Wartime and Public Health N< Antiparasitic Agents in Tropical >ther Than Malaria. W'LLARD H. WRIGHT Zoology Lab^ptory, National Infitute of Health, Botfiesda, M d .
IN ATTEMPTING to discuss the present • problem, I am assuming more or less the role of a clairvoyant, for which I have no qualifications whatsoever. Actually, it is extremely difficult to predict requirements for antiparasitic agents in our Armed Forces, in our postwar civilian population, or in relief and rehabilitation work, of which we shall be expected to assume a large share as time goes on. A few of the tropical parasitic diseases under discussion occur in this country at the present time, at least one has been endemic in the continental United States but is no longer so, while others, although probably introduced at various times, have never become established here. In order to evaluate the question properly, we must consider the distribution of these diseases as related to our present and future military operations, the opportunities for acquiring a given disease in these various areas, the relative degree of protection afforded by preventive medicine as practiced by our Armed Forces, the possibilities of introduction of these diseases by returning military personnel, the possible establishment of these diseases in the continental United States, and the 1360
adequacy or inadequacy of the remedies now available. In general, our troops are being exposed and will be exposed further to many tropical diseases. The introduction into the United States of parasitic diseases by returning troops is much more probable than is the introduction of bacterial, virus, or rickettsial diseases. Many of the tropical parasitic diseases are characterized by a relatively long incubation period, by difficulties in diagnosis, by pronounced chronicity, and by lack of permanent immunity. While we have means of immunizing individuals against such diseases as yellow fever, typhus, typhoid, cholera, and plague, no method of immunization is available against the parasitic diseases., These facts all add to the probability that the parasitic diseases will be the ones most likely to be brought back by returning troops and the ones which may prove to be of concern from a public health standpoint. With this general over-all picture, we can proceed to the discussion of specific diseases, taking into consideration in connection with each,the questions which have been raised above, and attempting to CHEMICAL
in the light of our nited States Ancylostomiasis (Hookworm Disease). The New World hookworm, Necator americanus, has long been prevalent in parts of the South. Considerable progress has been made in the control of this parasite through the work of the U. S. Public Health Service, the campaign of the Rockefeller Sanitary Commission from 1910 to 1914, and the efforts of the individual states since that time. While the disease has been reduced both in extent and severity, there are still some parts of our southern states in which clinical hookworm infections occur in considerable numbers. Hookworm disease is prevalent in many of the areas in which our troops are operating—in the Southwest Pacific, Australia, India, Central and South America, Africa, Sicily, and Southern Italy. Undoubtedly, hookworm infection will be acquired by some of our troops in these areas. """"""I Since the discovery of hookworm disease as a clinical entity, various drugs have been employed in its treatment, chief among which have been thymol, beta-naphthol, AND
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oil of chenopodium, carbon tetrachloride, and tetrachloroethylene. The latter compound is the treatment of choice at the present time. It is somewhat less efficient "t,han carbon tetrachloride, but possesses a -wider margin of safety. In many cases, iiowever, one treatment is not sufficient to remove all worms and in some, cases a single treatment will not even effect a «c)inicfrl cure. Because of its tendency occasionally to cause dizziness, delirium, sand transitory loss of consciousness, it is tbest used under hospital conditions, so •*hat the patient may be kept under observation following treatment. While tetrachloroethylene approaches about as high a standard of efficacy as we can expect with most anthelmintics, there is still need for a inoxe efficient remedy which would also have the advantage of greater safety. However, this need is not the most paramount in connection with the treatment of tropical parasitic diseases. Amebiasis. Infection is widespread in temperate and tropical zones. In this country about 10 per cent of persons examinedin surveys have been found to harbor the parasite. Many of these persons have not l>een known to show clinical symptoms. There is some difference of opinion at the present time concerning the obligatory pathogenicity of this organism. Some authorities believe that lesions, even though mild in character, are always associated with the parasite, while others maintain that it is possible for individuals to act as carriers without suffering in any way from the presence of the organism. Regardless of this question, persons exposed to infection in tropical countries frequently acquire a seveie form of the disease. It is not known whether such a result is due to a greater virulence of tropical strains, greater opportunities for acquiring heavier infections, or lack of resistance associated with lack of previous exposure. The dysenteries have always been the plague of armies and even though every possible effort on the part of military authorities is made to practice effective preventive medicine, protection against the dysenteries frequently breaks down. The present war is no exception, even though more and better sanitary safeguards are provided for troops than ever before. In many combat areas, the dysenteries have been an important cause of morbidity. The bacillary types have been responsible for the vast majority of this morbidity; however, amebiasis has also played a role. I t is said that about one eighth of the hospitalized dysentery cases in the British campaigns in North Africa were due to infection with Endamoeba histolytica, although amebic dysentery is reported to be the type chiefly encountered in British troops in India (8). For the prevention of water-borne infection, the tablets now in use for canteen water sterilization are effective under most VOLUME
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conditions for the destruction of cysts of E. histolytica (Si). Calcium hypochlorite ampoules are being used for the sterilization of water in the Army Lyster bag, but cysticidal action is obtained only through the use of superchlorination and adequate exposure time (8). The portable sand niters used in advanced zones will probably remove cysts of E. histolytica from raw wTater supplies if such units are properly operated (#). However, a new and more efficient type of filtering unit has been devised. Outbreaks of fly-borne amebic dysentery have been known to occur. Because complete protection cannot be provided under all conditions, it is inevitable that some of our troops will contract amebiasis and will return to this country with this infection. What effect these carriers will have on our civilian health is questionable, but their dispersal may lead to a higher morbidity rate from this disease and possibly be the means of spreading new and more virulent strains of the organism. Even though considerable progress has been made in the last 20 years in developing more efficient amebicidal drugs, there is still need for a better treatment for this condition. Emetine hydrochloride will control the acute dysentery but will not control intestinal infection; it is a dangerous drug and should be used only in the initial stages of severe cases. Carbarsone (4-carbaminophenylarsonic acid), Chiniofon (sodium iodoxyquinolinsulfonate), Vioform (iodochlorohydroxyquinoline), Diodoquin (5,7-diiodo-8-hydroxyquinohne), and some other drugs provide good results in many cases but sometimes fail to effect cures. Even after several courses of treatment with one or more of these compounds, we find persistent infections.
Certainly none of these drugs can be regarded as a specific for the condition and we are in distinct need of better amebicidal compounds which will give more dependable action and yet possess a margin of safety which will permit their use under most conditions. This need has been very apparent in the past but will become more acute if a larger number of cases appear in our military forces and our postwar civilian population. Diseases Formerly Endemic in the United States Filariasis. Bancroft's filariasis i s caused by two species of filarid worms, Wuchereria bancrofii and W. malayi. The first-named species has a widespread distribution in tropical and subtropical countries, occurring in a broad belt through Central Afric from the east to the west coast, in North Africa, Southern Asia as far north as Southern Korea and the southern half of Japan, in the East Indies, the islands of Oceania, Northeastern Australia, the West Indies, Brazil, and the northern part of South America. W. malayi is found in the East Indies, Ceylon, India, French IndoChina, the Federated Malay States, and parts of China. The clinical manifestations of the infection with these two species are very similar. The only known focus of this disease in the continental United States was discovered in Charleston, S. C , by Guite'ras (7) in 18S6. Since that time several surveys have been made of the situation, a t Charleston. There is good evidence at the present time that the disease has entirely disappeared from this locality (0). This disappearance is associated with slum-clearance programs and the removal of the household cistern which contributed heavily to the
Vegetative, motile forms of Endamoeba histolytica, the causative agent of amebic dysentery. (Greatly enlarged)
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breeding of the chief mosquito vector, Culex quinquefasciatus. Nothing is known concerning the circumstances which led to the establishment of the disease at Charleston and not at other points in the southern states, since it was undoubtedly also introduced elsewhere by slaves imported from Africa. As with malaria, certain optimum conditions are required for the establishment and perpetuation of filariasis. There must be in the community a high rate of infection, the occurrence in the blood stream of infected individuals of an optimum number of microfilariae, the presence of a suitable mosquito host in numbers sufficient to provide an optimum rate of infection in that host, suitable conditions of temperature and humidity for the development of the microfilariae in the mosquito host, and accessibility of susceptible individuals to the bites of such mosquitoes. All these conditions have been amply fulfilled in certain of the areas in which our troops are operating and as a consequence a considerable number of cases of filariasis has appeared among such troops. While every effort is being made t o practice effective preventive medicine in endemic zones of filariasis, as with the dysenteries, it is not always possible t o achieve the ideal. It appears probable that many more cases of filariasis will b e invalided back t o the United States. S o far, from a public health standpoint it has been fortunate that most of t h e returned cases of filariasis have not shown microfilariae in t h e peripheral circulation and therefore have not been capable of transmitting infection. However, not all persons with microfilariae develop clinical symptoms, and it is possible that numbers of such persons have returned or will return t o this country and act as sources of infection for others. While little is known concerning the infectibility of domestic species of mosquitoes, other than Culex quinqtiefascialits, many other suitable vectors no doubt occur in the United States. If a sufficient number of infected returning troops is concentrated in areas in which intermediate hosts are prevalent, it is conceivable that filariasis m a y become re-established in this country. However, at t h e present time such a possibility seems remote. There is n o specific treatment for filariasis. I n searching for such a treatment, t w o objectives m a y b e kept in mind. One concerns t h e destruction of the adult worms, and the other t h e destruction of microfilariae in the blood and t h e sterilization of adult female worms. In neither case do w e know t h a t we should actually benefit the patient. I t does not seem probable that t h e destruction of larvae in the blood stream would result in any material clinical improvement or contribute t o t h e more prompt disappearance of the periodic attacks of lymphangitis, lymphadenitis, and other manifestations of the disease. T h e destruction of the adult
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worms might even result in an exacerbation of t h e clinical symptoms and cause more profound reactions, at least for t h e period of t i m e require*! for the dead worms t o be walled off through connective tissue formation. On the other hand, a drug of no material benefit t o the patient might provide a powerful public health weapon in limiting the spread of filariasis. Any drug which would kill microfilariae in the peripheral circulation and sterilize productive female worms could be employed to eliminate infected individuals as reservoirs of infection. In fact, were such a compound available, it might be possible t o control filariasis even in areas of high endemieity. It would appear that some such result is taking place in connection with the dog heartworm, Dirofdaria im-mitis, in our southern states. Since 1934, when the first successful treatment was brought out, incidence of infection has materially declined, not as a result of any concerted effort but principally through the widespread voluntary application of chemotherapy. Many drugs have been tried in filariasis. From extensive experience, Chopra and Sundar R a o (d) stated t h a t Soamin (sodium p-aminophenylarsonate) and Fouadin (sodium antimony III bis-pyrocatechin disulfonate of sodium) are the only compounds which they have found of value. Soamin g a v e good clinical results although it had no effect on the microfilariae; Fouadin caused a disappearance of the microfilariae for several days and seemed to clear u p chyluria and give definite relief from the symptoms. Brown (4) has recently shown t h a t Anthiomaline (lithium antimony thiomalate) in relatively large doses will bring about a marked reduction in the numbers of microfilariae in the peripheral circulation, a reduction which m a y prove t o b e permanent in character. In contrast t o the trivalent antimonials, pentavalent compounds, m a n y of which are of value in certain protozoal infections, have shown little promise against filarid parasites.
Exotic Diseases Leishmaniasis. There are three forms of this protozoal disease, visceral, dermal, and muco-cutaneous, usually regarded as being caused b y three separate species of Leishmania, L. donovani, L. tropica, and L. brasiliensis. T h e disease is transmitted b y species of sandflies of the genus Phlebotomus, although there is some evidence that it can be acquired b y direct contact, through food and drinking water, and b y the respiratory route. Kala-azar, the visceral form of the disease, is endemic in certain areas in the Near East, India, Burma, parts of China and Manchuria, the Mediterranean littoral, scattered areas in Central Africa, Northeastern Brazil, and Northern Argentina. Dermal leishmaniasis, or oriental sore, occurs over much the s a m e regions as kala-azar, except that in m a n y of these
areas the t w o forms d o not overlap and L. tropica is probably not present in South America. The muco-cutaneous form, or American leishmaniasis, is found in various parts of South and Central America and in Mexico. W e h a v e troop concentrations in many areas in which leishmaniasis exists. Prevention of the disease is difficult. In other than permanent military establishments, it would be impracticable to attempt destruction of breeding places of the flies. Insecticide sprays are of some value and repellents may help to ward off attacks of the flies. T h e use of bed nets having no less than 22 meshes to the square inch is advocated, but such a procedure adds considerably to discomfort in hot climates. Contact with infected dogs and other domestic animals should be avoided, but dangers from this source are n o t usually" known to the average soldier. Under the circumstances, it may be expected that cases of leishmaniasis will appear among our troops stationed in endemic areas. As the incubation period m a y extend over weeks and months, it is possible that infected individuals m a y return to this country before their infection is detected. Establishment of leishmaniasis in the continental United States does n o t appear at all probable. Three species of Phlebotomus have been described in this country, but only one of these is known to feed on man. Three other species have been found b u t have not been described; at present nothing is known concerning the feeding habits of these forms. While we have no information concerning the capaci t y of domestic species to transmit leishmaniasis, their present known occurrence would seem to indicate little danger in this respect even though one or more might prove to be vectors. However, we do need to know more about the distribution of these flies in this country. T h e need for new chemotherapeutic agents in the treatment of leishmaniasis is less acute than it is in connection with some other tropical parasitic diseases. In kala-azar a number of pentavalent antimonials have been used very successfully. These include Neostibosan, Neostam, Solustibosan, and Ureastibamine. More recently diamidino stilbene and pentane have been found of considerable value, particularly in the Sudan type of t h e disease and in antimonial-resistant cases in other countries. In oriental sore, pentavalent and trivalent antimonials have been employed with good results, a s has berberine sulfate. Treatment of the mucocutaneous form is more difficult and results in general have not been satisfactory. Trypanosomiasis. There are two tyi>es of this disease, the African and South American. T h e former is caused b y Trypcfc" nosoma gambiense and T. rhodesiense, t h e latter b y T. cruzi. African trypanosomiasis occurs in a broad belt through that con-
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tment from Senegal and Angola onfeheAtlantic to Lakes Victoria, Tanganyika, and Nyasa, and into Portuguese East -Africa*. American trypanosomiasis or Chagas' disease is found in various parts of Soutli and Central America and Mexico. A-fricam sleeping sickness is transmitted tlirougli the bites of tsetse flies of the genus G^los$in
