CHAPTER XVI
Clinical Aspects of Malaria
Harold D. Levine, M.D.
To most medical officers, malaria was a wholly newexperience. By and large, they had never seen the disease before and were notlikely 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 WarII with previous observations. Perhaps for this reason, perhaps because interestin the bedside aspects of malaria was dwarfed by the tremendous advances made inthe field of personal and group prophylaxis against the disease, amazingly fewattempts were made to document its anamnestic features, symptomatology, andphysical findings.
Another reason may underlie the dearth of clinical data onmalaria during this war period. It is common experience that the clinicalpicture of a disease may be modified by its treatment, particularly if thetreatment is effective. Thus, full-fledged use of digitalis, diuretics, and saltmanipulations has modified the clinical characteristics of congestive heartfailure. Likewise, the employment of antibiotics has altered the symptomatologyof pneumococcal pneumonia. The same appears to have been true of malaria. In theoverwhelming majority of cases, therapy was promptly effective in aborting thedisease. Except during the very earliest phases of the war, when dosage was notyet adequate, and in some studies of recurrent cases, or in therapeutic malariafor neurosyphilis, in which treatment was deliberately withheld, the classicalpicture was blotted out in its earliest stages. Thus, the spontaneous pattern ofa clinical attack of malaria was simply not observed in its entirety. To mostphysicians, 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 smallcollection of documents, official and nonofficial, particularly the reports fromthose theaters of operations where malaria rates were highest; namely, theMediterranean (formerly North African) Theater of Operations, U.S. Army, and theSouth and Southwest Pacific Areas. A number of thoroughgoing studies ofrelapsing malaria due to Plasmodium vivax were also conducted in the Zoneof Interior at Harmon General Hospital, Longview, Tex. The author has also drawnupon a number of publications in the medical literature and, of necessity, fromhis personal experience with the disease. A convenient baseline against whichwartime clinical experiences with malaria may be compared is a series of papersentitled "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 aclinical attack of malaria, either initial attack or relapse, would beprecipitated. One was the intrinsic or host factor; after the earlier phases ofthe war, this boiled down simply to the question whether the soldier wasreceiving optimum suppressive doses of Atabrine (quinacrine hydrochloride). Inthe absence of adequate prophylaxis, a number of extrinsic factors, such asinjuries, acute illnesses, and surgical operations, appeared to be capable ofupsetting the delicate physiological balance between the micro-organism and thehost. It was common to find malaria developing on surgical, orthopedic, orgeneral medical wards. In the Mediterranean theater, Lt. Col. (later Col.) JamesB. McLester, MC, noted, during a period when malaria transmission probably didnot occur, that malaria made its appearance in about 5 percent of patients withatypical pneumonia, in a similar percentage of patients with infectioushepatitis, and in about 1 percent of those with trenchfoot.lOther factors that were thought to be important in activating the disease werefatigue or exhaustion, hemorrhage, alcoholic bouts, the use of anesthetics, orexposure to extreme or sudden changes in temperature. There seemed little doubtthat once the stage was set, any one or more of these factors could trigger aclinical attack. Contrariwise, it must be stated that in numerous trials it wasdemonstrated conclusively that even excessive physical activity was not a causeof breakdown of Atabrine suppression ("breakthrough").
In addition to these intrinsic (host) and extrinsic(environmental) factors in the precipitation of a malarial paroxysm, there wasthe parasite factor. It is well known that there are certain attributes residentin the individual Plasmodium itself that must not only determine whethera 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 peculiarattributes and individual potentialities.2 Mostdescriptions of the disease available to the writer, however, failed todistinguish between the various plasmodial species responsible for the attack.In the text that follows, a description referring to a definite species can beassumed by the reader to be an exception to this generalization either stated inthe 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 verydifficult to draw a dividing line between prodromal symptoms and the actualonset of an attack of malaria. Patients with a brisk onset often stated thatthey had felt perfectly well on the preceding day. When prodromata weredescribed, they lasted 2 or 3 days and were generally the usual symptoms of thefrank attack presenting in lesser intensity. The most frequent complaints wereheadache, backache, weakness, and generalized aches. In a study at HarmonGeneral Hospital of 435 soldiers with malaria due to P. vivax who werepermitted to relapse, three-fourths had prodromal symptoms.3Most 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 indistribution, occurred in almost all cases. In some, it was described as havinga retrobulbar component. In general, this symptom outlasted the fever and othersymptoms by several days. In Plasmodium falciparum cases, it wasoccasionally the harbinger of an impending cerebral syndrome.4In some cases there was an associated meningismus.
Chill-In 80percent of the attacks observed in the study at Harmon General Hospital, therewas an acute rigor or chill; in another 8 percent, there was at least asensation of chilliness.
Fever.-The greatmajority of patients showed fever peaks ranging from 102? to 105?F. by mouth. Since the response to treatment was generally prompt andconvincing, the fever was generally interrupted after one or two peaks so thatthe 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 patientshad thus attained a normal temperature after 3 days of treatment, and over 90percent by 5 days after the beginning of treatment. Although the war experienceafforded some opportunity to study the detailed morphology of the fever coursein the various forms of malaria, a careful documentation of intermittency,remittency, periodicity, regimentation, anticipation, postponement of feverpeaks, continued fever, or of the fever spikes characterized as being broadbased or narrow based, could not be found. Nor is it clear that this would haveserved a useful purpose.5 In the SouthwestPacific 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 tospecies identification. In general, initial attacks were much more likely to becharacterized by continued fever and relapses by a hectic fever.
Sweats-Profuse perspiration wascharacteristic of the overt paroxysm. A few observers felt that a sweat out ofproportion to the fever in the absence of an antecedent chill was actually ahelpful aid in the diagnosis of malaria.
Splenomegaly-At a Marine installation inOregon,6 splenomegaly was noted in less than 5percent of cases acquired in the Southwest Pacific Area, even after 20 to 30recrudescences. Transient splenomegaly, generally of only mild degree, wasdetected in only about 8 percent immediately after acute attacks of malariacaused by P. vivax. Such experiences are in conformity with previousobservations regarding splenomegaly in malaria. Increase in the size of thespleen apparently depends upon the possession of some degree of immunity. It isalso well known that the enlargement rapidly diminishes on cessation of theparoxysm, particularly if interrupted by treatment. In a tabulation of thesymptoms of malaria as observed in the Mediterranean theater, based upon aquestionnaire sent to medical officers, splenomegaly was reported in a range offrom 27 to 85 percent. This wide divergence was attributed to differences in thethoroughness with which the examination was conducted. A low incidence was,however, reported from all other theaters and is probably real. What enlargementtook place was not striking and was generally transient. This low percentage ofpalpable spleens stands in marked contrast to the accepted high incidence ofthis finding in seasoned immune natives exposed presumably to the same malarialparasites as were these unseasoned, nonimmune troops.
American medical officers who had the opportunity of working with Australianmedical officers learned one technique of palpating spleens which is worthy ofrepetition. So far as this author knows, the method is virtually unknown in theUnited States. It consists in having the patient sit up in bed drooped forwardover his knees. A remarkable degree of relaxation of the abdominal muscles isoften thus attained. With the examiner at the patient's back, the fingers ofboth of the examiner's hands are curled around the left lower flank of thepatient while the patient takes deep breaths. Frequently, the palpating fingerscan extend well up under the rib margin. In a number of cases, the spleen can befelt by this method and by none other. The technique is perhaps best adapted toyoung individuals of military age.
Hepatomegaly-In aconsiderable percentage of cases, the liver was palpable one or twofingerbreadths 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.7In the North African-Mediterranean theater this was noted in from 5 to 20percent of cases. In the Southwest Pacific Area, this finding actuallyapproached or exceeded the frequency of splenomegaly. This may be due to thefact that slight degrees of hepatomegaly are more readily detected than theslight degrees of splenomegaly that occur in nonimmune, promptly treatedsoldiers. It is conceivable, although less likely, that this discrepancy isrelated to a predilection of the Southwest Pacific malarial strains to liverinvolvement. This observation appears to have been anticipated by the peacetimefindings of Gunther,8 who noted the frequentfinding of tenderness in the right hypochondrium in New Guinea malaria. Hedesignated this as gallbladder tenderness.
Lymphadenopathy-It was theobservation of the author that the most common cause of slight to moderatedegrees of generalized glandular enlargement in the Southwest Pacific Area wasmalaria. The pronounced grade of enlargement characteristic, for example, ofscrub typhus was never observed in malaria.
Abdominal symptoms-Halfof the patients complained of abdominal pain. This was more frequent on theleft than on the right side and occasionally radiated to the left lower chest.When bilateral it was generally sharper on the left. Although this wasattributed to splenomegaly, the spleen was felt in only a minority of thesepatients. 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 rightupper quadrant. Nausea occurred in 59 percent, and vomiting in 36 percent ofattacks, but troublesome vomiting was very infrequent. The relative role oftreatment with quinine or Atabrine on the one hand, and of the disease itself,on the other, in the development of these symptoms was uncertain, sincetreatment was started promptly in the great majority of cases. Diarrhea was notuncommon as the presenting complaint in uncomplicated malaria, regardless oftype, in tropical areas where it occurred in mild form in about 10 percent ofcases. This symptom was no more common in P. falciparum cases but whenpresent was more severe and at times dysenteric and associated with bloodystools.9
Upper respiratory symptoms-Thesewere quite common and almost certainly a part of the disease itself. Themost common symptom was a dry, painless cough. This was generally associatedwith musical rates, squeaks, and groans throughout the lung fields, signs quitecharacteristic of bronchial asthma but disappearing promptly on therapy. Coryzaand bronchitis were less frequent manifestations. Malaria was frequentlyassociated with bronchitis, and roentgenographic examination frequently showedinfiltrations 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 bacterialpneumonia. It would be difficult to determine to what extent these were actuallypart and parcel of the malarial infection.
Miscellaneous symptoms-Herpeslabialis was seen in a rather high percentage of cases in the Mediterraneantheater. Urticaria, generally transitory, was occasionally seen, particularly inthe earlier phases of the war when quinine was used more frequently. Tinnituswas 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 treatmentin its development. Cerebral symptoms such as drowsiness, fainting,disorientation, change in disposition, or meningismus were complaints in a fewcases of malaria due to P. falciparum.10The prompt subsidence of these symptoms in malaria caused by P. vivax ledto the impression that they were the result of the associated fever per se andnot of cerebral malaria. In the alleged instances of cerebral malaria due to P.vivax infection,11 the possibility of anundetected mixed infection including P. falciparum cannot be excluded.
In one exceptional experience, a number of patients with malaria presentedsymptoms suggesting hyperthyroidism.12 Theseindividuals showed prominent eyes, loss of weight, sudoresis, wet palms,tachycardia, and fine tremor of hands and tongue. The basal metabolic rate wasnormal in these cases.
COMPLICATIONS OF MALARIA
In the past, involvement of every organ or organ system hasbeen described as complicating malarial fever, particularly when caused by P.falciparum. These have generally been ascribed to capillary infarctionresulting from agglutination of the parasites along the capillary endothelium.Experience in World War II emphasized the extreme infrequency of suchcomplications in adequately treated malaria and recalled the admonition ofStratman-Thomas that "the innumerable clinical manifestations, symptoms andsequelae which have been ascribed to malaria are unflattering demonstrations ofthe imagination and credulity of the human mind."13The following manifestations appear, however, to be fairly welldocumented.
1. Cerebral malaria.-Almostwithout exception, malaria deaths were due to cerebral involvement.14A clear-cut picture of just what constitutes cerebral malaria was oftendifficult to draw.15 Empirically, the term maybe
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 thefollowing findings: Meningismus, convulsions, persistent delirium, orwell-defined neurological signs. An index of the prevalence of cerebral malariain World War II may be taken from the records of one U.S. Army general hospitalin 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 theMediterranean theater, when the bulk of our troops were in Italy, medicalofficers of approximately 25 evacuation, station, and general hospitals reported163 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 dueto P. falciparum infections, and of these 8 were cases of cerebral malaria.Preliminary tabulations of individual medical records indicate that there were57 deaths due to malaria, all forms, originating in the Mediterranean theaterduring 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 theclinical attack of malaria, following a day or two of precoma with persistentvomiting, increasing restlessness, mental confusion, and severe headache, butsometimes cerebral malaria developed abruptly without warning even after 1 or 2days of treatment. Blurring of vision or diplopia were not uncommon. Acutelydeveloping psychotic or psychoneurotic states were particularly alarming.
After the onset of the syndrome, the patient might show aprofound stupor deepening into a coma; he might develop convulsive seizures17or exhibit nuchal rigidity, maniacal states, or various reflex disturbances. Thetemperature would rise progressively or abruptly to extremely high levels beforedeath. In many respects, the illness resembled meningitis, encephalitis, orsevere typhus fever. The spinal fluid was generally under increased pressure.Half of the spinal fluids examined showed an increased globulin content and manyshowed cell counts ranging between 20,000 and 30,000. The blood smear oftenfailed to reveal malarial parasites until after repeated examination. Whenrecovery occurred, it was generally completed, although a few patients showedresidual cranial nerve palsies, hemiplegia, paresis, or psychosis.
2. Other involvement of the nervous system.-In theMediterranean theater, patients were seen with peripheral neuritis involving thelower extremities. Three patients exhibited transient blanching of the opticnerve, one facial neuritis and homolateral brachial neuritis. In one hospital inthe Southwest Pacific,18 16 patients were seen with a severe irritativeneuritis with hyperalgesia, hyperhidrosis, and increase in muscle tone withactual con-
16Fitz-Hugh, T., Jr., Pepper, D. S., and Hopkins, H. U.: The Cerebral Formof Malaria. Bull. U.S. Army M. Dept. No. 83, pp. 39-48, December 1944.
17Simpson, W. M., and Sagebiel, J. L.: Symposium on FirstYear of Activities at U.S. Naval Base Hospital-; Cerebral Malaria. A Report of12 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, usuallythe forearm and hand. Milder forms of neuritis, occurring in 18 of 100consecutive cases of malarial fever, presented only subjective manifestationswith transient attacks of numbness and tingling. With recurrent attacks ofmalarial fever, the nervous symptoms increased. The majority of these cases weredue to a mixed infection. Distinction had to be drawn between these neuritidesand those following that almost ubiquitous tropical disease, cutaneousdiphtheria.
3. Blackwater fever.-This was rare. Twenty-five cases of acutehemolytic anemia and hemoglobinuria were reported as blackwater fever from theSouth Pacific Area. There were three deaths in this group, a much lowermortality than is usual for blackwater fever. Fifteen of the twenty-five casesoccurred in Negro troops stationed on one island.19
4. Cardiac malaria.-Functional cardiac disorders, such as irritable heartwith tachycardia, premature beats, and systolic murmurs, were, of course, notextremely rare in patients during malarial attacks or between relapses. But trueorganic cardiac changes, such as cause death from myocardial inflammation orcapillary infarction, were extremely rare.20 These generally occurred inindividuals with malaria due to P. falciparum. The author saw two such patientswho developed severe cerebral malaria in the combat area, both cases caused by P. falciparum. One had auriculoventricular and intraventricular blockand the other a moderately enlarged, possibly dilated heart. The subsequent fateof these soldiers could not be followed. Two other patients with P. falciparuminfection died at a nearby hospital. Both showed agglutination of the parasitesalong the capillary endothelium in the myocardium.21 This experienceled to the suspicion that microscopic coronary occlusions might be as importanta factor in fatal P. falciparum cases as occlusion of cerebral vessels.
5. Rupture of the spleen.-This was a rare complication correspondingwith the low incidence of splenomegaly.
6. Ocular complications.-A few cases of iridocyclitiscoincided with attacks of malaria. In one patient, transient edema of the corneaoccurred in each of two attacks of malaria due to P. vivax in the Mediterraneantheater.
7. Medical shock.-If nothing else was done about theancient terminology of clinical malaria, the record was set straight regardingthe obsolete designation algid malaria. The fact that this is nothing more norless than medical shock complicating malaria22 should have been acknowledgedlong before World War II. This reorientation is of more than academic importancefor it provides the clinician with a whole group of well-recognized
19Harper, Paul A., Butler, Fred A., Lisansky, Ephraim T., andSpeck, CarlosD.: 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; TheCoronary and Myocardial Lesions Observed at Autopsy in Two Cases of AcuteFulminating P. Falciparum Infection. Arch. Path. 41: 290-298, March 1946.
22Kean, B. H., and Taylor, C. E.: Medical Shock in the Pathogenesis of AlgidMalaria. Am. J. Trop. Med. 26: 209-219, March 1946.
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therapeutic aids for the treatment of this serious complication. Thediscovery of adrenal hemorrhages in Filipinos who died with this syndrome23suggests the feasibility of steroid replacement therapy, but whether this wouldbe 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 ofchronic malaria was wasting, anemia, and splenic enlargement. It was notobserved in the U.S. Army, where troops were well fed and given adequatesuppressive therapy. The extraordinarily low incidence of splenomegaly andanemia has already been discussed. Due significance must be accorded the role ofhydration and of slight loss of weight as early adaptive processes attendingacclimatization to the Tropics-the former might suggest anemia; the latter,wasting.24 In contrast to the native with chronic malaria, exhibitingthe characteristic triad of intermittent fever, anemia, and splenic enlargement,the U.S. Army patients who were incapacitated between relapses presentedcomplaints generally falling into four categories: (1) Neurocirculatoryasthenia, (2) symptoms referable to the musculoskeletal system, (3) vaguesymptoms 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 soldierssuffering from repeated P. vivax relapses and who complained of not feeling upto their usual health between attacks.26 These men described thefollowing 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 anothergroup of observers who thoroughly studied this symptom complex in 50 servicemenconceded that malaria itself might be of prime importance in its production,27 itwas their further conviction, strongly concurred in by others, that the way inwhich the individual adjusted himself to his malaria and to concurrentsituational factors was more significant in the development of symptoms, intheir perpetuation, and intensification. It was the impression of most medicalofficers that these were exaggerated symptoms in men who were actually moreinterested in returning to their homeland than in rehabilitation for active
23Garcia, Eusebio Y.: Malaria in War and Peace. Manila: GraceTrading Co., 1945, p. 49.
24Lee, D. H. K.: The Human Body and Hot Environments; Factors InfluencingMan's Reactions to Heat Stress. [Unpublished manuscript.]
25Levine, H. D.: Medical Experiences With American Troopsin the Pacific, With Remarks on the Diagnostic Value of Sternal Puncture inMalaria 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 andPsychological Analysis of 50 Soldiers. Medicine 25: 17-75, February 1946.
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duty. In the majority of cases, the symptoms obviously werestrongly conditioned by such factors as exposure to combat and adverse livingconditions or previous personality problems. None of the patients complaining ofdyspnea on exertion presented evidence of heart disease as judged by physicalexamination, exercise tolerance tests, roentgenographic examinations orelectrocardiograms. 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 damageor dysfunction of the organ systems could be found. These observers condemnedthe practice of repeated or prolonged hospitalization for these individuals,contact with neuropsychiatric patients, or with patients about to be returned tothe United States.
RELAPSES IN MALARIA
The tendency of malaria due to P. vivax to recrudescence was well documentedbefore World War II, and subspecies variability in this respect has beenrecognized.28 Relapsing malaria caused by P. vivax in World War II should nottherefore 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 belittle doubt as to the remarkable relapsing tendencies of the P. vivax strainsin the South and Southwest Pacific Areas. The author first became aware of themagnitude of this problem while on detached service with an Australian hospital.The medical officers there, only recently returned from service in theMediterranean, were appalled by the stubborn relapsing tendency of the NewGuinea strains of P. vivax, contrasting with the relative infrequency of relapsein the strains to which they had become accustomed in the Middle East. That thiswas the result of species specificity was subsequently confirmed in reports fromEurope and the Mediterranean and in experience at Harmon General Hospital withmalaria inocula of Pacific and Mediterranean origin. With the Pacific strains,relapses occurred in 70 percent of cases, and 75 percent of the relapsesdeveloped within 60 days of completion of Atabrine therapy. In the Mediterraneanstrains, there was a much lower incidence of relapses (30.6 percent) and a muchlonger delay (150 to 200 days) before relapse. There was other inferentialevidence that malaria caused by P. vivax in the South Pacific Area differed fromthe same type of malaria seen elsewhere. Of the men in that area, 57 percent hadin excess of 14 acute attacks, some as many as 40. The relapses appearedmoreover to have a greater rhythmicity and regularity than those caused by otherstrains.31 It should be borne in mind that all the
28Hackett, L. W.: Malaria in Europe, An Ecological Study. London: OxfordUniversity Press, 1937.
29Russell, P. F.: Lessons in Malariology From World War II. Charles FranklinCraig 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 infectionscontracted by persons who had no immunity whatever to malaria.32
Malaria caused by P. falciparum exhibited relatively littletendency to relapse in the Mediterranean and Southwest Pacific, and when relapsesubsequently occurred in these cases, it was only occasionally due to this samemicro-organism. It appears more than likely that their original infection wasactually a mixed one, P. falciparum being the dominant organism in the firstattack, the subsequent relapses resulting from the emergence of the originallyrecessive P. vivax strain.33 Thus, in advance areas in the SouthwestPacific, P. falciparum infections accounted for about 40 percentof all attacks,34 while in the rear nonmalarious areas P. falciparumwas found in only 8 percent of cases, P. vivax in 68 percent. Suchusurpation of the dominant role in the relapse by P. vivax was well known longbefore the war.35 Quartan malaria has long been regarded as relapsingmalaria par excellence, but experience with quartan malaria in World War II wastoo 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. Thetechniques principally used have been discussed elsewhere. Variable success wasreported in experiences with sternal puncture. In a number of studies,36occasional marrow smears were reported positive when the thick and thin bloodsmears were negative. Subsequent improvement in the accuracy of routine bloodexaminations for malarial plasmodia, however, dampened interest in sternalpuncture.
Blood studies-The white blood cell count was generallybelow normal, usually in the range between 4,000 and 6,000 in theMediterranean theater study. This fact was frequently of diagnosticsignificance. In a small percentage of cases, a more marked leukopenia (lessthan 3,000) was recorded. Leukocytosis was seen under three conditions; namely,in the presence of a concomitant or complicating bacterial infection, in somesevere uncomplicated cases, and in cerebral malaria. In the latter groups, itwas apparently related to necrosis of tissues. Mild lymphocytosis was the rule.In a series reported from the Mediterranean theater, 45 to 65 percentof the lymphocytes resembled those observed in infectious mononucleosis.
32Dieuaide, F. R.: Chronic Relapsing Vivax Malaria in theArmy, 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.,: RelapsingMalaria: 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 Summaryof 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 oneinstance of mild normocytic, normochromic anemia was found in a group of50 well-studied patients with malaria due to P. vivax at the 118th GeneralHospital in the South Pacific.37 This was the general experience. Inthe Mediterranean theater, however, 29.5 percent of patients with malaria causedby P. vivax had red cell counts of 4 million or less. Anemia was somewhat morecommon in malaria due to P. falciparum, particularly during or shortly afterthe paroxysm. Counts of less than 3? million were stated to havebeen common in P. falciparum infections.
In a small percentage of cases, the sedimentation rate wasincreased. In about half of these, this finding was accounted for by somecomplicating infection; in the remainder, it was unexplained and presumablyrelated to the malaria per se. Erythrocyte fragility was probably normal.
Serological tests-The serological tests for syphilis were frequentlypositive for longer or shorter periods after the acute paroxysms. The exact incidence of this finding cannot be stated. Dawber38 found false-positivetests in 12.5 percent of 64 cases of malaria, generally becoming seronegative in10 days after the last chill. One case remained positive for 18 days. At the118th 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-positivereactions 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 5.8percent by the Hinton technique.39 Rosenberg40 likewisefound that the Hinton test yielded the smallest proportion of falsely positivereactions. He found that the strongest false reactions were obtained between 7and 10 days after the chill and persisted for 4 to 6 weeks. He felt thatpersistence of positive serology by any test beyond 6 weeks, in the absence ofcontinued evidence of malarial infection, should arouse the suspicion ofsyphilis.
The complement fixation test for malaria in general gaveunsatisfactory results. In the Mediterranean theater, this was attributed to afaulty antigen. The consensus furthermore was that the adrenalin provocationtest (Ascoli) was not helpful in diagnosis.
A number of studies were made of liver function in malariapatients. A study of 317 patients with chronic relapsing malaria due to P. vivaxat 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 PositiveSerologic 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 Thepercentage of abnormal response to tests was somewhat higher in a studyconducted in North Africa, but this was not limited to P. vivax cases. In thislatter group, the liver was enlarged in 20 percent of cases.
DIFFERENTIAL DIAGNOSIS
The morbid conditions that had to be differentiated frommalarial fever were legion. They varied, of course, with geographic location.Thus, sandfly fever (in the Mediterranean), dengue or scrub typhus fever (in thePacific), and pneumonia (in Panama)42 had to be given importantconsideration. The medical school teaching that it is wisest in a given case toexplain a symptom complex on the basis of a single diagnosis rather thanmultiple diagnoses was not justifiable in malarious areas. Malaria being almostubiquitous, the medical officer had to be prepared to find it as a complicatedor a complicating disease. When the smear was positive, the decision had to bemade whether the Plasmodium was there as an active hidden partner or whetherthis finding represented a mere parasitic relapse of little or no clinicalimportance. Almost all of the patients with salmonellal infection described byBaker and Bragdon,43 for example, showed smears positive for malaria.A large majority of the patients with scrub typhus fever who came to the 105thGeneral Hospital in the Southwest Pacific had positive smears.
A complete elaboration of the different conditions that wouldhave to be considered in the differential diagnosis would be too formidable atask to be undertaken here. Such a list would certainly have to includetuberculosis, typhoid fever, amebic and bacillary dysentery, amebic hepatitis,preicteric infectious hepatitis, meningitis, Hodgkin's disease, subacutebacterial endocarditis, leishmaniasis, and schistosomiasis as well as theconditions that have just been enumerated; namely, dengue fever, sandfly fever,salmonellal infection, and scrub typhus. At times, the symptoms of a paroxysmwould simulate an acute surgical emergency, such as biliary colic, rupturedpeptic ulcer, ruptured spleen, or acute appendicitis. And here again, with anestablished surgical condition, a complicating malarial infection was notuncommon. At the 105th General Hospital, for example, about a fifth of thepatients with malaria were battle casualties on the surgical service. Hymananalyzed the records of 100 patients admitted to a naval base hospital in thePacific with a diagnosis that was subsequently changed to malaria.44These
41Lippincott, S. W., Ellerbrook, L. D.,Hesselbrock, W. B.,Gordon, H. H., Gottlieb, L., and Marble, A.: Liver Function Tests in ChronicRelapsing 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 SouthPacific 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 predominatingsymptom that led to the erroneous diagnoses, as follows:
| 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 |
|
| 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 treatedin the nonimmune American soldier it was generally a brief, grippelike illnesswith headache, backache, pain in the abdomen, chills or chilliness, nondescriptfever, and sweating. These patients showed very little splenomegaly, moreimpressive hepatomegaly. Diarrhea and wheezing occurred in many of the acutecases. There was very little, if any, tendency to complication. Anemia was not aproblem in P. vivax infection; in some P. falciparum cases it was a moderateand transient phenomenon. The Pacific strains of P. vivax showed anextraordinarily stubborn tendency to relapse. Disability between relapses waslargely related to prolonged tropical or combat service, to ennui or nostalgia,or to the soldier's reaction to his illness. The mortality rate was phenomenallylow. (See p. 460.) Death was generally the result of cerebral malaria due inmost, if not all, cases to P. falciparum.
