 0.1 gm. three times a day for 5 days followed by a 2-day rest period, and then 0.1 gm. of Plasmochin two or three 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 an alternative, Atabrine alone, 0.2 gm. three times a day for 5 days. Finally, on 14 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 for five 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 dosage of 1.0 gm. three times a day for 3 days and then 0.3 gm. three times a day for 10 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 that the use of quinine in the therapy of relapsing malaria had shown no advantages over 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 with quinine. Formerly, it had been observed that Atabrine did not effect a temperature drop as promptly as did quinine. At that time, it was not the practice to administer loading doses of Atabrine during the first day or two of treatment. This objection was largely eliminated after it was found that the plasma concentration of the drug was a measure of its therapeutic effectiveness and that effective levels were more rapidly attained when larger doses were given at the start of a therapeutic regimen.
It was the experience of all the medical officers of the Mediterranean theater that many soldiers said they were intolerant of Atabrine, but when the drug was given in either suppressive or therapeutic doses, no such intolerance was demonstrated. Toxic reactions from therapeutic Atabrine were extremely rare. There were probably few if any medical officers in this theater who were not finally convinced that Atabrine was at least as effective and safe as quinine. This attitude represented a complete reversal of opinion within 2 years and, as such, was an eloquent testimonial to the value of the drug. When Atabrine was introduced 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 drug fell into some measure of disrepute. Medical officers were wary and suspicious of it, and only its continued use at the insistence of higher authority served to dispel these fears. A few officers still remained somewhat reluctant to accept Atabrine as the drug of choice. They were mainly physicians who had become thoroughly indoctrinated with the virtues of quinine when it was the only efficient antimalarial available.
The chief remaining differences of opinion regarding the effectiveness of the two drugs were concerned with the speed of action in bringing the temperature into the normal zone. When Atabrine was given as directed in Circular Letter No. 34 and quinine as directed in Circular Letter No. 10, many officers thought that quinine brought the temperature to normal 24 to 48 hours sooner than did Atabrine and that in most cases patients did not have another chill after quinine was started, whereas most had one additional paroxysm after Atabrine. A smaller group of officers could observe no difference in this respect between the two drugs, and a small minority thought that Atabrine produced faster results. Obviously, these differences of opinion were largely due to the fact that they were based upon clinical impressions. The only factual 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 24 cases treated with Atabrine, in such dosage as has been described. His results are summarized in table 69 and show that there was little difference between the two drugs.
In many hospitals, 0.4 gm. Atabrine by intramuscular injection was substituted for the initial dose of 0.2 gm. Atabrine given orally. Officers who used this modification of the routine plan were enthusiastic over the results. There were no toxic effects; temperatures fell to normal within 24 hours; there was no secondary rise in temperature and no additional paroxysms; and convalescence was quicker. Several other hospitals initiated treatment with 0.2 gm. given intramuscularly. The results were not as good as with the larger dose. The 118th Station Hospital gave 0.4 gm. Atabrine orally in one dose and followed it with 0.1 gm. three times daily. Results were said to be comparable with those obtained from the larger of the doses given intramuscularly.
Plasmochin-The drug was dropped from the therapeutic armamentarium early because no peculiarly beneficial effect was ascribed to it and because of the narrow margin of safety between therapeutic and toxic doses.
Quinine-For reasons of supply, its use was limited. Patients were occasionally seen who failed to respond to quinine given orally and in whom no
trace of the drug could be found in the urine. In certain types of cases, it was freely used intravenously, in all instances well diluted and given slowly. Circular letters directed that quinine should be administered in at least 300 cc. of normal saline or glucose and saline. Reactions other than mild cinchonism were not seen. In cerebral malaria, this was the routine method of treatment. It was usually given in infections with P. falciparum when patients were vomiting. One hospital gave at least one dose of quinine intravenously in all falciparum infections. The dose employed was almost invariably 10 gr., and it was repeated at 6- to 8-hour intervals when necessary.
Sulfonamides.-Occasionally, a misdiagnosed case of malaria was treated with one of the sulfonamide drugs. It was observed that the drug, usually sulfadiazine, did suppress clinical symptoms and parasitemia. A few reports were received indicating that sulfadiazine in full therapeutic doses might possess some merit in the treatment of falciparum gametocytemia resistant to Atabrine and quinine.
Sontoquine-A limited supply of Sontoquine bisulfate and Sontoquine naphtholate was received in the theater and divided between the 225th and 182d Station Hospitals. It was planned that each hospital should treat equal numbers of malaria cases with each of the two drugs and that a third group should be treated with Atabrine for comparison. Unfortunately, the experiments were undertaken 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 in Italy. 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 then 0.1 gm. three times a day for 6 days. There was no difference noted between the two salts of Sontoquine and no difference between these drugs and Atabrine. Temperatures returned to normal and blood smears were negative within 48 hours in the patients treated with Sontoquine and in all but one of the patients treated with Atabrine. This one patient had fever and positive smears until the fifth day of treatment. No sign or symptom of intolerance to Sontoquine was noted, and repeated blood counts and urinalyses failed to show any ill effects whatsoever. It was planned to continue this study.
Iron.-Routine use of iron in all cases of malaria in some hospitals was thought to speed convalescence.
Other measures-Intravenous glucose and saline were freely used to combat dehydration. In vivax cases with vomiting, the fluids often seemed to allay this symptom so that patients could retain oral therapy. One hospital reported that a single dose of morphine had a similar effect.
In patients gravely ill with falciparum infections, repeated infusions of plasma and whole blood were frequently employed. Several medical officers felt that these measures were frequently lifesaving.
Treatment To Reduce Relapse Rate
Throughout the entire history of the theater, officers were searching for a therapeutic regimen that would reduce the relapse rate in vivax infections. The 7th Station Hospital reported that relapse after Atabrine treatment appeared to be considerably delayed and that recurrence frequently followed quinine treatment within a matter of days or weeks.
Many different dosage schedules and combinations of Atabrine, quinine, and Plasmochin were used in the various hospitals and some of these programs required weeks of hospitalization. The criticism common to all of these studies was that they were done in only a very small series of cases; they were not controlled, and followup studies were either inadequate or completely lacking. It is perhaps significant that not a single officer was found who had any faith whatsoever in any of these or other plans of treatment designed to prevent relapses. For the sake of interest and completeness, several of these plans will be noted.
One hospital supplemented routine Atabrine or quinine treatment with a modified Ascoli treatment plan. Adrenalin was given intravenously in graduated doses beginning with 0.01 mg. and increasing to 0.1 mg. or to tolerance. Eight patients received this treatment daily for 15 days and four received it twice daily for 10 days.
Another hospital gave quinine intravenously with Adrenalin three times daily for 7 days. Another hospital gave 0.2 gm. Atabrine every 6 hours intramuscularly 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 quinine followed by a routine course of Atabrine followed by four weekly doses of Mapharsen. Another hospital gave a routine course of Atabrine, followed by a routine course of quinine, followed by a routine course of Atabrine. On the first 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 he received 60 mg. of Mapharsen twice weekly for six doses.
In many of the above instances patients relapsed within a month or two after completion of treatment.
Capt. (later Maj.) John C. Ransmeier, MC, of the 300th General Hospital treated three cases of relapsing vivax malaria with Fuadin (stibophen) (one with quinine as well, two with Fuadin only) reasoning that its penetration into the cells of the reticuloendothelial system might be effective. One patient received 6 daily doses of 5 cc. intramuscularly, another 10 cc. doses daily, and the third 10 doses of 5 cc. each at 24-to 48-hour intervals. The patient who received quinine as well was followed for only 1 month, during which he was well. In the second patient, the temperature became normal within 48 hours and parasites disappeared from the peripheral blood within 96 hours. He relapsed on the 13th day after completing treatment. The third patient became afebrile within 72 hours. At the conclusion of treatment parasites were absent from the peripheral blood for only 72 hours. Clinical relapse occurred in the ninth posttreatment day. Mild neutropenia was observed in all three cases.
As a result of experiences such as those cited, few medical officers in this theater believed that current methods of treatment could do more than suppress symptoms and parasitemia in vivax malaria. In another theater, prolonged experience suggested that Atabrine therapy not only was effective in
suppressing relapsing malaria but, if continued long enough, might ultimately cure it (p. 497). There is no indication in Colonel Golz's report that such consistently long-sustained therapy was ever carried through in the Mediterranean theater where, indeed, conditions were lacking for such continuous observations on identical groups of men as were possible in the Pacific area. The desideratum was a method of treatment that would obviate relapses. The British thought they had achieved this goal, or come near it, by their use of Plasmochin in conjunction with quinine. U.S. Army medical officers had early discarded Plasmochin, finding it of no particular merit as used by them, and very toxic, especially in Negro troops. Our achievement was rather in the increasingly more efficient use of Atabrine. Both lines of thought were fruitful and, during and since World War II, have been carried to more effective therapy and new drugs.
Results of Treatment
Mortality-One measure of the effectiveness of treatment is the death rate which in the Mediterranean, as in all theaters, was extraordinarily low. In the entire history of the theater, there were approximately 62,000 definitely diagnosed new cases of malaria in U.S. Army troops. According to individual medical records for 1942-45, there were 57 deaths due to malaria among cases originating in the Mediterranean theater. There were 3 deaths in 1942, 40 in 1943, 13 in 1944, and 1 in 1945. After an extensive search, Colonel Golz discovered only 11 deaths that actually occurred in the Mediterranean theater. Of 8 deaths ascribed to malaria on clinical grounds in official records for 1944, post mortem studies showed that death was due to other causes in 5 (1 Hodgkin's disease, 1 brain tumor, 1 infectious hepatitis, 1 hemorrhagic bronchopneumonia, and 1 "cause undetermined but not malaria"). By any calculation, the mortality was surprisingly low.
There are several reasons for this. Table 67 shows that in Italy the incidence of infection caused by P. falciparum was low. Other factors were Atabrine suppressive treatment (curing many falciparum infections) and the excellent distribution and the high caliber of medical care available to U.S. troops.
Morbidity-The malaria relapse rate was 28 percent in the Mediterranean theater and 23 percent in the Pacific areas. These figures are gross figures in that they have not been adjusted to take into account evacuation, death, or transfer of cases. The figures merely reflect a ratio of readmissions to new admissions.
Several attempts were made to assay the dimensions of the problem by indirect means. Colonel Golz, on the basis of data shown in tables 70 and 71, concluded by one line of reasoning that, of any group of primary malaria cases, 30.6 percent might be expected to relapse at least once, with the average number of relapses being 2.08 for the group. He also cited Lt. Col. (later
Col.) James B. McLester, MC, of the 17th General Hospital who, using the same data and some of his own, made a somewhat different approach. Of a group of cases followed from 1 to 10 months, 30.5 percent relapsed. Over one-half of the relapses during the first 9 months occurred in the first 2 months and another quarter, in the next 2 months. Since after 6 months, the monthly rate remained between 1 and 2 percent, it seemed probable that the relapse rate would be found to be between 50 and 60 percent if the followup were more complete and continued longer. Other data, more extensive numerically, derived from 27 hospitals by questionnaire by the malariologist of NATOUSA, suggested, by several lines of reasoning, a relapse rate of about 50 to 55 percent.
1Data not available from field hospitals.
Colonel McLester stressed the obstacles to statistical accuracy. In the Mediterranean theater, the number and composition of troops were constantly changing 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-
mary attack. Fresh troops might come in who had not previously been exposed to malaria and might have time for only one attack. Soldiers who had had a primary attack might be evacuated, or killed, or transferred to another theater before relapse could develop. Furthermore, in an attempted followup of patients who had been treated in the 17th General Hospital, gross errors were found in their medical histories. Also, the record was 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 of Interior is not a valid figure for the malaria question as a whole. Many of the admissions to general hospitals were transferred from other hospitals, and with few exceptions only general hospitals had the power to transfer cases to the Zone of Interior.
Many of the cases found in general hospitals had been transferred there by other hospitals specifically for Zone of Interior disposition because of repeated recurrences. Nevertheless, a study was undertaken at the 182d Station Hospital to determine the final disposition of its malaria cases: 757 cases were investigated, of which 437 were recurrent and 320 were primary. Of these, 103 cases were transferred to other hospitals for reasons other than malaria and could not be traced as to disposition. Of the remaining 654, those who were transferred were satisfactorily traced. The result of this study showed that 641 went to general military service, 5 went to limited assignment, and 8 (1.22 percent) were recommended for evacuation to the Zone of Interior by a general hospital.
5Although complete and accurate statistics on the incidence
of relapse are not available from any theater, similar relapse rates for
Mediterranean strains (approximately 30 percent) were found elsewhere in
this theater and also in the Zone of Interior during periods of 120 days
following treatment with various antimalarials. Relapse rates were much higher
with Pacific strains during like observation periods of 120 days, being
approximately 80 percent in one study and 80 to 90 percent in another. It should
be noted, however, that a very much higher percentage of relapses of Pacific
origin will fall within the 120-day period (75 percent occurring within the
first 60 days in one study). With the Mediterranean strains, there is a longer
average interval to the first relapse (150 to 200 days). Even when this is taken
into account, the estimated rate of 50 to 60 percent remains appreciably lower
for the Mediterranean strains of P. vivax.
Machine records data concerning cases sent to the Zone of Interior are available for the period 15 September 1944 to 6 April 1945. During this time, 8,055 cases of malaria were disposed of and, of these, 90 cases (1.1 percent) were returned to the Zone of Interior for this cause. An additional 36 cases were found with a secondary diagnosis and the available records were not clear as to which diagnosis was responsible for the evacuation. If these two groups are combined, the total number of cases is 126 or 1.6 percent.
In the 13 case histories6 which follow, examples of particular problems-most of them exceptional, some more typical-are described briefly. Included are eight fatalities.
Herpes labialis occurred in some cases, and occasionally urticaria, which was usually transitory. Urticaria had been seen more often in the early days of the theater, when quinine therapy was still popular. Colonel Golz reported an interesting case, summarized in case 1. Four hospitals reported seven cases of purpura simplex, beginning shortly after or concomitantly with the clinical onset, and clearing completely soon after the start of antimalarial treatment; in four cases this was associated with vivax infections, in three, with falciparum infections. One hospital reported 10 cases of erythema multiforme.
Case 1- In one unusual case, the maturation of each cycle of parasites was accompanied by a severe attack of generalized urticaria and angioneurotic edema of about 12 hours' duration. These attacks occurred three times at 48-hour intervals without any sign or symptom to suggest malaria. There was no elevation of temperature. With the fourth such attack the patient had his first chill and rise in temperature. P. vivax was found in his blood. Atabrine treatment resulted in prompt cessation of his hives and he had no further chill or fever. During the 4 months following his discharge from the 182d Station Hospital he had five relapses for which he was admitted to other hospitals, and in each relapse the same train of events occurred. He was then evacuated to the Zone of Interior.
Four cases were reported in the Mediterranean theater. Case abstracts of two of these patients are appended, one of whom died. Available data on the third patient were so meager as to raise the question of diagnostic accuracy. Records of the fourth were not available.
Case 2.-The soldier was admitted to the 33d General Hospital with a history of chills, jaundice, and dark urine for 4 days. The record did not state whether he had previously had malaria. Prior to admission he had no treatment. On the day of admission he was stuporous and icteric but malaria smears were negative and the leukocyte count
6In another theater, however, under more favorable conditions for prolonged observations on the same body of men, there was shown a reversal of species incidence from 55 percent P. falciparum, 24 percent P. vivax during an epidemic in a malarious environment, to zero percent P. falciparum, 99 percent P. vivax, after the troops were removed to a nonmalarious environment.-P. H. L.
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 of albumin. On the second and third days he was given 2.7 gm. of quinine orally and 1.3 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 the urine became reddish brown in color, showed 3+ albumin and was positive to test for occult blood. The red blood cell count had dropped to 3,060,000 and the hemoglobin to 11.5 gm. per 100 cc. Trophozoites of P. falciparum were still present in the blood. The blood nonprotein nitrogen was 37.5 mg. percent and the icteric index, 9 units. Quinine treatment was stopped; Atabrine, given orally, was started cautiously; and the patient was given a transfusion of 500 cc. of whole blood. On the fifth day he was much improved; the urine was negative; the red blood cell count, 3,780,000; the hemoglobin, 12.0 gm. per 100 cc.; and gametocytes of P. falciparum were present on blood smear. The Atabrine dosage was then increased. Thereafter the course on full doses of Atabrine was uneventful. The urine remained normal although the anemia persisted at a level of about 3,500,000 red cells per cu. mm. Gametocytes of P. falciparum were found on the smear daily until the day after Atabrine was stopped.
Case 3.-A 32-year-old soldier was admitted to a station hospital in August 1943 complaining of chills, fever, and general malaise for 4 days. He stated that he had had malaria several years previously in the United States. He also stated that he had been taking Atabrine in suppressive doses regularly. Physical examination 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 his general condition had deteriorated and quinine was increased to four times daily. 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 test for 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. He was given a transfusion of whole blood and an intravenous infusion of sodium bicarbonate solution. This treatment was repeated on the fifth day. The course, however, had been progressively unfavorable and he died on the fifth hospital day with a clinical diagnosis of blackwater fever. Autopsy confirmed the cause of death as malaria.
Every hospital representative interviewed in this theater reported occasionally seeing patients who complained of vague symptoms of fatigue, headache, and malaise; whose temperatures remained perfectly normal, and whose blood smears were positive for vivax trophozoites. Asymptomatic carriers of falciparum gametocytes were relatively more common. Not infrequently met were cases of proved malaria with recent histories of one or more hospitalizations for fever of undetermined origin, with spontaneous remission. It is highly probable that these previous febrile episodes were due to malarial activity.
Case 4-A soldier without a previous history of malaria was admitted to a station hospital with the admitting diagnosis from his dispensary as "Vague complaints-nervous." The hospital history indicated that he had had a poor appetite, general malaise, and chilly sensations at night for a week. During the first 24 hours in the hospital his temperature remained normal and he showed what were interpreted as signs of an anxiety neurosis. On the evening of the second day in the hospital, the patient had a chill, his temperature rose sharply and he became irrational, confused, and restless. Examination of the blood showed a marked anemia, leukocytosis of 14,000 and a heavy infestation of the red blood cells with P. falciparum. In spite of 5 gr. of quinine intra-
venously every 6 hours and four whole blood transfusions of 500 cc. each, his condition gradually deteriorated. He lapsed into coma on the third hospital day and died on the fifth.
In approximately 75 percent of vivax infections, the typical intermittent temperature graph with quotidian or tertian paroxysms was seen. The relatively high percentage of remittent fever (25 percent) may be ascribed 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 clinical course.
Case 5-A soldier was admitted to a station hospital with a history of having had chills and fever, nausea and vomiting for a week. On admission jaundice was observed and the liver was palpated three fingerbreadths below the costal margin. He was afebrile and malaria was not suspected. Two days after admission the patient became stuporous. His red blood cell count was 2,700,000, his leukocyte count 40,000, blood nonprotein nitrogen 99 mg. percent, and his blood smear was positive for P. falciparum. Despite vigorous treatment with 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 in about 15 or 20 percent of cases. Minimal scleral icterus was seen in less than 5 percent and was thought to be an expression of the blood destructive process that accompanies malaria. Definite jaundice was occasionally seen concurrently with malaria and was thought to be due to complicating infectious hepatitis. Definite jaundice due to malaria did occur in blackwater fever and moribund cases. The term "malarial hepatitis" was freely and glibly used in this theater, but no evidence was adduced to show that such a condition existed. Pathologists found no parenchymal lesion; liver function tests showed only transitory changes, and enlargement of the liver was usually only transitory.
The spleen was often found palpably enlarged during the second week of the acute attack. It was usually soft and tender in the acute stages, and was firm and not tender in the chronic stages. Reports from various hospitals 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 the cases that had frequent relapses had a chronic splenomegaly. In one case, a ruptured spleen was found at autopsy.
Case 6-A soldier was admitted to a station hospital in a moribund condition. He was reported to have fainted shortly before admission and on recovering consciousness complained of substernal pain and vomiting. He denied any injury. In the emergency room he showed extreme pallor, air hunger, and restlessness. His pulse was imperceptible. The abdomen was not distended nor tender. A blood smear showed 4 percent parasitization of the red cells with P. vivax. Plasma was administered as an emergency measure, but the patient ceased breathing while the plasma was being given. At autopsy the peritoneal cavity was found to be filled with blood and a 4 cm. tear was noted in
the spleen. The pathological diagnosis was splenomegaly due to vivax infection, and spontaneous rupture of the spleen.
Vomiting, occurring in about 20 percent of vivax infections, was usually not severe and was associated only with the paroxysms; in falciparum infections, it tended to be more severe and persistent and was one of the frequent indications of the cerebral syndrome.
Abdominal pain was very common. Most frequent was an achy pain high in the left upper quadrant, sometimes radiating to the left lower chest and often aggravated by respiratory excursions. Infrequent cases were seen simulating acute surgical emergencies. Two in which laparotomy was performed are described:
Case 7-A soldier was admitted to an evacuation hospital with a history suggestive of a ruptured abdominal viscus. There was boardlike rigidity of the abdominal muscles, and the leukocyte count was 14,000. Exploratory laparotomy revealed nothing abnormal. Subsequently P. falciparum was discovered in the peripheral blood. Antimalarial therapy produced complete recovery.
Case 8-A soldier was admitted to a station hospital with a diagnosis of acute appendicitis, having experienced 24 hours previously the onset of generalized cramping abdominal pain, which subsequently localized in the right lower quadrant. There was nausea but no vomiting or disturbance of bowel habit. There was no history of malaria. The temperature was 102.8° F. and the leukocyte count 5,900. Marked tenderness was noted in the right lower quadrant on direct palpation and on rectal examination. Emergency appendectomy was performed but a normal appendix was removed. The postoperative course for 2 weeks was complicated by intermittent fever of 100° or 102° F. exhibiting a tertian periodicity. (On one occasion he had a chill and a temperature rise to 105° F.) Repeated malaria smears were negative. On the 19th postoperative day P. vivax was found. Antimalarial therapy resulted in disappearance of all signs and symptoms.
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 cases sometimes contained red blood cells but never pus, parasites, or pathogenic bacteria. A brief description of a fatal case follows.
Case 9.-A 24-year-old soldier was admitted to a station hospital in October 1943 complaining of severe diarrhea of 5 days' duration. The diarrhea was accompanied by severe abdominal cramps and grossly bloody stools. He had had one chill prior to admission. There was no previous history of malaria but the soldier had fought through the Sicilian campaign several months previously. On examination he was found to be in shock. The pulse was almost imperceptible, blood pressure was 70 systolic and 60 diastolic, and temperature 97° F. The abdomen was rigid, leukocyte count was 25,000 and the red blood cell count was below 3 million. The stools contained dark blood and blood smears were positive for P. falciparum. The surgical consultant felt that there was no indication for surgical intervention. On the first hospital day he was given 10 gr. of quinine intravenously, a transfusion of one liter of citrated blood and apparently adequate amounts of physiological saline solution intravenously. Oral quinine therapy
was started. On the second day he was markedly improved. Diarrhea and vomiting ceased; temperature rose to 101° F. and the systolic blood pressure to 110. Oral quinine three times daily was continued. On the third day he suddenly went into a state of peripheral circulatory collapse and promptly died. Autopsy showed an extensive hemorrhagic enterocolitis. Malaria parasites were found in sections of the intestinal tract and the heart showed numerous 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 theater during 1942-45 (p. 514), 14 were ascribed to vivax malaria, 27 to falciparum malaria, and 16 to "other or unclassified malaria" (the "other malaria" excluding quartan malaria and mixed malaria infections). In the 11 deaths reported by Colonel Golz, 10 were due to malignant tertian malaria, and of these, 8 were caused by the cerebral form of the disease. All eight cases illustrated the grave danger attendant upon failure, for whatever cause, to initiate vigorous treatment early.
Case 10-A soldier was admitted to an evacuation hospital with a history of chills and fever for 4 days. There was no past history of malaria. 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 his temperature was 98.8° F. and his general condition seemed to be fair. Blood counts showed a marked anemia and smears showed all stages of P. falciparum. Spinal fluid was negative except for increased pressure. On the second hospital day he suddenly became stuporous, psychotic, and could not be aroused. There was only a slight pupillary reaction and his neck was rigid. On this day the patient received a total of 3.3 gm. of quinine intravenously. In spite of this he developed tonic convulsions and died. Blood quinine level was 7.1 mg. per liter.
Case 11-A 45-year-old soldier was admitted to a station hospital in the spring of 1943 in a marked state of mental confusion and delirium. Because of his mental state no history could be obtained. Persistent vomiting was present. Red blood cell count was 2,000,000 and leukocyte count 12,000. Diagnosis was made on the second day with the identification of P. falciparum in the peripheral blood. Ten grains of quinine were given orally three times daily. However, vomiting persisted. On the fourth day 10 gr. of quinine intravenously every 8 hours was instituted, and the patient received this medication four times. He was also given two whole blood transfusions. He lapsed into coma in spite of this treatment and died on the fifth day. Autopsy report was not available.
Case 12-A soldier was admitted to a station hospital in a comatose state. Signs of lobar pneumonia were present. There was marked anemia, and blood smears were positive for P. falciparum. In spite of treatment with sulfadiazine, intravenous quinine, whole blood transfusions, and oxygen, the patient died on the third hospital day. Death was ascribed clinically to cerebral malaria. Autopsy showed lobar pneumonia and numerous malaria parasites in the brain, heart, and muscles.
The incidence of this ill-defined syndrome varied widely among the hospital representatives questioned although none declared it to be common. Restricted to cases showing one or more of such signs as coma, meningismus, convulsions, persistent delirium, and well-defined neurological signs, 144 cases were reported due to P. falciparum and 19 due to P. vivax. This did not
represent total theater experience, since it was not possible to survey all of the hospitals in the theater.
Of the eight deaths in this theater due to cerebral malaria, all were falciparum infections. The modern concept of the pathological physiology of cerebral 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 for analysis, and in this case the accuracy of the diagnosis was questionable. A summary follows.
Case 13-The patient became ill 6 October 1944 with nausea and some vomiting. Began "shaking." No further coherent story could be elicited. Temperature was 97° F., pulse 104, and respiration 24. There were no abnormal findings. The battalion surgeon who sent the patient to the station hospital on 7 October, suspected malaria. Temperature was 100.2° F. at time of onset.
The patient was semicomatose on 8 October 1944. Lumbar puncture was done on the same day. Pressure was elevated. The first tube contained red cells; the second was crystal clear. There were 84 cells, 30 polymorphonuclears, and 58 lymphocytes. The examining medical officer was not certain that the patient had meningitis. Lymphocytic choriomeningitis or encephalitis was considered. The patient had four generalized convulsions on 11 October and was transferred on that date in deep coma to a general hospital with the diagnosis of epilepsy. On admission considerable motor unrest was noted but no movements of right side. Examination was difficult but did show bilateral ankle clonus and Babinski's and Oppenheim's signs. Abdominal reflexes were absent. Right side of face did not move as well as left; slight internal squint, right eye. Pendular nystagmus, on looking ahead, changed to definite slow vestibular variety on looking to right. Conjugate movements of eyes were preserved; pupils dilated, reacted poorly to light; fundi normal. Patient gave no response to painful stimuli. Definite meningitis neck with direct Brudzinski's sign and bilateral Kernig's sign. Temperature was 102.2° F., pulse 96, respiration 22, and blood pressure 126 systolic and 80 diastolic.
The picture was that of an acute meningoencephalitis. How many of the focal signs were due to the illness per se and how many a product of the postconvulsive state could not then be determined.
Spinal puncture yielded clear fluid; 280 mm. of water pressure; normal dynamics; 4 white blood cells (lymphocytes); sugar, 100 mg. percent; chlorides, 733 mg. percent; globulin, negative. Total protein, 22 mg. percent. Kahn negative. Gold curve, 1,111,000,000. Subsequent smear, culture, and pellicle studies were negative.
12 October 1944: Temperature dropped to normal. Patient responded to questions but was confused much of the time. Neurological signs persisted.
13 October 1944: Spinal fluid examination showed: 260 mm. of water pressure; clear; pressure dropped to 70 mm. of water after removal of 30 cc. of fluid; 5 white blood cells (lymphocytes); sugar, 62 mg. percent (simultaneous blood 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 of delirium 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. No astereognosis. Some tendency toward preservation. Meningeal signs persist.
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 tertian parasites.
25 October 1944: Temperature rose to 103.4° F. during morning. Second slide positive for malaria (P. vivax). Quinine sulfate, 15 gr., three times a day by mouth started.
Four previous smears had been negative for malaria and he had been 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, 17 October. All spinal Kahns negative. Blood bromide, 75 mg. percent, 25 October 1944.
Spinal puncture on 25 October: Pressure 200 mm. of water; 2 white 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. Cleared mentally. All neurological signs cleared up except the homonymous field defect which was still present when he was transferred.
Regardless of some diagnostic confusion, all medical officers in the theater acquired a wholehearted respect for the cerebral manifestations of the disease. The grave prognosis of the frank cerebral syndrome and the serious implications of persistent vomiting in falciparum infections were quickly learned, and this was responsible for the early institution of vigorous therapy in such cases.
As with cerebral malaria, the incidence varied widely as reported by the various hospitals because of lack of uniformity in the criteria for diagnosis. When the discussion was limited to chronic, truly cachectic states, 12 hospitals reported a total of only 26 cases. It is probable that the theater experience did not greatly exceed this figure. Many medical officers noted that the American soldier stood repeated attacks of vivax malaria remarkably well, and a study in the South Pacific confirmed their impression.
From the reports cited, it can be seen that in all theaters of operations in which command and medical officers found malaria a major problem their experiences were very similar, and the stages of their education in dealing with this disease were painfully alike. Rarely has the old adage, "Experience is a hard teacher" been so well illustrated in the annals of medico-military history. The same prejudices, the same mistakes, the same fumblings, and the same slow correction of errors in tactical and medical thinking mark the evolution toward solution of the problem of malaria as exhibited in the reports of the consultants in medicine. Lack of foresight, on the one hand, caught us with scant supplies of quinine; on the other hand, enterprise and ingenuity found ways to improve upon quinine. Under the pressures of war, we learned the chapter on malaria and expanded the section on chemother-
apy. Military medicine, like war itself and the events that lead to war, is full of such ironies; of failures to do something relatively simple that would save much trouble, and then doing something prodigious under the most trying circumstances; in other words, of the human capacity for getting ourselves into the most dreadful difficulties, and then, by summoning great vigor, intelligence, and fortitude, getting ourselves out again. The great wars of our times might be in general so described. The question for the future is how long the human race can take its victories by hairsbreadth; whether, as the wheel spins, we shall always come out on top.