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Chapter XVI

Contents

CHAPTER XVI

Clinical Aspects of Malaria

Harold D. Levine, M.D.

To most medical officers, malaria was a wholly new experience. By and large, they had never seen the disease before and were not likely to see it again. Except such textbook knowledge as they might possess, they had very little basis for comparison of its clinical features in World War II with previous observations. Perhaps for this reason, perhaps because interest in the bedside aspects of malaria was dwarfed by the tremendous advances made in the field of personal and group prophylaxis against the disease, amazingly few attempts were made to document its anamnestic features, symptomatology, and physical findings.

Another reason may underlie the dearth of clinical data on malaria during this war period. It is common experience that the clinical picture of a disease may be modified by its treatment, particularly if the treatment is effective. Thus, full-fledged use of digitalis, diuretics, and salt manipulations has modified the clinical characteristics of congestive heart failure. Likewise, the employment of antibiotics has altered the symptomatology of pneumococcal pneumonia. The same appears to have been true of malaria. In the overwhelming majority of cases, therapy was promptly effective in aborting the disease. Except during the very earliest phases of the war, when dosage was not yet adequate, and in some studies of recurrent cases, or in therapeutic malaria for neurosyphilis, in which treatment was deliberately withheld, the classical picture was blotted out in its earliest stages. Thus, the spontaneous pattern of a clinical attack of malaria was simply not observed in its entirety. To most physicians, therefore, malaria was a brief, grippelike illness with fever, chills and sweats, headaches, and generalized aches and pains.

Source material for the present review consists of a small collection of documents, official and nonofficial, particularly the reports from those theaters of operations where malaria rates were highest; namely, the Mediterranean (formerly North African) Theater of Operations, U.S. Army, and the South and Southwest Pacific Areas. A number of thoroughgoing studies of relapsing malaria due to Plasmodium vivax were also conducted in the Zone of Interior at Harmon General Hospital, Longview, Tex. The author has also drawn upon a number of publications in the medical literature and, of necessity, from his personal experience with the disease. A convenient baseline against which wartime clinical experiences with malaria may be compared is a series of papers entitled "The Infection in the Intermediate


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Host," which appeared in "A Symposium on Human Malaria" published by the American Association for the Advancement of Science in 1941.

PREDISPOSING FACTORS

There appeared to be two factors in determining whether a clinical attack of malaria, either initial attack or relapse, would be precipitated. One was the intrinsic or host factor; after the earlier phases of the war, this boiled down simply to the question whether the soldier was receiving optimum suppressive doses of Atabrine (quinacrine hydrochloride). In the absence of adequate prophylaxis, a number of extrinsic factors, such as injuries, acute illnesses, and surgical operations, appeared to be capable of upsetting the delicate physiological balance between the micro-organism and the host. It was common to find malaria developing on surgical, orthopedic, or general medical wards. In the Mediterranean theater, Lt. Col. (later Col.) James B. McLester, MC, noted, during a period when malaria transmission probably did not occur, that malaria made its appearance in about 5 percent of patients with atypical pneumonia, in a similar percentage of patients with infectious hepatitis, and in about 1 percent of those with trenchfoot.l Other factors that were thought to be important in activating the disease were fatigue or exhaustion, hemorrhage, alcoholic bouts, the use of anesthetics, or exposure to extreme or sudden changes in temperature. There seemed little doubt that once the stage was set, any one or more of these factors could trigger a clinical attack. Contrariwise, it must be stated that in numerous trials it was demonstrated conclusively that even excessive physical activity was not a cause of breakdown of Atabrine suppression ("breakthrough").

In addition to these intrinsic (host) and extrinsic (environmental) factors in the precipitation of a malarial paroxysm, there was the parasite factor. It is well known that there are certain attributes resident in the individual Plasmodium itself that must not only determine whether a paroxysm will be inducted but what sort of clinical picture it will present. In short, although the malarial fevers possess certain common characteristics, they are actually a group of several distinct entities each with its peculiar attributes and individual potentialities.2 Most descriptions of the disease available to the writer, however, failed to distinguish between the various plasmodial species responsible for the attack. In the text that follows, a description referring to a definite species can be assumed by the reader to be an exception to this generalization either stated in the quoted document or personally known to the author.

1McLester, J. B.: Relapsing Malaria. M. Bull. Mediterranean Theat. Op. 3: 111-113, April 1945.
2Kitchen, S. F.: Symptomatology: General Considerations. In Malariology, A Comprehensive Survey of All Aspects of This Group of Diseases from a Global Standpoint. Philadelphia: W. B. Saunders Co., 1949, pp. 966-994.


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PRODROMAL SYMPTOMS

Especially in cases that began insidiously, it was very difficult to draw a dividing line between prodromal symptoms and the actual onset of an attack of malaria. Patients with a brisk onset often stated that they had felt perfectly well on the preceding day. When prodromata were described, they lasted 2 or 3 days and were generally the usual symptoms of the frank attack presenting in lesser intensity. The most frequent complaints were headache, backache, weakness, and generalized aches. In a study at Harmon General Hospital of 435 soldiers with malaria due to P. vivax who were permitted to relapse, three-fourths had prodromal symptoms.3 Most of these patients could reliably predict the imminence of an attack.

CLINICAL SYMPTOMS OF THE ACUTE ATTACK

Headache-Headache, generally severe, of a pounding character, and frontal or bitemporal in distribution, occurred in almost all cases. In some, it was described as having a retrobulbar component. In general, this symptom outlasted the fever and other symptoms by several days. In Plasmodium falciparum cases, it was occasionally the harbinger of an impending cerebral syndrome.4 In some cases there was an associated meningismus.

Chill-In 80 percent of the attacks observed in the study at Harmon General Hospital, there was an acute rigor or chill; in another 8 percent, there was at least a sensation of chilliness.

Fever.-The great majority of patients showed fever peaks ranging from 102 to 105 F. by mouth. Since the response to treatment was generally prompt and convincing, the fever was generally interrupted after one or two peaks so that the remainder of the spontaneous febrile pattern of the attack was not observed. In the study made by Gordon and his coworkers, well over 80 percent of patients had thus attained a normal temperature after 3 days of treatment, and over 90 percent by 5 days after the beginning of treatment. Although the war experience afforded some opportunity to study the detailed morphology of the fever course in the various forms of malaria, a careful documentation of intermittency, remittency, periodicity, regimentation, anticipation, postponement of fever peaks, continued fever, or of the fever spikes characterized as being broad based or narrow based, could not be found. Nor is it clear that this would have served a useful purpose.5 In the Southwest Pacific Area, remittent quotidian fever was seen more often

3Gordon, H. H., Lippincott, S. W., Marble, A., Ball, A. L., Ellerbrook, L. D., and Glass, W. W., Jr.: Clinical Features of Relapsing Plasmodium Vivax Malaria in Soldiers Evacuated from the South Pacific Area. Arch. Int. Med. 75: 159-167, March 1945.
4All material on malaria in the Mediterranean (formerly North African) Theater of Operations, U.S. Army, except when otherwise noted, is taken from Golz, Harold H.: Human Malaria in the North African and Mediterranean Theaters of Operations, U.S. Army. [Official record.]
5Kitchen, S. F.: Falciparum Malaria. In Malariology, A Comprehensive Survey of All Aspects of This Group of Diseases From a Global Standpoint. Philadelphia: W. B. Saunders Co., 1949, pp. 995-1016.


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than anticipated and this apparently without regard to species identification. In general, initial attacks were much more likely to be characterized by continued fever and relapses by a hectic fever.

Sweats-Profuse perspiration was characteristic of the overt paroxysm. A few observers felt that a sweat out of proportion to the fever in the absence of an antecedent chill was actually a helpful aid in the diagnosis of malaria.

Splenomegaly-At a Marine installation in Oregon,6 splenomegaly was noted in less than 5 percent of cases acquired in the Southwest Pacific Area, even after 20 to 30 recrudescences. Transient splenomegaly, generally of only mild degree, was detected in only about 8 percent immediately after acute attacks of malaria caused by P. vivax. Such experiences are in conformity with previous observations regarding splenomegaly in malaria. Increase in the size of the spleen apparently depends upon the possession of some degree of immunity. It is also well known that the enlargement rapidly diminishes on cessation of the paroxysm, particularly if interrupted by treatment. In a tabulation of the symptoms of malaria as observed in the Mediterranean theater, based upon a questionnaire sent to medical officers, splenomegaly was reported in a range of from 27 to 85 percent. This wide divergence was attributed to differences in the thoroughness with which the examination was conducted. A low incidence was, however, reported from all other theaters and is probably real. What enlargement took place was not striking and was generally transient. This low percentage of palpable spleens stands in marked contrast to the accepted high incidence of this finding in seasoned immune natives exposed presumably to the same malarial parasites as were these unseasoned, nonimmune troops.

American medical officers who had the opportunity of working with Australian medical officers learned one technique of palpating spleens which is worthy of repetition. So far as this author knows, the method is virtually unknown in the United States. It consists in having the patient sit up in bed drooped forward over his knees. A remarkable degree of relaxation of the abdominal muscles is often thus attained. With the examiner at the patient's back, the fingers of both of the examiner's hands are curled around the left lower flank of the patient while the patient takes deep breaths. Frequently, the palpating fingers can extend well up under the rib margin. In a number of cases, the spleen can be felt by this method and by none other. The technique is perhaps best adapted to young individuals of military age.

Hepatomegaly-In a considerable percentage of cases, the liver was palpable one or two fingerbreadths below the right costal margin, firm, sharp, and slightly tender. Kern and Norris found such involvement in 60 percent

6Coggeshall, L. T.: Malaria and Filariasis in the Returning Serviceman. Ninth Charles Franklin Craig Lecture. Am. J. Trop. Med. 25: 177-184, May 1945.


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of 1,153 cases of malaria seen on a hospital ship.7 In the North African-Mediterranean theater this was noted in from 5 to 20 percent of cases. In the Southwest Pacific Area, this finding actually approached or exceeded the frequency of splenomegaly. This may be due to the fact that slight degrees of hepatomegaly are more readily detected than the slight degrees of splenomegaly that occur in nonimmune, promptly treated soldiers. It is conceivable, although less likely, that this discrepancy is related to a predilection of the Southwest Pacific malarial strains to liver involvement. This observation appears to have been anticipated by the peacetime findings of Gunther,8 who noted the frequent finding of tenderness in the right hypochondrium in New Guinea malaria. He designated this as gallbladder tenderness.

Lymphadenopathy-It was the observation of the author that the most common cause of slight to moderate degrees of generalized glandular enlargement in the Southwest Pacific Area was malaria. The pronounced grade of enlargement characteristic, for example, of scrub typhus was never observed in malaria.

Abdominal symptoms-Half of the patients complained of abdominal pain. This was more frequent on the left than on the right side and occasionally radiated to the left lower chest. When bilateral it was generally sharper on the left. Although this was attributed to splenomegaly, the spleen was felt in only a minority of these patients. In a quarter of the patients the left side of the abdomen was tender; in some there was tenderness on the right side as well, generally in the right upper quadrant. Nausea occurred in 59 percent, and vomiting in 36 percent of attacks, but troublesome vomiting was very infrequent. The relative role of treatment with quinine or Atabrine on the one hand, and of the disease itself, on the other, in the development of these symptoms was uncertain, since treatment was started promptly in the great majority of cases. Diarrhea was not uncommon as the presenting complaint in uncomplicated malaria, regardless of type, in tropical areas where it occurred in mild form in about 10 percent of cases. This symptom was no more common in P. falciparum cases but when present was more severe and at times dysenteric and associated with bloody stools.9

Upper respiratory symptoms-These were quite common and almost certainly a part of the disease itself. The most common symptom was a dry, painless cough. This was generally associated with musical rates, squeaks, and groans throughout the lung fields, signs quite characteristic of bronchial asthma but disappearing promptly on therapy. Coryza and bronchitis were less frequent manifestations. Malaria was frequently associated with bronchitis, and roentgenographic examination frequently showed infiltrations inter-

7Kern, R. A., and Norris, R. F.: Liver Involvement in Malaria. U.S. Nav. M. Bull. 43: 847-858, November 1944.
8Gunther, C. E. M.: Practical Malaria Control. Sydney: Consolidated Press, Ltd., 1943, p. 47.
9Hughes, S. B., and Bomford, R. R.: Clinical Features and Treatment of Malaria in British Troops in West Africa. Brit. M. J. 1: 69-73, 15 Jan. 1944.


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preted as the result of complicating viral or bacterial pneumonia. It would be difficult to determine to what extent these were actually part and parcel of the malarial infection.

Miscellaneous symptoms-Herpes labialis was seen in a rather high percentage of cases in the Mediterranean theater. Urticaria, generally transitory, was occasionally seen, particularly in the earlier phases of the war when quinine was used more frequently. Tinnitus was noted in about a quarter of the cases. In most patients with this complaint, it was difficult to determine the relative role of the disease or the treatment in its development. Cerebral symptoms such as drowsiness, fainting, disorientation, change in disposition, or meningismus were complaints in a few cases of malaria due to P. falciparum.10 The prompt subsidence of these symptoms in malaria caused by P. vivax led to the impression that they were the result of the associated fever per se and not of cerebral malaria. In the alleged instances of cerebral malaria due to P. vivax infection,11 the possibility of an undetected mixed infection including P. falciparum cannot be excluded.

In one exceptional experience, a number of patients with malaria presented symptoms suggesting hyperthyroidism.12 These individuals showed prominent eyes, loss of weight, sudoresis, wet palms, tachycardia, and fine tremor of hands and tongue. The basal metabolic rate was normal in these cases.

COMPLICATIONS OF MALARIA

In the past, involvement of every organ or organ system has been described as complicating malarial fever, particularly when caused by P. falciparum. These have generally been ascribed to capillary infarction resulting from agglutination of the parasites along the capillary endothelium. Experience in World War II emphasized the extreme infrequency of such complications in adequately treated malaria and recalled the admonition of Stratman-Thomas that "the innumerable clinical manifestations, symptoms and sequelae which have been ascribed to malaria are unflattering demonstrations of the imagination and credulity of the human mind."13 The following manifestations appear, however, to be fairly well documented.

1. Cerebral malaria.-Almost without exception, malaria deaths were due to cerebral involvement.14 A clear-cut picture of just what constitutes cerebral malaria was often difficult to draw.15 Empirically, the term may be

10Talbot, D. R.: New Aspects of Malaria. J.A.M.A. 123: 192-194, 25 Sept. 1943.
11McGinn, S., and Carmody, J. T. B.: Cerebral Symptoms in Malaria. U.S. Nav. M. Bull. 43: 1157-1162, December 1944.
12Weeks, D. A.: Observations on Malaria. U.S. Nav. M. Bull. 43: 1171-1177, December 1944.
13Stratman-Thomas, Warren K. : The Infection in the Intermediate Host: Symptomatology, Vivax Malaria. In A Symposium on Human Malaria. Washington: American Association for the Advancement of Science, 1941, pp. 183-189.
14(1) Russell, Paul F., West, Luther S., and Manwell, Reginald D.: Practical Malariology. Philadelphia: W. B. Saunders Co., 1946, p. 293. (2) Medical Department, United States Army. Preventive Medicine in World War II. Volume VI. Communicable Diseases: Malaria. [In preparation.]
15See footnote 11, above.


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applied to any case exhibiting any one or more of the following findings: Meningismus, convulsions, persistent delirium, or well-defined neurological signs. An index of the prevalence of cerebral malaria in World War II may be taken from the records of one U.S. Army general hospital in India where in 6 months of 1943 there were 40 cerebral cases among 1,764 U.S. soldiers and 100 cases among 4,295 Allied personnel.16 In the Mediterranean theater, when the bulk of our troops were in Italy, medical officers of approximately 25 evacuation, station, and general hospitals reported 163 cases of cerebral malaria. Of these, 144 were recognized as caused by P. falciparum, and 19 were ascribed to P. vivax. There were 11 deaths due to P. falciparum infections, and of these 8 were cases of cerebral malaria. Preliminary tabulations of individual medical records indicate that there were 57 deaths due to malaria, all forms, originating in the Mediterranean theater during the years 1942-45. Of these, 27 were due to P. falciparum infections. Usually, the symptoms made their appearance a week or so after the onset of the clinical attack of malaria, following a day or two of precoma with persistent vomiting, increasing restlessness, mental confusion, and severe headache, but sometimes cerebral malaria developed abruptly without warning even after 1 or 2 days of treatment. Blurring of vision or diplopia were not uncommon. Acutely developing psychotic or psychoneurotic states were particularly alarming.

After the onset of the syndrome, the patient might show a profound stupor deepening into a coma; he might develop convulsive seizures17 or exhibit nuchal rigidity, maniacal states, or various reflex disturbances. The temperature would rise progressively or abruptly to extremely high levels before death. In many respects, the illness resembled meningitis, encephalitis, or severe typhus fever. The spinal fluid was generally under increased pressure. Half of the spinal fluids examined showed an increased globulin content and many showed cell counts ranging between 20,000 and 30,000. The blood smear often failed to reveal malarial parasites until after repeated examination. When recovery occurred, it was generally completed, although a few patients showed residual cranial nerve palsies, hemiplegia, paresis, or psychosis.

2. Other involvement of the nervous system.-In the Mediterranean theater, patients were seen with peripheral neuritis involving the lower extremities. Three patients exhibited transient blanching of the optic nerve, one facial neuritis and homolateral brachial neuritis. In one hospital in the Southwest Pacific,18 16 patients were seen with a severe irritative neuritis with hyperalgesia, hyperhidrosis, and increase in muscle tone with actual con-

16Fitz-Hugh, T., Jr., Pepper, D. S., and Hopkins, H. U.: The Cerebral Form of Malaria. Bull. U.S. Army M. Dept. No. 83, pp. 39-48, December 1944.
17Simpson, W. M., and Sagebiel, J. L.: Symposium on First Year of Activities at U.S. Naval Base Hospital-; Cerebral Malaria. A Report of 12 Cases Encountered at U.S. Naval Base Hospital-.U.S. Nav. M. Bull. 41: 1596-1602, November 1943.
18Harvey, A. M.: A Type of Neuritis Associated With Malarial Fever. Bull. Johns Hopkins Hosp. 75: 225-231, October 1944.


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traction occurring in bilaterally symmetrical areas, usually the forearm and hand. Milder forms of neuritis, occurring in 18 of 100 consecutive cases of malarial fever, presented only subjective manifestations with transient attacks of numbness and tingling. With recurrent attacks of malarial fever, the nervous symptoms increased. The majority of these cases were due to a mixed infection. Distinction had to be drawn between these neuritides and those following that almost ubiquitous tropical disease, cutaneous diphtheria.

3. Blackwater fever.-This was rare. Twenty-five cases of acute hemolytic anemia and hemoglobinuria were reported as blackwater fever from the South Pacific Area. There were three deaths in this group, a much lower mortality than is usual for blackwater fever. Fifteen of the twenty-five cases occurred in Negro troops stationed on one island.19

4. Cardiac malaria.-Functional cardiac disorders, such as irritable heart with tachycardia, premature beats, and systolic murmurs, were, of course, not extremely rare in patients during malarial attacks or between relapses. But true organic cardiac changes, such as cause death from myocardial inflammation or capillary infarction, were extremely rare.20 These generally occurred in individuals with malaria due to P. falciparum. The author saw two such patients who developed severe cerebral malaria in the combat area, both cases caused by P. falciparum. One had auriculoventricular and intraventricular block and the other a moderately enlarged, possibly dilated heart. The subsequent fate of these soldiers could not be followed. Two other patients with P. falciparum infection died at a nearby hospital. Both showed agglutination of the parasites along the capillary endothelium in the myocardium.21 This experience led to the suspicion that microscopic coronary occlusions might be as important a factor in fatal P. falciparum cases as occlusion of cerebral vessels.

5. Rupture of the spleen.-This was a rare complication corresponding with the low incidence of splenomegaly.

6. Ocular complications.-A few cases of iridocyclitis coincided with attacks of malaria. In one patient, transient edema of the cornea occurred in each of two attacks of malaria due to P. vivax in the Mediterranean theater.

7. Medical shock.-If nothing else was done about the ancient terminology of clinical malaria, the record was set straight regarding the obsolete designation algid malaria. The fact that this is nothing more nor less than medical shock complicating malaria22 should have been acknowledged long before World War II. This reorientation is of more than academic importance for it provides the clinician with a whole group of well-recognized

19Harper, Paul A., Butler, Fred A., Lisansky, Ephraim T., and Speck, Carlos D.: Malaria and Epidemic Control in the South Pacific Area, 1942-44, pp. 195-207. [Official record.]
20Sprague, H. B.: The Effects of Malaria on the Heart. Am. Heart J. 31: 426-430, April 1946. 
21Merkel, W. C.: Plasmodium Falciparum Malaria; The Coronary and Myocardial Lesions Observed at Autopsy in Two Cases of Acute Fulminating P. Falciparum Infection. Arch. Path. 41: 290-298, March 1946.
22Kean, B. H., and Taylor, C. E.: Medical Shock in the Pathogenesis of Algid Malaria. Am. J. Trop. Med. 26: 209-219, March 1946.


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therapeutic aids for the treatment of this serious complication. The discovery of adrenal hemorrhages in Filipinos who died with this syndrome23 suggests the feasibility of steroid replacement therapy, but whether this would be a universal finding is not known.

CHRONIC MALARIA

All observers agreed that in the absence of other factors, such as concomitant infection or malnutrition, the classical textbook picture of chronic malaria was wasting, anemia, and splenic enlargement. It was not observed in the U.S. Army, where troops were well fed and given adequate suppressive therapy. The extraordinarily low incidence of splenomegaly and anemia has already been discussed. Due significance must be accorded the role of hydration and of slight loss of weight as early adaptive processes attending acclimatization to the Tropics-the former might suggest anemia; the latter, wasting.24 In contrast to the native with chronic malaria, exhibiting the characteristic triad of intermittent fever, anemia, and splenic enlargement, the U.S. Army patients who were incapacitated between relapses presented complaints generally falling into four categories: (1) Neurocirculatory asthenia, (2) symptoms referable to the musculoskeletal system, (3) vague symptoms referable to the central or autonomic divisions of the nervous system, and (4) combinations of two or more of these three groups.25

A careful study was made of a very large number of soldiers suffering from repeated P. vivax relapses and who complained of not feeling up to their usual health between attacks.26 These men described the following symptoms: Weakness, fatigability, tension, excessive sweating, headaches, exertional dyspnea, anorexia, palpitation, blackouts, insomnia, nervousness, splenic pain, muscle pain, indigestion, and urinary frequency. These symptoms were always extremely difficult to evaluate. Although another group of observers who thoroughly studied this symptom complex in 50 servicemen conceded that malaria itself might be of prime importance in its production,27 it was their further conviction, strongly concurred in by others, that the way in which the individual adjusted himself to his malaria and to concurrent situational factors was more significant in the development of symptoms, in their perpetuation, and intensification. It was the impression of most medical officers that these were exaggerated symptoms in men who were actually more interested in returning to their homeland than in rehabilitation for active

23Garcia, Eusebio Y.: Malaria in War and Peace. Manila: Grace Trading Co., 1945, p. 49.
24Lee, D. H. K.: The Human Body and Hot Environments; Factors Influencing Man's Reactions to Heat Stress. [Unpublished manuscript.]
25Levine, H. D.: Medical Experiences With American Troops in the Pacific, With Remarks on the Diagnostic Value of Sternal Puncture in Malaria and on the Innocuousness of Hookworm Infection. New England J. Med. 235: 933-938, 26 Dec. 1946.
26See footnote 3, p. 481.
27Tumulty, P. A., Nichols, E., Singewald, M. L., and Lidz, T.: An Investigation of the Effects of Recurrent Malaria; An Organic and Psychological Analysis of 50 Soldiers. Medicine 25: 17-75, February 1946.


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duty. In the majority of cases, the symptoms obviously were strongly conditioned by such factors as exposure to combat and adverse living conditions or previous personality problems. None of the patients complaining of dyspnea on exertion presented evidence of heart disease as judged by physical examination, exercise tolerance tests, roentgenographic examinations or electrocardiograms. A red blood cell count below 4 million was extremely rare. Half of them had weight losses of from 10 to 30 pounds. But no measurable damage or dysfunction of the organ systems could be found. These observers condemned the practice of repeated or prolonged hospitalization for these individuals, contact with neuropsychiatric patients, or with patients about to be returned to the United States.

RELAPSES IN MALARIA

The tendency of malaria due to P. vivax to recrudescence was well documented before World War II, and subspecies variability in this respect has been recognized.28 Relapsing malaria caused by P. vivax in World War II should not therefore have been a surprise,29 nor should the particular character of one P. vivax strain as contrasted with another.30

Accurate statistics are not available, but there can be little doubt as to the remarkable relapsing tendencies of the P. vivax strains in the South and Southwest Pacific Areas. The author first became aware of the magnitude of this problem while on detached service with an Australian hospital. The medical officers there, only recently returned from service in the Mediterranean, were appalled by the stubborn relapsing tendency of the New Guinea strains of P. vivax, contrasting with the relative infrequency of relapse in the strains to which they had become accustomed in the Middle East. That this was the result of species specificity was subsequently confirmed in reports from Europe and the Mediterranean and in experience at Harmon General Hospital with malaria inocula of Pacific and Mediterranean origin. With the Pacific strains, relapses occurred in 70 percent of cases, and 75 percent of the relapses developed within 60 days of completion of Atabrine therapy. In the Mediterranean strains, there was a much lower incidence of relapses (30.6 percent) and a much longer delay (150 to 200 days) before relapse. There was other inferential evidence that malaria caused by P. vivax in the South Pacific Area differed from the same type of malaria seen elsewhere. Of the men in that area, 57 percent had in excess of 14 acute attacks, some as many as 40. The relapses appeared moreover to have a greater rhythmicity and regularity than those caused by other strains.31 It should be borne in mind that all the

28Hackett, L. W.: Malaria in Europe, An Ecological Study. London: Oxford University Press, 1937.
29Russell, P. F.: Lessons in Malariology From World War II. Charles Franklin Craig Lecture, 1945. Am. J. Trop. Med. 26: 5-13, January 1946.
30Essential Technical Medical Data, European Theater of Operations, U.S. Army, for May 1944, inclosure 17 thereto.
31See footnote 6, p. 482.


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experience here described was derived chiefly from P. vivax infections contracted by persons who had no immunity whatever to malaria.32

Malaria caused by P. falciparum exhibited relatively little tendency to relapse in the Mediterranean and Southwest Pacific, and when relapse subsequently occurred in these cases, it was only occasionally due to this same micro-organism. It appears more than likely that their original infection was actually a mixed one, P. falciparum being the dominant organism in the first attack, the subsequent relapses resulting from the emergence of the originally recessive P. vivax strain.33 Thus, in advance areas in the Southwest Pacific, P. falciparum infections accounted for about 40 percent of all attacks,34 while in the rear nonmalarious areas P. falciparum was found in only 8 percent of cases, P. vivax in 68 percent. Such usurpation of the dominant role in the relapse by P. vivax was well known long before the war.35 Quartan malaria has long been regarded as relapsing malaria par excellence, but experience with quartan malaria in World War II was too limited to justify more than passing mention.

SUPPORTING EVIDENCE FROM THE LABORATORY

Parasite identification-Most of the time during the war, the diagnosis of malaria was made with positive support from the laboratory. The techniques principally used have been discussed elsewhere. Variable success was reported in experiences with sternal puncture. In a number of studies,36 occasional marrow smears were reported positive when the thick and thin blood smears were negative. Subsequent improvement in the accuracy of routine blood examinations for malarial plasmodia, however, dampened interest in sternal puncture.

Blood studies-The white blood cell count was generally below normal, usually in the range between 4,000 and 6,000 in the Mediterranean theater study. This fact was frequently of diagnostic significance. In a small percentage of cases, a more marked leukopenia (less than 3,000) was recorded. Leukocytosis was seen under three conditions; namely, in the presence of a concomitant or complicating bacterial infection, in some severe uncomplicated cases, and in cerebral malaria. In the latter groups, it was apparently related to necrosis of tissues. Mild lymphocytosis was the rule. In a series reported from the Mediterranean theater, 45 to 65 percent of the lymphocytes resembled those observed in infectious mononucleosis.

32Dieuaide, F. R.: Chronic Relapsing Vivax Malaria in the Army, 1942-44. [Official record.]
33(1) Malaria in the First Marine Division While Staged in Base Section No. 4, 1943. [Official record.] (2) Metcalf, R. J., and Ungar, J., Jr.,: Relapsing Malaria: Analysis of Cases from the Solomons. U.S. Nav. M. Bull. 43: 859-870, November 1944.
34Baker, M. P., Lyman, J. R., and Coons, A. H.: A Summary of Three Months' Experience With Malaria at the 105th General Hospital, U.S. Army, Southwest Pacific Area, December 1942-February 1943. [Official record.]
35See footnote 28, p. 488.
36(1) See footnote 25, p. 487. (2) Jacobson, B. M., and Russell, H. K.: Sternal Puncture in Diagnosis of Malaria. U.S. Nav. M. Bull. 45: 429-432, September 1945.


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The reported incidence of anemia was variable. Only one instance of mild normocytic, normochromic anemia was found in a group of 50 well-studied patients with malaria due to P. vivax at the 118th General Hospital in the South Pacific.37 This was the general experience. In the Mediterranean theater, however, 29.5 percent of patients with malaria caused by P. vivax had red cell counts of 4 million or less. Anemia was somewhat more common in malaria due to P. falciparum, particularly during or shortly after the paroxysm. Counts of less than 3 million were stated to have been common in P. falciparum infections.

In a small percentage of cases, the sedimentation rate was increased. In about half of these, this finding was accounted for by some complicating infection; in the remainder, it was unexplained and presumably related to the malaria per se. Erythrocyte fragility was probably normal.

Serological tests-The serological tests for syphilis were frequently positive for longer or shorter periods after the acute paroxysms. The exact incidence of this finding cannot be stated. Dawber38 found false-positive tests in 12.5 percent of 64 cases of malaria, generally becoming seronegative in 10 days after the last chill. One case remained positive for 18 days. At the 118th General Hospital, 15.6 percent of 900 cases of malaria ascribed to P. vivax were positive to Kahn tests. In the South Pacific Area, false-positive reactions were found in 51 percent by the Mazzini test, 47.5 percent by Kahn, 33.6 percent by Kline, 20.4 percent by Kolmer, 10.4 percent by Eagle, and 5.8 percent by the Hinton technique.39 Rosenberg40 likewise found that the Hinton test yielded the smallest proportion of falsely positive reactions. He found that the strongest false reactions were obtained between 7 and 10 days after the chill and persisted for 4 to 6 weeks. He felt that persistence of positive serology by any test beyond 6 weeks, in the absence of continued evidence of malarial infection, should arouse the suspicion of syphilis.

The complement fixation test for malaria in general gave unsatisfactory results. In the Mediterranean theater, this was attributed to a faulty antigen. The consensus furthermore was that the adrenalin provocation test (Ascoli) was not helpful in diagnosis.

A number of studies were made of liver function in malaria patients. A study of 317 patients with chronic relapsing malaria due to P. vivax at Harmon General Hospital disclosed transient disturbances of function but gave

37See footnote 27, p. 487.
38Dawber, T. R.: On the Importance of Malaria as a Cause of False Positive Serologic Reactions. Ann. Int. Med. 19: 651-655, October 1943.
39Simpson, W. M., Leake, W. H., McMahon, A., Gudex, T. V., and Rueckert, R. R.: Symposium on First Year of Activities at U.S. Naval Base Hospital-; Experiences With Malaria at an Advance Base in the South Pacific. Report of 4,647 Admissions at -. U.S. Nav. M. Bull. 41: 1588-1595, November 1943.
40Rosenberg, A. A.: Effect of Malaria on Serologic Tests for Syphilis. Bull. U.S. Army M. Dept. No. 84, pp. 74-80, January 1945.


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little or no indication of permanent hepatic dysfunction.41 The percentage of abnormal response to tests was somewhat higher in a study conducted in North Africa, but this was not limited to P. vivax cases. In this latter group, the liver was enlarged in 20 percent of cases.

DIFFERENTIAL DIAGNOSIS

The morbid conditions that had to be differentiated from malarial fever were legion. They varied, of course, with geographic location. Thus, sandfly fever (in the Mediterranean), dengue or scrub typhus fever (in the Pacific), and pneumonia (in Panama)42 had to be given important consideration. The medical school teaching that it is wisest in a given case to explain a symptom complex on the basis of a single diagnosis rather than multiple diagnoses was not justifiable in malarious areas. Malaria being almost ubiquitous, the medical officer had to be prepared to find it as a complicated or a complicating disease. When the smear was positive, the decision had to be made whether the Plasmodium was there as an active hidden partner or whether this finding represented a mere parasitic relapse of little or no clinical importance. Almost all of the patients with salmonellal infection described by Baker and Bragdon,43 for example, showed smears positive for malaria. A large majority of the patients with scrub typhus fever who came to the 105th General Hospital in the Southwest Pacific had positive smears.

A complete elaboration of the different conditions that would have to be considered in the differential diagnosis would be too formidable a task to be undertaken here. Such a list would certainly have to include tuberculosis, typhoid fever, amebic and bacillary dysentery, amebic hepatitis, preicteric infectious hepatitis, meningitis, Hodgkin's disease, subacute bacterial endocarditis, leishmaniasis, and schistosomiasis as well as the conditions that have just been enumerated; namely, dengue fever, sandfly fever, salmonellal infection, and scrub typhus. At times, the symptoms of a paroxysm would simulate an acute surgical emergency, such as biliary colic, ruptured peptic ulcer, ruptured spleen, or acute appendicitis. And here again, with an established surgical condition, a complicating malarial infection was not uncommon. At the 105th General Hospital, for example, about a fifth of the patients with malaria were battle casualties on the surgical service. Hyman analyzed the records of 100 patients admitted to a naval base hospital in the Pacific with a diagnosis that was subsequently changed to malaria.44 These

41Lippincott, S. W., Ellerbrook, L. D., Hesselbrock, W. B., Gordon, H. H., Gottlieb, L., and Marble, A.: Liver Function Tests in Chronic Relapsing Vivax Malaria. J. Clin. Investigation 24: 616-622, September 1945.
42Applebaum, I. L., and Shrager, J.: Pneumonitis Associated With Malaria. Arch. Int. Med. 74: 155-162, September 1944.
43Baker, M. P., and Bragdon, J. H.: Septicemia Due to Salmonella Enteritidis. New England J. Med. 237: 175-179, 7 Aug. 1947.
44Hyman, A. S.: Clinical Masquerades of Malaria; Observations in South Pacific Combat Areas. U.S. Nav. M. Bull. 45: 287-303, August 1945.


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cases fell into groups classified according to the major predominating symptom that led to the erroneous diagnoses, as follows:


Diagnoses

Number

Simulated diseases of the chest

34

    

With cardiac symptoms

21

    

With pulmonary symptoms

13

Diseases of the abdomen

26

    

Stomach

9

    

Liver and gallbladder

8

    

Spleen

6

    

Appendix

3

Diseases of the bones and joints

21

Diseases of the head

12

    

Brain

7

    

Eyes

3

    

Other

2

Miscellaneous

7

    

Kidney

4

    

Other

3


Total

100


These diagnoses were made during the early days of the Solomon Islands campaign before most of the medical officers had become familiar with the bizarre manifestations of malaria and before an adequate schedule of Atabrine suppression had been worked out.

SUMMARY

When malaria was promptly recognized and effectively treated in the nonimmune American soldier it was generally a brief, grippelike illness with headache, backache, pain in the abdomen, chills or chilliness, nondescript fever, and sweating. These patients showed very little splenomegaly, more impressive hepatomegaly. Diarrhea and wheezing occurred in many of the acute cases. There was very little, if any, tendency to complication. Anemia was not a problem in P. vivax infection; in some P. falciparum cases it was a moderate and transient phenomenon. The Pacific strains of P. vivax showed an extraordinarily stubborn tendency to relapse. Disability between relapses was largely related to prolonged tropical or combat service, to ennui or nostalgia, or to the soldier's reaction to his illness. The mortality rate was phenomenally low. (See p. 460.) Death was generally the result of cerebral malaria due in most, if not all, cases to P. falciparum.

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