The American Journal of Tropical Medicine and Hygiene - Volume 1, Issue 1, January 1952

This is the first issue of the American Journal of Tropical Medicine & Hygiene, which takes the place of the American Journal of Tropical Medicine and the Journal of the National Malaria Society. The fusion came about quite naturally as a consequence of the amalgamation of the two Societies of which these journals were the official organs. The reasons for such a step are convincingly set forth in Dr. Justin Andrews' Presidential Address to the National Malaria Society, which will be found on another page. Hundreds of us who were members of both Societies have welcomed this important event in the world of tropical medicine as a sign of the times. Both the perpetuation and the blending of interests and activities which this union brings about are now particularly desirable and opportune.

For the disappearance of malaria as a public health problem in the United States, and the dissolution of the National Malaria Society does not signify in any way a cessation of interest in it as a disease.

Upon the death of Charles Franklin Craig on December 9, 1950, a group of his colleagues and former students, members of the American Society of Tropical Medicine, proposed that a special number of the American Journal of Tropical Medicine be dedicated to his memory in recognition of his great services to the Journal and to the Society, and this was approved by the Council.

Dr. Craig had been Colonel of the Medical Corps, United States Army; Commandant of the Army Medical School; and Professor of Tropical Medicine at George Washington University and at Tulane University Medical Schools. Thus he was bound by the closest ties to both the military and civilian medical circles of our country, and in both, for his unusual abilities as teacher, author and investigator, he came to occupy a position of eminent authority.

But overlapping these careers and extending well into his retirement, his editorship of the American Journal of Tropical Medicine for two decades, from 1927 to 1946, developed into an outstanding accomplishment.

When your committee invited me to prepare and deliver this, the sixteenth Charles Franklin Craig Lecture, my first reaction was to decline the honor, knowing full well that I could not hope to present an address to equal some of the previous masterful lectures of this series. However, since it would afford an opportunity to remind ourselves of the vast amount of valuable work and service in the field of tropical medicine done during the past half century by a worthy contemporary and friend, there was no choice but to accept.

The medical career of Charles Franklin Craig began towards the close of the nineteenth century. He was born and reared at Danbury, Connecticut, and received his medical degree from Yale University in 1894. Following his graduation, he returned to Danbury to practice. The Spanish-American war came in 1898 and was followed by several years of occupation and the rehabilitation of the health and welfare of the people of tropical lands which had been liberated from long years of tyranical Spanish domination and misrule.

This issue of the American Journal of Tropical Medicine is dedicated to the high purpose of paying tribute to a great medical scientist, Colonel Charles Franklin Craig. As one of Colonel Craig's former students, as his devoted assistant during many stimulating years of teaching and research in the Department of Bacteriology at the Army Medical School, and as a comrade who has always cherished his friendship and advice, I welcome the opportunity to join with his many other admirers in this Salute to my Chief.

Colonel Craig is probably best known for his scientific contributions in the fields of parasitology and tropical medicine, and especially for his pioneer work on malaria, amebiasis, and dengue fever. His interests and experience, however, were much broader; in fact, his first love was bacteriology, and even before he entered the Medical Corps of the Regular Army he was recognized as a bacteriologist.

In this presentation dealing with the Armed Forces' interest in tropical medicine, I must emphasize that the views presented are primarily those of the Army; however, the principles apply to the other services. The Armed Forces' interest in tropical medicine must always be primarily influenced by its actual or potential bearing on manpower, particularly during critical phases of military operations. The magnitude of such influence dictates the emphasis to be placed on the disease or other health factors concerned. For example, some of the Army's experience in World War II with some communicable diseases usually considered in the category of tropical disease is shown in table 1.

It can be seen that the dysenteries, particularly those bacterial in type, malaria, and virus hepatitis influenced manpower in a major way whereas diseases such as filariasis, schistosomiasis, and leishmaniasis were of very little significance.

What are the current military interests in tropical diseases?

Research on dengue in the U. S. during World War II provided the following new information of special interest to military preventive medicine:

• 1.  Proof of the existence of multiple immunological types of dengue.
• 2.  The long persistence of immunity to homologous types of virus under conditions precluding reenforcement of immunity by subclinical reinfection.
• 3.  The modifications of the clinical manifestations of the disease which result from reinfection with a heterologous type of virus at various periods after the primary attack.
• 4.  The demonstration that in areas (e.g., New Guinea) where more than one imunological type of virus is present, fevers of unknown origin, clinically not recognizable as dengue, are actually caused by the dengue viruses.
• 5.  The demonstration that type-specific immunity to dengue is associated with neutralizing antibodies for the virus, which can be used for diagnostic and epidemiologic survey purposes.
• 6.  The propagation of dengue virus in mice with the resulting appearance of a mutant or variant strain which could be used for active immunization.

In addition to the discoveries listed above, a great deal more was learned about the basic properties of the dengue viruses. Thus was dengue research brought from the field into the laboratory and further progress has been made possible by work on experimental animals instead of on human volunteers.

• 1.  The New Guinea C and D strains were readily adapted to unweaned mice after a relatively small number of serial intracerebral passages.
• 2.  Work with dengue virus may be greatly facilitated by using unweaned mice rather than older animals for isolation and passage, and, with certain strains, for neutralization tests.
• 3.  The 5 strains of dengue virus studied behaved relatively uniformly in unweaned mice 2–6 days of age but differed sharply in their behavior in mice 3–4 weeks old.
• 4.  Cross-neutralization tests in mice corroborated earlier observations that the New Guinea C and D strains are immunologically different from the Hawaiian and Mochizuki strains.

By serial intracerebral passages, the New Guinea C and Hawaiian strains of dengue virus were adapted to growth in hamsters of 2–5 days of age.

Dengue virus should no longer be described, without qualification, as non-pathogenic for the hamster.

Additional data are presented showing that the New Guinea C and Hawaiian strains represent 2 different immunologic types of dengue virus.

The New Guinea “B” strain of dengue virus has been propagated in mouse brain. Initially, the virus was carried through eight serial intracerebral passages in mice of the dba strain. It produced weakness or paralysis in about 50 per cent of these animals. A sample derived from the fourth passage was transferred to Swiss baby mice after it had been lyophilized for five years. After two passages, the virus was consistently infectious and lethal for 1 to 7 day old baby mice. The lethal titer of infected baby mouse brain was of the order of 10-7 to 10-8. Upon continued serial transfer in baby mice, the virus gradually acquired an increasing capacity for producing paralysis and death in adult mice as well. After a total of 26 passages, the transformation of the virus into a form consistently pathogenic for adult Swiss mice was complete. The titer in such animals then was similar to that in baby mice. Adult mice infected with samples derived from earlier baby mouse passages also supported viral multiplication, but the virus arising in them was qualitatively similar to the virus inoculated in that it was likewise of low-grade pathogenicity for adult mice but invariably lethal for baby mice. The nature of the change in the character of the mouse-adapted virus has been discussed. It is believed that the virus arising in early baby mouse passages consists of two types of particles, one pathogenic for baby mice only, the other for mice of either age, and that the latter gradually replace the former upon continued adaptation to the mouse brain.

Neutralization tests carried out with the mouse-adapted New Guinea “B” strain indicate that it is immunologically identical with the New Guinea “C” and “D” strains and distinct from the Hawaiian type. It is concluded that all known strains of dengue virus belong to one of two separate immunological types.

My service on the Isthmus of Panama began December 9, 1909, as pathologist in the Board of Health Laboratory at Ancon, C. Z. So much publicity had been given this region for many years that it seemed likely that yellow fever and plague would crowd out most of the other causes of death. Imagine my surprise to find that malaria, dysentery, tuberculosis and pneumonia were the high ranking causes of death. No cases of yellow fever developed in the Canal Zone or in the terminal cities during my service from 1909 to 1922. However, rare cases arrived at the quarantine stations and sometimes these were transferred to Ancon Hospital (now Gorgas Hospital) for better hospital care and observation. Most of those cases came from the west coast of South America. It is only in fairly recent years that laboratory methods have been developed that help in establishing a diagnosis of yellow fever.

• 1.  The immunity which developed in volunteers as a result of suppressed infection with R. tsutsugamushi, obtained by inoculation of living vaccine followed by a course of chloramphenicol chemoprophylaxis, was essentially the same as that displayed by volunteers who, following inoculation, experienced overt disease which was terminated by specific therapy.
• 2.  Immunity to the homologous strain of rickettsiae persisted at a high level in most persons for at least 1 year and in some for longer periods.
• 3.  Resistance to infection with heterologous strains of R. tsutsugamushi was of a transient nature. Even within a month after inoculation with one strain, an appreciable number of persons became ill following injection with a heterologous strain. By the end of a year, all were again susceptible to heterologous infection. During the period of waning immunity, the disease which resulted from the heterologous strain was modified from the classical picture. Indeed, the illness observed in the test shortly after recovery was so mild that it would probably not have been recognized as scrub typhus if rickettsemia had not been demonstrated. On the other hand, the disease which resulted when the individuals were tested after 1 year generally presented the typical picture of scrub typhus.

Of the 29 “charter” members (1, 2) of the National Malaria Committee, 3 are still alive. Since the Committee's founding less than a score of years after Ross discovered the key to malaria transmission, they have witnessed the conquest of malaria, and the resultant relief from its baneful effects upon human existence in this land. This transition is memorable in the annals of communicable disease control, but as some anonymous author has said, “What's past is soon forgotten and in the forgetting loses all substance.”

It was estimated in 1916—the year the Committee was started—that not less than 1,000,000 cases and 15,000 deaths due to malaria occurred in the continental United States. 2 (1) Malaria was not the scourge then that it had been in pioneering days, but there were still plenty of areas in the southeastern coastal and fluvial plains where crops could not be made on good bottom land because of the ague, where wishful investors passed by promising industrial sites because of the local reputation for fever, where many of the white rural schools had “chillin'” beds, and where all country stores carried quinine and bewildering assortments of patent antimalarials.

INTRODUCTION Malaria in recent years has been reported as far north as the Dvina River near Archangel in the USSR (65°) and as far south as Córdoba in Argentina (32°). Intense endemicity is still found in some areas of the Americas between 15°N. and 15°S., in Europe south of 45°N., in Asia south of 30°N., in Indonesia and the Philippines, Southwest Pacific (west of 180° and north of 20°S.) and Africa, north of 25°N. In the central and south Pacific, such islands as the Galapagos, Marquesas, Fiji, New Caledonia, New Zealand, Marshalls and Carolines, are entirely without anopheline mosquitoes and consequently are nonmalarious. During World War II A. subpictus indefinitus appeared on Guam but so far no indigenous malaria has been reported.

Transmission occurs as high as 2,591 meters (8,500 feet) near Londiani in Kenya, Africa, where A. gambiae and A. funestus shelter in native huts; at 2,770 meters (9,086 feet) in the Cochabamba region of Bolivia where A. pseudopunctipennis is the vector.

Prior to the discovery of the sulfonamides and antibiotics, few diseases, if any, responded more favorably to a drug than did malaria to quinine. The importance of this drug to civilization can never be overestimated. Nevertheless, over the centuries the natural incidence of the disease was not altered by quinine or later by quinacrine (Atabrine) because of a common shortcoming, the inability to eradicate an infection completely. Their usefulness was largely limited to the suppression of the clinical manifestations of the infection or the early termination of the acute attack. However, since malaria is chiefly characterized by its tendency to relapse, particularly vivax infections which is the more prevalent variety, the constant search by scientists for improved compounds continued. These efforts were relatively meager and sporadic until the Germans began a systematic and intensive program following World War I. From this effort they were rewarded with the discovery of quinacrine, an important substitute for quinine, and pamaquine, potentially a curative but relatively toxic compound.

A series of compounds was tested for antimalarial activity in vitro against the erythrocytic forms of Plasmodium gallinaceum. Chloroquine, quinacrine, quinine, and the naphthoquinone, SN 12,320, were active at concentrations approximating those found in the blood of adequately treated chicks. Pamaquine was relatively inactive in vitro, but when administered to chickens gave rise to active metabolic intermediates. Sulfadiazine, metachloridine, chlorguanide, and two of its metabolic intermediates from monkeys, a number of 2,4-diaminopyrimidines, and a 2,4-diaminopterin were relatively inactive in vitro.

Clinically speaking, the term “amebiasis” refers to human infection with the pathogen Endamoeba histolytica. While an experienced physician may obtain considerable evidence that his patient is suffering from amebiasis, his presumptive diagnosis needs laboratory confirmation. Moreover, a large proportion of infected individuals present no clear-cut symptoms referable to this disease and the first evidence is provided when a stool specimen of the patient is sent to the laboratory for microscopic examination. Thus, amebiasis, like brucellosis, depends primarily on the laboratory for its diagnosis.

REQUIREMENTS FOR DEPENDABLE LABORATORY DIAGNOSIS OF AMEBIASIS 1. Demonstration of Endamoeba histolytica. Although the time may come (or possibly soon be at hand) when relatively dependable diagnosis of amebiasis can be made by serologic methods, today, just as a quarter of a century ago, proof of infection requires that the ameba itself must be demonstrated under the microscope.

In unformed stools and tissue aspirates E. histolytica typically occurs in the trophozoite stage.

Amebiasis at the present time is a confused, incompletely understood, and much misunderstood, disease. The real prevalence is unknown. The epidemiology remains to be clarified. The clinical manifestations are typically atypical, and are frequently not referable to the intestinal tract. The diagnosis of the disease, even though it is entirely a laboratory matter, is sometimes in dispute. The criteria of cure differ from physician to physician, and no entirely satisfactory amebicidal drug is presently available. The pupils and associates of the late Colonel Charles Franklin Craig have wide avenues of opportunity open to them in the investigation of every phase of amebiasis, but much of the confusion which now beclouds the disease might be cleared away if more attention were paid to the principles which he enunciated concerning it.

• 1.  A modification of the zinc sulfate centrifugal flotation technique is described for concentrating cysts of E. coli and E. histolytica from stools and cultures in watch glasses with minimum amounts of foreign material.
• 2.  Several strains of E. coli have been cultivated from cysts that were freed by microisolation from bacteria and transferred into riced whole egg medium that was seeded with organism t and B. subtilis.
• 3.  Encystation of E. coli in vitro was obtained by the method of Dobell in cultures with an undetermined number of species of bacteria and also with only three species, organism t, B. subtilis and Streptococcus zymogenes.
• 4.  On the basis of culturability and microscopic appearance the cysts of E. coli were not demonstrably affected by drying; cysts of E. histolytica were irreversibly damaged by drying.

Experimental infections of Endamoeba histolytica have been established in several laboratory animals, many of which have been utilized in chemotherapeutic studies. Jones (1948) ably reviewed the history of the infection of dogs, cats, and monkeys with E. histolytica and stated that “such valuable amebicides as stovarsol, carbarsone, Vioform, and Diodoquin have resulted.” Anderson et al. (1947, 1950) have further shown the activity of some thioarsenites and antibiotics against natural amebic infection in the monkey. The suitability of the dog as a test animal was studied critically by Thompson et al. (1949, 1950) who reported a satisfactory correlation between the response of canine and human amebiasis and stated that the dog should be particularly useful in the search for new chemotherapeutic agents. Clampit (1948) found that some cases of acute fulminating amebiasis produced experimentally in the kitten were cured by the use of Vioform, chiniofon, and carbarsone but none were cured by emetine.

History abounds with examples of dysentery as a disease of wars. “No major military campaign has been free of its ravages” (Felsen). But it is one with which our medical and sanitation officers cannot become familiar in their civilian experiences. The filth-borne diseases are fast disappearing in this country and our young clinicians and public health workers, who predominate in the medical services of the Armed Forces, scarcely encounter cases of typhoid fever or dysentery during their training. There is even less opportunity for contact with epidemics of enteric infections. Certain aspects of an epidemic in Korea involving prisoners of war, will be considered here as illustrative of the peculiar nature of the problem of dysentery in the Armed Forces.

The most unusual feature of the epidemic was its size. An outbreak of enteric infections with 161 hospitalized cases with a fatality rate of 9 per cent, and some 800 milder nonhospitalized cases, would be regarded as a major epidemic.