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The Malaria Problem*
THE MALARIA PROBLEM* LIEUTENANT COMMANDER ELLlS HERNOON HUDSONt Medical Corps, United States Naval Reserve
IN the present war the forces of the United States confront a malaria problem of unprecedented magnitude. Enumeration of the various theaters of operation underlines the fact that thus far this war is being fought largely in malarious regions. This disease is prevalent in the Caribbean and on the northern coasts of South America, in the North African and Near Eastern theaters, in India, Burma and Malaya, and on the northern coast of Australia. Finally, although many of the islands of the Pacific are free of malaria, some of them on the contrary are hyperendemic spots, with exceedingly refractory strains. THE FACTOR OF WAR
Complex as malaria is, with its epidemiological triad of physical enviroment, insect vector and man, the additional factor of war compounds all difficulties. War introduces large groups of nonimmune men into areas of high endemicity where malaria and the mosquito both flourish virtually without curb or restraint. Further, these nonimmunes often lack care and comfort, are exposed to cold, heat and wet, suffer from physical strain and fatigue, are unaccustomed to tropical climate or fully aware of the dangers of malaria, and perforce have to live in proximity to native villages in which the population is soaked with malaria . and in which the silent pool of circulating infective gametocytes is huge. There are difficulties in getting nonmedical personnel to appreciate the necessity for regular and systematic .. From the Department of Tropical Medicine and Parasitology, U. S. Naval M~diqal School. Bethesda, Maryland. The substance of this paper was presented for Medical and Dental Officers of the Service Commands, at the Mayo Clinic, Rochester, Minnesota, December 8-9, 1942. Released for publication by the Division of Publications of the Bureau of Metlicine and Surgery of the United States Navy. The opinions or assertions contained herein are the private ones of the writer, and are not to be construed as official or as reflecting the views of [he Navy Department or the Naval service at large. "f FA.C.P., D.T.M.8tH. (London). 1417
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ELLIS HERNDON HUDSON
suppressive treaunent, and the importance of nets and repellents. Ail of the above conditions are inevitable concomitants of war, and all predispose to the successful propagation of malaria. Most anophelines bite at night, but night biters also feed during the day in the obscure light of the jungle when they are disturbed from their resting places. Since anophelines attack most fiercely just after sundown, it is good epidemiological practice to have as many men as possible under nets or in screened barracks when the light fades. Evening liberty is tradi"tional in the Army and Navy, but in malarious regions such as Panama it is often restricted to daylight hours with the use of a staggered schedule. The carriers of malaria, both anopheline and human, are largely absent from movies and other places of entertainment in malarious regions during the daylight hours. TWO TYPES OF MALARIA
The parasitologist subdivides malaria into vivax, quartan and falciparum on the basis of its three species. * The student and the technician in the laboratory are required to distinguish the morphological differences between these three forms. This is fundamental to diagnosis, and diagnosis is fundamental in malaria to an extraordinary degree. However, this classification does not go far enough for the physician who has to treat malaria. Without surrendering any of the significance granted to "species diagnosis," the clinician at the same time must remember that there are clinically t'Wo kinds of malaria, viz., that which does not have an immediate mortality (caused by vivax and quartan), and that which does (caused by falciparum). Let us briefly contrast these two types of malaria. The first type, so-called benign malaria, causes in nonimmune humans severe paroxysms of chills, fever and sweat, at intervals of forty-eight or seventy-two hours according to definite periodic patterns. This kind of malaria produces distressing and sometimes alarming symptoms and the patient may be exceedingly uncomfortable, but the margin of safety for survival is wide, and sudden death in the acute stage is very rare. Further, • This terminology follows the suggestion offered in Human Malaria (A Symposium, American Association for the Advancement of Science, 1941). "Quartan" is preferred to "malariae" on grounds of clarity and euphony.
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. both qumme and atabrine are effective not only against the trophozoites and schizonts circulating in the peripheral blood, but also against the infective presexual forms known as gametocytes. Balanced against these favorable features of the benign type is its baffling tendency to repeated relapse, and the apparent reluctance of the body to make an immunological response to the infection. Thus, in spite of several successive and excellent courses of treatment, each time with apparent "cure," this type of malaria will continue to relapse at intervals. The infection may thus reappear as many as six, eight, or ten times, or even more. When relapse occurs the medical officer is prone to conclude that in his previous treatment he has not given enough of his drugs, so, often in exasperation, he gives more and more. But though he may increase his dosage schedule tremendously, and extend it over a long period, a certain proportion of these cases will continue to relapse. The physician and the patient have to face the fact that the body itself must be given time to build up sufficient immunity to overcome the infection, and that in the meantime the symptoms must be treated as they arise, with the routine and conventional dosage schedule. They must console themselves with the fact that the prognosis in this type of malaria is good for eventual recovery whether with or without treatment, and in the absence of reinfection (or more accurately, superinfection) the body will gradually build up immunity against vivax and quartan infections to the point where, with very rare exceptions, they will be eradicated in the course of three (vivax) to six (quartan) years. This seems a long time, but most cases fade out before these limits, and even in those which linger longest, cooperation and vigilance on the pan of patient and physician can largely prevent a measurable morbidity and loss of time. In marked contrast to the above is the so-called malignant or pernicious type of malaria, caused by falciparum, and often called aestivo-autumnal fever. This type is characterized by a capricious fever without definite periodicity, and is therefore frequently confused with other febrile conditions. It rises rapidly to a high parasite density, is capable at any time of suddenly assuming a prognosis of grave omen, and carries a
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definite risk of sudden death even in apparently mild infections. Fa1ciparum malaria is as truly an emergency as an acute appendix or a coronary thrombosis. Note the paradox between falciparum infections which frequently combine mild and bizarre symptoms with lethal prognosis, and vivax and quartan infections which frequently combine an excellent prognosis with symptoms which make the patient look-and feel-sick unto death. The clinician who remembers this paradox will be well served in his evaluation of a given case.
Continuing with the characteristics of falciparum infections, we must mention two striking and encouraging features, viz., disinclination to relapse, and ready response to treatment. The body builds up immunity to P. falciparum more easily and quickly than to the benign type, as shown by the fact that relapses when they do occur tend to become rapidly less severe, are more widely spaced in time, and are not so numerous. Furthermore, in the absence of reinfection or the supervention of death, complete recovery is accomplished well within two years, whether with or without treatment. Seldom does a falciparum infection "hang on" or "come back" as does vivax or quartan, and when a patient has it simultaneously with one of the other infections, falciparum will fade out under treatment long before either of the other two. This brings us to the second favorable feature of falciparum infections. Though the trophozoites of such cases circulate in the peripheral blood in great numbers, they are very susceptible to the antimalarial drugs, quinine and atabrine. The schizonts, or segmenting forms, which in this type of malaria retire to the marrow, liver and spleen, are also killed (or suppressed) by these drugs. Only the gametocytes or presexual forms are resistant to quinine and atabrine. Fortunately we have in plasmochin* a compound which sterilizes, if it does not kill, these infective forms. Summarizing this clinical analysis of malaria, we may say that vivax and quartan infections are principally a menace because of their resistance to treatment and their tendency to repeated relapse; while falciparum infections, though more sus.. British writers sometimes call atahrine "mepacrine" and plasmochin ··pamaquin."
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ceptible to treatment and not so prone to relapse, are insidious, unpredictable, and in a proportion of cases definitely lethal. HOW DOES P. FALCIPARUM KILL1t
The answer to this question is not far to seek, though the actual mechanism is not known. Falciparum parasites cause the red cells to stick to each other and to the walls of the capillaries, so that the normally smooth flow of the blood is interrupted. Not only are the parasitized corpuscles sticky, but also the uninfected red cells, the leukocytes and the endothelial lining. Consequently, the capillaries of vital organs become choked with thrombi thus formed, vessels rupture, infarcts occur, and irreversible damage results when such tissues as the brain are involved. Falciparum therefore kills not because of some powerful toxin or metabolic disorganization, but by causing agglutination of the red cells. It is mechanical obstruction and apoplexy of some vital blood vessel which causes death in malignant malaria. This fact has been known for some time, but visual evidence has been recently produced by Kniselyl and others. They describe the red blood corpuscles of rhesus monkeys infected with knowlesi malaria and canaries infected with an avian plasmodium, as forming clumps which grow progressively greater until the blood resembles sludge or even paste. The final picture shows clumps of erythrocytes clinging to the capillary walls, and there is leakage of plasma, increasing viscosity of the blood, retardation of blood flow, production of numerous thromboses, and finally death of the bird from ischemia or anoxemia of vital areas. Obviously, similar phenomena could be observed in the cerebral capillaries of man were it possible to inspect them during the terminal hours of a falciparum infection of the brain; for the microscopical picture after death is congestion, block and rupture, with formation of thrombi composed of both parasitized and nonparasitized cells. Why vivax and quartan infections never cause agglutinative block like their more dangerous relative is not known; nor is it l}nown why a falciparum infection which will carry on for days, weeks and even months, with and without symptoms, and t Discussion of the role of P. falciparum in blackwater fever is omitted hy design.
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ELLIS HERNDON HUDSON
with varying numbers of parasites circulating in the blood, without showing any clinical sign of this agglutinative tendency of the erythrocytes, will then suddenly within a few hours precipitate a grave state of vascular thrombosis in some vital organ. We do not know what acts as the trigger or initiating mechanism, or what relation the event has to agglutinins, agglutinogens and the physicochemical properties of the red cells. Paradoxically, clumping is less likely to be precipitated in the old case of malaria which has had poor treatment and developed good tolerance, than in the more recently acquired case which, though it has been treated well, has not had enough of the infection to develop a good state of tolerance. The two features of falciparum infection which give it its malignant character are its tendencies to cause agglutination (e.g., cerebral malaria) and hemolysis (e.g., blackwater fever). Is it chance that these are also the two characteristic features of an incompatible blood transfusion? Would heparin (or dicoumarin) influence the phenomenon of agglutination in cerebral malaria? On a priori grounds and judging from incomplete knowledge of clotting time and prothrombin levels one would not expect heparin to have any direct influence in malarial clotting, but who can be certain until it is actually tried in aclinical series? These and many other questions present themselves in a consideration of the immunology and serology of falciparum infections. No practicable method of culturing the three species of human malaria has ever been found, nor have any been transmitted successfully to an experimental animal. These are tremendous handicaps upon research, but investigation of malaria in the human subject in malarious areas has neither used all the potential investigative tools at hand nor received the endorsement and support which it deserves, proportionate to its civilian and military hazard and in comparison with other infections. Research which would explain the agglutinating tendency of falciparum infections and point the way to a remedy would convert a dreaded disease into one of the most benign. No research problem offers higher rewards. PROBLEMS OF CONTROL AND TREATMENT
It is well known that only female anophelines carry malaria. It is also a fact that though there are about 200 species of
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anophelines in the world, all of them theoretically capable of carrying malaria, actually only some sixty species have ever been found to do so. Further, of these sixty species, only ten or fifteen are of sufficient importance to require measures of control. There are usually only one or two mosquitoes in each theater of malaria that are overwhelmingly and almost exclusively responsible for malaria transmission. Thus, there is quadrimacularus in the southern United States, albimanus in South America, maculipennis in Europe, funesrus and gambiae in Africa, elutus in the Near East, hyrcanus and culicifacies in India and Burma, minimus in Malaya and the Philippines, and puncrularus in the southwest Pacific. No species of anopheles is linked with anyone species of plasmodia; that is, an anopheline can serve equally well as vector for vivax, quartan, or falciparum infections. Each mosquito species has its peculiar ecology and is vulnerable to a particular mode of attack, and theoretically malaria can be held under control in a given area by taking sanitary measures appropriate to the principal vector in that area. Malaria control officers disregard the other so-called "pest" species, and concentrate on abating the breeding of the guilty anopheline. However, in the case of a military party landing on a hostile shore this abatement activity is a counsel of perfection and must be postponed until the situation is in hand. Possibly all that can be done during the preliminary period of occupation is to give the troops suppressive treatment, supplemented with such aids as nets and repellents. Later on, the control officer will have opportunity to identify the main vector, establish its breeding habits, and take abatement measures such as draining, filling and oiling-in short, carry out species sanitation. Since more troops are incapacitated by malaria than by bullets, responsibility for malaria discipline and control should be a vital interest not only to the Medical Corps but also to the Line. Malaria in many theaters has prime military importance. S,,!ppressive Treatment-Dosages
The conventional suppressive treatment in the naval forces is four tablets of atabrine (0.4 gm.) per week, i.e., two a day for two days, separated by an interval of at least two days. When
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the period of exposure to atabrine seems to be prolonged, a month of quinine can be interpolated, but in this case the atabrine should be re-commenced a few days before the quinine is discontinued. There is some tendency to favor use of a tablet of atabrine (0.1 gm.) daily for six days a week. This 50 per cent augmentation increases the likelihood of skin pigmentation, but the weekly total of 0.6 gm. seems to be within safe limits of dosage. Another variation is one-half tablet (0.05 gm.) daily for six days, and a whole tablet (0.1 gm.) on Sunday. This does not increase the total weekly dose above the conventional 0.4 gm., but has the advantage of small dosage (fewer complaints of discomfort) and daily dosage (less likely to be overlooked or forgotten in administration). Atabrine has now been used as a suppressive drug for continuous periods of several months for many thousands of men in the military forces of the United Nations, without report of serious toxicity in the dosage employed. Therapeutically, atabrine is given for clinical malaria of all three species, by the oral and intramuscular routes, but never subcutaneously or intravenously. In particular, the intravenous use of atabrine is unreservedly condemned, because of the proximity of the therapeutic and toxic (fatal) doses, when it is given by this route. Atabrine affects the liver, causing acute yellow atrophy in toxic concentrations. The liver of a well nourished person can withstand assaults by such substances better than the livers of starving subjects. In other words, plentiful well-balanced food buffers the liver. Alcohol, on the other hand, when used in excess and in lieu of food, "sensitizes" the liver to damage by atabrine. The application of these facts is obvious. In recent months some suggestions have been made that atabrine be given in larger initial dosage. Our present schedule carries over from the time when atabrine was a new drug and less was known of its toxic properties and propensities. There now seems to be some justification for a radical change in the schedule, by which a larger amount is given during the first twenty-four hours, and subsequent doses are dropped to a maintenance level. This is comparable to the accepted schedule for administration of the sulfonamides, and we shall probably hear more if its application to atabrine in the near future.
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Time Factor in Military Operations
In the course of the malaria life cycle there are two periods when the paras.ite withdraws from public view, as it were. Each of these periods consumes ten to fourteen days. One, which we may call the extrinsic incubation period, commences when the mosquito in the course of a blood meal takes up gametocyte~ from a human carrier. The parasite thus withdraws from its warm-blooded intermediate host to go through its sexual cycle in the poikilothermal mosquito. This incubation period ends when the sporozoites which have subsequently developed in the definitive host descend through the proboscis and enter another human in the course of another blood meal. The other, or intrinsic, incubation period begins at this point. The sporozoites introduced by this bite cannot immediately be found in the human blood stream, but hide somewhere in the body in what is sometimes called the exo-erythrocytic stage. It is assumed that during this time the parasite has withdrawn to the deep sinuses of the marrow and viscera. Recently it has been suggested that they are actually passing through a metamorphosis somewhere in the reticulo-endothelial system. However this may be, the fact of importance is that during this stage of ingress and concealment there is no known drug which will kill the parasite. In other words, we have as yet no drug which is a true causal prophylactic. Quinine, atabrine and plasmochin are all ineffective in killing the sporozoites as they enter the body, or the parasites while they are in the enigmatic exo-erythrocytic stage. This fact is of military significance, for it follows that suppressive drugs are useless for troops prior to landing or during their first week in a malarious area. Realization of this fact will avoid waste of drugs and will diminish the burden of administrative details for the first few days after landing. Advocates of this point of view make the justifiable claim that if troops are not receiving drugs at the time of the initial attack, their efficiency will not be impaired at the time when efficiency is of most value. There is, however, another school of thought which holds that though atabrine given prior to landing is of questionable value so far as malaria is concerned, it has educational and psychological value for uninitiated troops. Furthermore, many of the abdominal discomforts due to atabrine when it is first
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taken fade out after a few days, and according to this view can be gotten out of the way under ideal and noncombat conditions. In any case, suppressive treatment should certainly be begun either well in advance of landing or several days after landing, and should never be initiated on the day of the attack. Diagnostic Blood Films
What is the most opportune time to secure diagnostic blood films in malaria? Obviously, in vivax and quartan infections, smears made from peripheral blood just before the expected chill will show schizonts (segmenters) and late trophozoites, which are diagnostic fonns. This is not true of falciparum infections, however. In these infections the trophozoites retire to the recesses of the viscera and marrow to segment, so that theoretically the blood will be swept clear of parasites just before the chill, and will be flooded with young parasites just after the paroxysm. On this theoretical basis one is advised to make postparoxysmal films in falciparum infections. The importance of this rule of thumb fades out somewhat in actual practice, since the course of falciparum infections is often so capricious that there is no well defined paroxysm. In general, therefore, it is well where falciparum is suspected, not to wait for a paroxysm which may never come, but to make smears at intervals of six to eight hours. This is further justified by the observation that the number of parasites in the peripheral blood in falciparum infections fluctuates considerably, sometimes within a short space of time. Sternal Puncture in Treatment and Diagnosis
Papper and Rovenstine 2 have recently reviewed the T ocantins method for administering fluids via the bone marrow, particularly the sternum. They describe the technic and discuss clinical experience with the procedure. Malariologists should read the article in its entirety, for sternal puncture should be more used in the study and treatment of malaria. Many of the more severe forms of the disease require parenteral administration of saline, glucose and chemotherapy continuously over considerable periods of time, conditions for which the sternal route is particularly suited. In research there is insufficient knowledge of the behavior of the bone marrow in malaria, and sternal PVnc-
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ture may prove to be a distinct help in accurate and speedy diagnosis, particularly in falciparum infections. SUMM~RY
1. Attention is again called to the importance of malaria in war, and the influence of the present war upon the problem of malaria. 2. Malaria should be divided clinically into two types, the one which will kill in the acute stage, and the one which will not. These two types are contrasted as to etiology, course and treatment. 3. Inclination to relapse is the curse of P. vivax. P. falciparum kills through a mechanism of intravascular agglutination. 4. Problems of control and treatment are discussed. Suppressive treatment must perforce precede species sanitation in newly occupied malarious areas. Atabrine in dosage of 0.4 to 0.6 gm. iler week is a safe suppressive drug. Atabrine should never be used intravenously. Troops need not be given suppressive treatment until several days-up to a week-after landing in a malarious region, but there are advantages in commencing it earlier. Sternal puncture may be a valuable aid in the treatment and diagnosis of malaria, and a useful agency in research. BIBLIOGRAPHY
1. Knisely, M. H., Stratman-Thomas, W. K. and Eliot, T. S.: Observations
on Circulating Blood in the Small Vessels of the Internal Organs in Living Macacus Rhesus Monkeys Infected with Malarial Parasites. Anatomical Record, 79:90 (March, Supp. 2) 1941. Knisely, M. H., and Block, E. H.: Microscopic Observations of Intravascular Agglutination of Red Cells and Consequent Sludging of the Blood in Human Diseases. Anatomical Record, 82:426 (March) 1942. Lack, A. R., Jr.: The Occurrence of Intravascular Agglutinations in Avian Malaria. Science, 96:520 (Dec. 4) 1942. Editorial: Malarial Hemagglutination. JA.MA., 121:263 (Jan. 23) 1943. Correspondence: J.A.M.A., 121:885 (March 13) 1943. 2. Papper, E. M. and Rovenstine, E. A.: Utility of Marrow Cavity of Sternum for Parenteral Fluid Therapy. War Medicine, 2:277 (March) 1942.
IN the present war the forces of the United States confront a malaria problem of unprecedented magnitude. Enumeration of the various theaters of operation underlines the fact that thus far this war is being fought largely in malarious regions. This disease is prevalent in the Caribbean and on the northern coasts of South America, in the North African and Near Eastern theaters, in India, Burma and Malaya, and on the northern coast of Australia. Finally, although many of the islands of the Pacific are free of malaria, some of them on the contrary are hyperendemic spots, with exceedingly refractory strains. THE FACTOR OF WAR
Complex as malaria is, with its epidemiological triad of physical enviroment, insect vector and man, the additional factor of war compounds all difficulties. War introduces large groups of nonimmune men into areas of high endemicity where malaria and the mosquito both flourish virtually without curb or restraint. Further, these nonimmunes often lack care and comfort, are exposed to cold, heat and wet, suffer from physical strain and fatigue, are unaccustomed to tropical climate or fully aware of the dangers of malaria, and perforce have to live in proximity to native villages in which the population is soaked with malaria . and in which the silent pool of circulating infective gametocytes is huge. There are difficulties in getting nonmedical personnel to appreciate the necessity for regular and systematic .. From the Department of Tropical Medicine and Parasitology, U. S. Naval M~diqal School. Bethesda, Maryland. The substance of this paper was presented for Medical and Dental Officers of the Service Commands, at the Mayo Clinic, Rochester, Minnesota, December 8-9, 1942. Released for publication by the Division of Publications of the Bureau of Metlicine and Surgery of the United States Navy. The opinions or assertions contained herein are the private ones of the writer, and are not to be construed as official or as reflecting the views of [he Navy Department or the Naval service at large. "f FA.C.P., D.T.M.8tH. (London). 1417
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ELLIS HERNDON HUDSON
suppressive treaunent, and the importance of nets and repellents. Ail of the above conditions are inevitable concomitants of war, and all predispose to the successful propagation of malaria. Most anophelines bite at night, but night biters also feed during the day in the obscure light of the jungle when they are disturbed from their resting places. Since anophelines attack most fiercely just after sundown, it is good epidemiological practice to have as many men as possible under nets or in screened barracks when the light fades. Evening liberty is tradi"tional in the Army and Navy, but in malarious regions such as Panama it is often restricted to daylight hours with the use of a staggered schedule. The carriers of malaria, both anopheline and human, are largely absent from movies and other places of entertainment in malarious regions during the daylight hours. TWO TYPES OF MALARIA
The parasitologist subdivides malaria into vivax, quartan and falciparum on the basis of its three species. * The student and the technician in the laboratory are required to distinguish the morphological differences between these three forms. This is fundamental to diagnosis, and diagnosis is fundamental in malaria to an extraordinary degree. However, this classification does not go far enough for the physician who has to treat malaria. Without surrendering any of the significance granted to "species diagnosis," the clinician at the same time must remember that there are clinically t'Wo kinds of malaria, viz., that which does not have an immediate mortality (caused by vivax and quartan), and that which does (caused by falciparum). Let us briefly contrast these two types of malaria. The first type, so-called benign malaria, causes in nonimmune humans severe paroxysms of chills, fever and sweat, at intervals of forty-eight or seventy-two hours according to definite periodic patterns. This kind of malaria produces distressing and sometimes alarming symptoms and the patient may be exceedingly uncomfortable, but the margin of safety for survival is wide, and sudden death in the acute stage is very rare. Further, • This terminology follows the suggestion offered in Human Malaria (A Symposium, American Association for the Advancement of Science, 1941). "Quartan" is preferred to "malariae" on grounds of clarity and euphony.
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. both qumme and atabrine are effective not only against the trophozoites and schizonts circulating in the peripheral blood, but also against the infective presexual forms known as gametocytes. Balanced against these favorable features of the benign type is its baffling tendency to repeated relapse, and the apparent reluctance of the body to make an immunological response to the infection. Thus, in spite of several successive and excellent courses of treatment, each time with apparent "cure," this type of malaria will continue to relapse at intervals. The infection may thus reappear as many as six, eight, or ten times, or even more. When relapse occurs the medical officer is prone to conclude that in his previous treatment he has not given enough of his drugs, so, often in exasperation, he gives more and more. But though he may increase his dosage schedule tremendously, and extend it over a long period, a certain proportion of these cases will continue to relapse. The physician and the patient have to face the fact that the body itself must be given time to build up sufficient immunity to overcome the infection, and that in the meantime the symptoms must be treated as they arise, with the routine and conventional dosage schedule. They must console themselves with the fact that the prognosis in this type of malaria is good for eventual recovery whether with or without treatment, and in the absence of reinfection (or more accurately, superinfection) the body will gradually build up immunity against vivax and quartan infections to the point where, with very rare exceptions, they will be eradicated in the course of three (vivax) to six (quartan) years. This seems a long time, but most cases fade out before these limits, and even in those which linger longest, cooperation and vigilance on the pan of patient and physician can largely prevent a measurable morbidity and loss of time. In marked contrast to the above is the so-called malignant or pernicious type of malaria, caused by falciparum, and often called aestivo-autumnal fever. This type is characterized by a capricious fever without definite periodicity, and is therefore frequently confused with other febrile conditions. It rises rapidly to a high parasite density, is capable at any time of suddenly assuming a prognosis of grave omen, and carries a
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ELLIS HERNDON HUDSON
definite risk of sudden death even in apparently mild infections. Fa1ciparum malaria is as truly an emergency as an acute appendix or a coronary thrombosis. Note the paradox between falciparum infections which frequently combine mild and bizarre symptoms with lethal prognosis, and vivax and quartan infections which frequently combine an excellent prognosis with symptoms which make the patient look-and feel-sick unto death. The clinician who remembers this paradox will be well served in his evaluation of a given case.
Continuing with the characteristics of falciparum infections, we must mention two striking and encouraging features, viz., disinclination to relapse, and ready response to treatment. The body builds up immunity to P. falciparum more easily and quickly than to the benign type, as shown by the fact that relapses when they do occur tend to become rapidly less severe, are more widely spaced in time, and are not so numerous. Furthermore, in the absence of reinfection or the supervention of death, complete recovery is accomplished well within two years, whether with or without treatment. Seldom does a falciparum infection "hang on" or "come back" as does vivax or quartan, and when a patient has it simultaneously with one of the other infections, falciparum will fade out under treatment long before either of the other two. This brings us to the second favorable feature of falciparum infections. Though the trophozoites of such cases circulate in the peripheral blood in great numbers, they are very susceptible to the antimalarial drugs, quinine and atabrine. The schizonts, or segmenting forms, which in this type of malaria retire to the marrow, liver and spleen, are also killed (or suppressed) by these drugs. Only the gametocytes or presexual forms are resistant to quinine and atabrine. Fortunately we have in plasmochin* a compound which sterilizes, if it does not kill, these infective forms. Summarizing this clinical analysis of malaria, we may say that vivax and quartan infections are principally a menace because of their resistance to treatment and their tendency to repeated relapse; while falciparum infections, though more sus.. British writers sometimes call atahrine "mepacrine" and plasmochin ··pamaquin."
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ceptible to treatment and not so prone to relapse, are insidious, unpredictable, and in a proportion of cases definitely lethal. HOW DOES P. FALCIPARUM KILL1t
The answer to this question is not far to seek, though the actual mechanism is not known. Falciparum parasites cause the red cells to stick to each other and to the walls of the capillaries, so that the normally smooth flow of the blood is interrupted. Not only are the parasitized corpuscles sticky, but also the uninfected red cells, the leukocytes and the endothelial lining. Consequently, the capillaries of vital organs become choked with thrombi thus formed, vessels rupture, infarcts occur, and irreversible damage results when such tissues as the brain are involved. Falciparum therefore kills not because of some powerful toxin or metabolic disorganization, but by causing agglutination of the red cells. It is mechanical obstruction and apoplexy of some vital blood vessel which causes death in malignant malaria. This fact has been known for some time, but visual evidence has been recently produced by Kniselyl and others. They describe the red blood corpuscles of rhesus monkeys infected with knowlesi malaria and canaries infected with an avian plasmodium, as forming clumps which grow progressively greater until the blood resembles sludge or even paste. The final picture shows clumps of erythrocytes clinging to the capillary walls, and there is leakage of plasma, increasing viscosity of the blood, retardation of blood flow, production of numerous thromboses, and finally death of the bird from ischemia or anoxemia of vital areas. Obviously, similar phenomena could be observed in the cerebral capillaries of man were it possible to inspect them during the terminal hours of a falciparum infection of the brain; for the microscopical picture after death is congestion, block and rupture, with formation of thrombi composed of both parasitized and nonparasitized cells. Why vivax and quartan infections never cause agglutinative block like their more dangerous relative is not known; nor is it l}nown why a falciparum infection which will carry on for days, weeks and even months, with and without symptoms, and t Discussion of the role of P. falciparum in blackwater fever is omitted hy design.
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ELLIS HERNDON HUDSON
with varying numbers of parasites circulating in the blood, without showing any clinical sign of this agglutinative tendency of the erythrocytes, will then suddenly within a few hours precipitate a grave state of vascular thrombosis in some vital organ. We do not know what acts as the trigger or initiating mechanism, or what relation the event has to agglutinins, agglutinogens and the physicochemical properties of the red cells. Paradoxically, clumping is less likely to be precipitated in the old case of malaria which has had poor treatment and developed good tolerance, than in the more recently acquired case which, though it has been treated well, has not had enough of the infection to develop a good state of tolerance. The two features of falciparum infection which give it its malignant character are its tendencies to cause agglutination (e.g., cerebral malaria) and hemolysis (e.g., blackwater fever). Is it chance that these are also the two characteristic features of an incompatible blood transfusion? Would heparin (or dicoumarin) influence the phenomenon of agglutination in cerebral malaria? On a priori grounds and judging from incomplete knowledge of clotting time and prothrombin levels one would not expect heparin to have any direct influence in malarial clotting, but who can be certain until it is actually tried in aclinical series? These and many other questions present themselves in a consideration of the immunology and serology of falciparum infections. No practicable method of culturing the three species of human malaria has ever been found, nor have any been transmitted successfully to an experimental animal. These are tremendous handicaps upon research, but investigation of malaria in the human subject in malarious areas has neither used all the potential investigative tools at hand nor received the endorsement and support which it deserves, proportionate to its civilian and military hazard and in comparison with other infections. Research which would explain the agglutinating tendency of falciparum infections and point the way to a remedy would convert a dreaded disease into one of the most benign. No research problem offers higher rewards. PROBLEMS OF CONTROL AND TREATMENT
It is well known that only female anophelines carry malaria. It is also a fact that though there are about 200 species of
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anophelines in the world, all of them theoretically capable of carrying malaria, actually only some sixty species have ever been found to do so. Further, of these sixty species, only ten or fifteen are of sufficient importance to require measures of control. There are usually only one or two mosquitoes in each theater of malaria that are overwhelmingly and almost exclusively responsible for malaria transmission. Thus, there is quadrimacularus in the southern United States, albimanus in South America, maculipennis in Europe, funesrus and gambiae in Africa, elutus in the Near East, hyrcanus and culicifacies in India and Burma, minimus in Malaya and the Philippines, and puncrularus in the southwest Pacific. No species of anopheles is linked with anyone species of plasmodia; that is, an anopheline can serve equally well as vector for vivax, quartan, or falciparum infections. Each mosquito species has its peculiar ecology and is vulnerable to a particular mode of attack, and theoretically malaria can be held under control in a given area by taking sanitary measures appropriate to the principal vector in that area. Malaria control officers disregard the other so-called "pest" species, and concentrate on abating the breeding of the guilty anopheline. However, in the case of a military party landing on a hostile shore this abatement activity is a counsel of perfection and must be postponed until the situation is in hand. Possibly all that can be done during the preliminary period of occupation is to give the troops suppressive treatment, supplemented with such aids as nets and repellents. Later on, the control officer will have opportunity to identify the main vector, establish its breeding habits, and take abatement measures such as draining, filling and oiling-in short, carry out species sanitation. Since more troops are incapacitated by malaria than by bullets, responsibility for malaria discipline and control should be a vital interest not only to the Medical Corps but also to the Line. Malaria in many theaters has prime military importance. S,,!ppressive Treatment-Dosages
The conventional suppressive treatment in the naval forces is four tablets of atabrine (0.4 gm.) per week, i.e., two a day for two days, separated by an interval of at least two days. When
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the period of exposure to atabrine seems to be prolonged, a month of quinine can be interpolated, but in this case the atabrine should be re-commenced a few days before the quinine is discontinued. There is some tendency to favor use of a tablet of atabrine (0.1 gm.) daily for six days a week. This 50 per cent augmentation increases the likelihood of skin pigmentation, but the weekly total of 0.6 gm. seems to be within safe limits of dosage. Another variation is one-half tablet (0.05 gm.) daily for six days, and a whole tablet (0.1 gm.) on Sunday. This does not increase the total weekly dose above the conventional 0.4 gm., but has the advantage of small dosage (fewer complaints of discomfort) and daily dosage (less likely to be overlooked or forgotten in administration). Atabrine has now been used as a suppressive drug for continuous periods of several months for many thousands of men in the military forces of the United Nations, without report of serious toxicity in the dosage employed. Therapeutically, atabrine is given for clinical malaria of all three species, by the oral and intramuscular routes, but never subcutaneously or intravenously. In particular, the intravenous use of atabrine is unreservedly condemned, because of the proximity of the therapeutic and toxic (fatal) doses, when it is given by this route. Atabrine affects the liver, causing acute yellow atrophy in toxic concentrations. The liver of a well nourished person can withstand assaults by such substances better than the livers of starving subjects. In other words, plentiful well-balanced food buffers the liver. Alcohol, on the other hand, when used in excess and in lieu of food, "sensitizes" the liver to damage by atabrine. The application of these facts is obvious. In recent months some suggestions have been made that atabrine be given in larger initial dosage. Our present schedule carries over from the time when atabrine was a new drug and less was known of its toxic properties and propensities. There now seems to be some justification for a radical change in the schedule, by which a larger amount is given during the first twenty-four hours, and subsequent doses are dropped to a maintenance level. This is comparable to the accepted schedule for administration of the sulfonamides, and we shall probably hear more if its application to atabrine in the near future.
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Time Factor in Military Operations
In the course of the malaria life cycle there are two periods when the paras.ite withdraws from public view, as it were. Each of these periods consumes ten to fourteen days. One, which we may call the extrinsic incubation period, commences when the mosquito in the course of a blood meal takes up gametocyte~ from a human carrier. The parasite thus withdraws from its warm-blooded intermediate host to go through its sexual cycle in the poikilothermal mosquito. This incubation period ends when the sporozoites which have subsequently developed in the definitive host descend through the proboscis and enter another human in the course of another blood meal. The other, or intrinsic, incubation period begins at this point. The sporozoites introduced by this bite cannot immediately be found in the human blood stream, but hide somewhere in the body in what is sometimes called the exo-erythrocytic stage. It is assumed that during this time the parasite has withdrawn to the deep sinuses of the marrow and viscera. Recently it has been suggested that they are actually passing through a metamorphosis somewhere in the reticulo-endothelial system. However this may be, the fact of importance is that during this stage of ingress and concealment there is no known drug which will kill the parasite. In other words, we have as yet no drug which is a true causal prophylactic. Quinine, atabrine and plasmochin are all ineffective in killing the sporozoites as they enter the body, or the parasites while they are in the enigmatic exo-erythrocytic stage. This fact is of military significance, for it follows that suppressive drugs are useless for troops prior to landing or during their first week in a malarious area. Realization of this fact will avoid waste of drugs and will diminish the burden of administrative details for the first few days after landing. Advocates of this point of view make the justifiable claim that if troops are not receiving drugs at the time of the initial attack, their efficiency will not be impaired at the time when efficiency is of most value. There is, however, another school of thought which holds that though atabrine given prior to landing is of questionable value so far as malaria is concerned, it has educational and psychological value for uninitiated troops. Furthermore, many of the abdominal discomforts due to atabrine when it is first
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ELLIS HERNDON HUDSON
taken fade out after a few days, and according to this view can be gotten out of the way under ideal and noncombat conditions. In any case, suppressive treatment should certainly be begun either well in advance of landing or several days after landing, and should never be initiated on the day of the attack. Diagnostic Blood Films
What is the most opportune time to secure diagnostic blood films in malaria? Obviously, in vivax and quartan infections, smears made from peripheral blood just before the expected chill will show schizonts (segmenters) and late trophozoites, which are diagnostic fonns. This is not true of falciparum infections, however. In these infections the trophozoites retire to the recesses of the viscera and marrow to segment, so that theoretically the blood will be swept clear of parasites just before the chill, and will be flooded with young parasites just after the paroxysm. On this theoretical basis one is advised to make postparoxysmal films in falciparum infections. The importance of this rule of thumb fades out somewhat in actual practice, since the course of falciparum infections is often so capricious that there is no well defined paroxysm. In general, therefore, it is well where falciparum is suspected, not to wait for a paroxysm which may never come, but to make smears at intervals of six to eight hours. This is further justified by the observation that the number of parasites in the peripheral blood in falciparum infections fluctuates considerably, sometimes within a short space of time. Sternal Puncture in Treatment and Diagnosis
Papper and Rovenstine 2 have recently reviewed the T ocantins method for administering fluids via the bone marrow, particularly the sternum. They describe the technic and discuss clinical experience with the procedure. Malariologists should read the article in its entirety, for sternal puncture should be more used in the study and treatment of malaria. Many of the more severe forms of the disease require parenteral administration of saline, glucose and chemotherapy continuously over considerable periods of time, conditions for which the sternal route is particularly suited. In research there is insufficient knowledge of the behavior of the bone marrow in malaria, and sternal PVnc-
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ture may prove to be a distinct help in accurate and speedy diagnosis, particularly in falciparum infections. SUMM~RY
1. Attention is again called to the importance of malaria in war, and the influence of the present war upon the problem of malaria. 2. Malaria should be divided clinically into two types, the one which will kill in the acute stage, and the one which will not. These two types are contrasted as to etiology, course and treatment. 3. Inclination to relapse is the curse of P. vivax. P. falciparum kills through a mechanism of intravascular agglutination. 4. Problems of control and treatment are discussed. Suppressive treatment must perforce precede species sanitation in newly occupied malarious areas. Atabrine in dosage of 0.4 to 0.6 gm. iler week is a safe suppressive drug. Atabrine should never be used intravenously. Troops need not be given suppressive treatment until several days-up to a week-after landing in a malarious region, but there are advantages in commencing it earlier. Sternal puncture may be a valuable aid in the treatment and diagnosis of malaria, and a useful agency in research. BIBLIOGRAPHY
1. Knisely, M. H., Stratman-Thomas, W. K. and Eliot, T. S.: Observations
on Circulating Blood in the Small Vessels of the Internal Organs in Living Macacus Rhesus Monkeys Infected with Malarial Parasites. Anatomical Record, 79:90 (March, Supp. 2) 1941. Knisely, M. H., and Block, E. H.: Microscopic Observations of Intravascular Agglutination of Red Cells and Consequent Sludging of the Blood in Human Diseases. Anatomical Record, 82:426 (March) 1942. Lack, A. R., Jr.: The Occurrence of Intravascular Agglutinations in Avian Malaria. Science, 96:520 (Dec. 4) 1942. Editorial: Malarial Hemagglutination. JA.MA., 121:263 (Jan. 23) 1943. Correspondence: J.A.M.A., 121:885 (March 13) 1943. 2. Papper, E. M. and Rovenstine, E. A.: Utility of Marrow Cavity of Sternum for Parenteral Fluid Therapy. War Medicine, 2:277 (March) 1942.