The first recorded case of histoplasmosis occurred in Panama in 1906. Its discoverer was Samuel T. Darling, chief pathologist at Ancon Hospital, in the Canal Zone, and a protégé of William Crawford Gorgas, the celebrated United States Surgeon General who directed the sanitation program that made possible the construction of the Panama Canal. On December 7th of that year, as Darling subsequently recounted in the pages of the Journal of the American Medical Association, "while examining smears [made in the course of an autopsy] from the lungs, spleen, and bone marrow in a case that appeared to be miliary tuberculosis of the lungs, I found enormous numbers of small bodies generally oval or round. Most of them were intracellular in the alveolar epithelial cells, while others appeared to be free in the plasma of the spleen and rib marrow. Tubercle bacilli were absent." A few months later, his report continued, chance provided him with two more post-mortem cases of the same distinctive stripe. He thus ventured to conclude that he had come upon a new infectious disease. Darling, however, failed to grasp the precise nature of his find. It was his belief that the "small bodies" he had observed, and to which (exercising the prerogative of a pioneer) he gave the name Histo- plasma capsulatum, were a species of protozoa. He also believed, with somewhat better reason, that histoplasmosis (as he chose to call an invasion of H. capsulatum) was "a fatal disease of tropical America" and, in all probability, a most uncommon one. The first of Darling's misconceptions, though sensed (by the Brazilian biologist Henrique da Rocha Lima) as early as 1912, was not corrected until 1934, when W. A. DeMonbreun, professor of pathology at Vanderbilt University School of Medicine, successfully isolated a colony of H. capsulatum spores and cultivated them to definitive fungoid maturity. Darling's other errors eluded detection even longer—until 1945. Their exposure was the joint accomplishment of three now classic studies. One of these was the Archives of Internal Medicine case review. The others were the work of the team of Amos Christie and J. C. Peterson, both professors of pediatrics at Vanderbilt, and a team headed by C. E. Palmer, then director of the United States Public Health Service Tuberculosis Research Office, in Washington. The Archives review abruptly revised the accepted view of histoplasmosis as an exclusively tropical disease. Of the seventy-one cases then on record, it showed, fifty-six had originated in the temperate United States. The rest had turned up in nearly a dozen widely separated countries. In addition to Panama, the list included Argentina, Southern Rhodesia, British Honduras, the Philippine Islands, Austria, Brazil, and England. To this cheerless revelation the Christie and Peterson study (which was published in the American Journal of Public Health) and that by the Palmer team (which appeared in Public Health Reports) added a double-barreled postscript. Histoplasmosis, the authors independently (and almost simultaneously) announced, was a good deal less deadly than had been universally thought. The fatal form was merely its more conspicuous manifestation. It also occurred in another form, which, while diagnostically slippery (because of its close resemblance to any pneumonitis) and capable of producing much misery, was relatively benign. On the other hand, they pointed out, the disease was a good deal less rare than theretofore supposed. There was, in fact, some reason to believe that the muted (or primary pulmonary) variety might be rather common. Just how common neither Christie and Peterson nor Palmer and his associates were at that time able to say. But subsequent investigators have amply answered for them. The best contemporary opinion holds that in the United States alone some thirty million people have had primary histoplasmosis, and its annual incidence here is estimated at around five hundred thousand cases.
Although histoplasmosis is now established as a disease of nearly universal distribution, it appears to be most prevalent in the United States. Its prevalence here is not, however, uniform. There is no considerable section of the country in which histoplasmosis is wholly unknown, and a total of forty outbreaks of epidemic sweep have been reported in eighteen states—New York, Maryland, Virginia, North Carolina, Florida, Alabama, Tennessee, Arkansas, Missouri, Oklahoma, Kansas, Ohio, Indiana, Illinois, Iowa, Wisconsin, Minnesota, and North Dakota—but it occurs with menacing frequency only in the central Mississippi Valley. In most of the states that lie in that area, its incidence ranges from thirty to eighty per cent, and there are some in which it runs even higher. These are the five river states, the states that converge on the Mississippi near its meeting with the Missouri and the Ohio, and from the heart of the region—Missouri, Illinois, Kentucky, Tennessee, and Arkansas. The disease is endemic there.
Why histoplasmosis should occur so variously is a matter of some dispute. It is obvious only that geography must be the determining factor in its spread—that its range reflects a physical environment hospitable to H. capsulatum. There is no reasonable alternative to this supposition. For histoplasmosis, an abundance of research has established, cannot be conveyed from one human being to another. Nor, it is equally clear, can it be communicated to man by any insect or higher animal. It is a disease that human beings (and other animals) contract directly from nature—by inhaling a quantity of H. capsulatum spores. The specific environmental factor that controls the organism's geographical range is less apparent. Three possible explanations have been seriously advanced. Its development may depend upon a certain type of soil (a red-yellow podsolic soil is peculiar to much of the high-incidence area), it may require a certain vegetable environment (some fifty common plants are more or less indigenous to the area), or it may be governed by a certain pitch of temperature and humidity. At the moment, the evidence, such as it is, most strongly supports the last of these hypotheses. Laboratory experience has conclusively shown that an exquisitely balanced microclimate— one hundred per cent humidity and a temperature ranging no higher than eighty-six degrees and no lower than sixty-eight degrees—is essential to the optimum growth and proliferation of H. capsulatum. So have numerous observations in the field. In nature, H. capsulatum flourishes only in the darkest, dampest, warmest, most snugly sheltered places. Its favorite habitats are belfries, silos, and abandoned chicken houses (probably because a constant humid heat is generated there by decaying bird droppings), but it also finds a salubrious home in caves, storm cellars, punky stumps, and densely wooded ravines and riverbanks. (Most epidemiologists believe that certain of the many mysterious ailments whose names have long enlivened regional medical literature—cave sickness, bat fever, speleologists' disease, Tingo Maria fever—are actually histoplasmosis.) Such places, of course, abound throughout the United States. Not everywhere in this country, however, is the microclimate they provide consistently warm and damp. In the central Mississippi Valley, where the mean temperature in summer is around seventy-five degrees and the average annual rainfall totals nearly fifty inches, violent extremes of rain and drought and heat and cold are notably infrequent. They are most infrequent in the five states that constitute the endemic area.
The second phase of the 1955 Mountain Home investigation differed from the first in two important respects. It was, for one thing, planned and actively headed by Dr. Furcolow. For another, it was undertaken with a much augmented team. In addition to Dr. Chin, Dr. Paxton, and Mrs. Rakich, this included not only Dr. Furcolow but three other members of the Kansas City station staff —Mrs. Dorothy Calafiore, a nurse; Peter Ney, a statistician; and Howard W. Larsh, a professor of mycology and bacteriology at the University of Oklahoma who serves as a consultant in mycology to the Public Health Service—and also Miss Whitmore (the Baxter County nurse) and two recruits from Arkansas. These were Mrs. Mildred Ware, the local district nursing supervisor, and V. E. Medlock, an X-ray technician on the staff of the Arkansas State Department of Health. The Kansas City contingent and the others met at Mountain Home on the evening of Monday, March 14. They got down to work the next morning.
"My decision to join the team had nothing to do with Dr. Chin," Dr. Furcolow says. "That is to say, it was not in any sense a criticism of his handling of the preliminary inquiry. He had done an excellent job. And if the trouble had turned out to be psitt
acosis —or any viral or bacterial disease—he would, of course, have continued to run the show. But histoplasmosis is a little out of his field. It is, however, very much in mine. It's been my special interest practically all my professional life. So I could hardly be expected to sit it out in Kansas City. Especially this particular outbreak, which had all the earmarks of being something quite out of the ordinary. In size, in kind, in almost every respect. The biggest histo outbreak on record at that time was one at Camp Gruber, Oklahoma, in 1944. It totaled twenty-seven cases. Another, involving twenty-five cases, occurred at Foreman, Arkansas, in 1947. One at Camp Crowder, Missouri, in 1943, involved twenty-two cases. And there was one in 1948 at Madison, Wisconsin, that involved a dozen. But the victims in all those outbreaks were almost invariably adults. This was children. It was, in fact, the first major outbreak of histoplasmosis ever observed among children. And not only that. With thirteen certain cases and twenty-three probable ones—to say nothing of that wave of skin- test positives in the general student body—it looked as if we might be up against the biggest histo outbreak of any kind in history.
"We were. By Wednesday evening, there was no longer any doubt about that. We had a record outbreak on our hands. I'd heard from our Rocky Mountain Laboratory on the second set of blood tests, and the results were the same as the first—all twenty- three of the recovered children were serologically positive for histo. That brought the total of certain cases up to thirty-six, or nine more than the Gruber outbreak. But it didn't add much to our store of useful knowledge. We still knew practically nothing.
To come right down to it, we weren't far past the point where most investigations start. The only thing we had clearly established was the nature of the outbreak. In the circumstances—I mean, in view of the fact that histo is an extremely difficult disease to diagnose that was no small accomplishment. Nevertheless, we had only just begun. The full extent of the outbreak, and just how and where the children had come in contact with H. capsulatum, were still to be determined. The major question was, of course, the source. But before we could hope to answer that, it was necessary to explain all those other positive skin-test reactions. The scope of the problem came first.
"When Dr. Chin gave me his progress report in Kansas City, he and Dr. Paxton had completed the skin-testing survey at the school, and they had read most of the reactions—about two hundred, as I remember, out of a total of three hundred and twenty. Or three hundred and twenty-one, counting the teacher, Miss Smith. They had also tested a control group of forty-eight sixth- graders at the Mountain Home junior high. And they had made u start on the job of sending the blood samples taken in the two surveys off to Rocky Mountain for laboratory test. The first thing on the general program was to finish up those jobs. Chin and I did the rest of the skin-test readings. The bloods were handled by I'axton, Ney, and the nurses. Larsh and Medlock had special programs of their own to set up. We started our readings where Chin had left off the week before—at the elementary school. Reading and recording the results took us a couple of days. We then moved over to the junior high and had a look at the controls. By the end of the week, or thereabouts, we had the total skin-test picture. I'm bound to say I've seldom seen a stranger one. Not that the final results at the school were especially startling. Chin's earlier findings had naturally prepared us for a high percentage of positive reactions there, and we got them. Of the three hundred and twenty children tested, two hundred and seventy-nine—or about eighty-seven per cent—were histo positive. But we certainly weren't prepared for the reactions we found at the junior high. The controls scored almost as high as the others. Thirty-three of the forty-eight—sixty-nine per cent—were also positive for histo. The picture was already cloudy enough. Now it was practically invisible.
"So, at the end of another week, we hadn't really made much progress. With the scope of the outbreak still unknown, we still had insufficient data to attempt to determine the source. In a sense, we had even less than before. We had more or less assumed that the focus of infection was in or near the elementary school. It had been our expectation that the control study would result in a high percentage of negative reactions, and thereby make it certain. That was largely the point of the study. I don't mean to say that those thirty-three positive controls at the junior high made us actually change our thinking. The study had failed to confirm our assumption. It didn't deny it, though. It didn't necessarily prove we were wrong. The meaning of a positive histo skin test is too equivocal for that—particularly in an area where the disease is known to be endemic. But it made us wonder a little. It also made us wait with some impatience for Rocky Mountain to come through with the blood-test results. Those would be definitive. They would tell us exactly where we stood. Then we could get down to fundamentals.
"The first report on the serological tests arrived on Saturday morning. It referred to the elementary-school survey, but that's about all I remember of it. No matter. It was far too small a sampling to signify—a couple of dozen cases at most; and merely the first of many. Another arrived on Monday, and after that, as I recall, reports turned up at the rate of one or more a day throughout the rest of the week. I passed them along to Ney to work into proper shape. There was nothing to be gained from puzzling them out piecemeal. It was better to wait until all the results were in and he had them correlated by grade and classroom and school. We didn't just wait, of course. There was plenty else to do. While Chin and I were reading skin tests and the others were packing and mailing the rest of the bloods, Medlock had made the necessary arrangements for a comprehensive X-ray study. He had fetched a mobile seventy-millimeter X-ray unit in from Little Rock, and had arranged with Dr. Saltzman and the other local physicians to use their standard fourteen-by-seventeen apparatus in case his smaller plates turned up something tricky. And, working through the State Tuberculosis Association, he had raised an appropriation to cover the cost of the film and other equipment. Chin and I talked to the school authorities, and they once more very kindly gave us permission to use the auditorium for a clinic. All we needed now were the customary releases from the parents. That took a little more time. But by the first of the week we had enough to provide an adequate study—all thirty-six of the established clinical cases, two hundred and fifty-seven children from the general student body, thirty-two of the sixth-grade controls, and Miss Smith.
"The X-ray study itself went off with reasonable dispatch. We finished up around noon on Thursday—films, prints, readings. Ney took it from there. His analytical breakdown of our data was ready the following morning. One look, and the clouds began to lift. The clinical cases, to nobody's surprise, all showed definite lung lesions. So did Miss Smith. And so did some of the general student body—thirty out of the two hundred and fifty-seven, or roughly ten per cent. The controls, however, were the thing. This time, they acted like controls. All but one of the thirty-two were as clean as a whistle. The next day—Saturday, March 26—we got Ney's blood-test correlation. Rocky Mountain confirmed the X-ray study at every significant point. Two controls—one of them the X-ray-positive child—gave positive reactions. The other controls were all negative. Miss Smith, as expected, was positive. So were approximately thirty per cent of the general group. Considering the X-ray findings—an X-ray study is never quite as comprehensive as a serological survey in histo—that was also about what we'd expected. Well, those were the high spots of the studies. Merely the high spots, I should say. But, taken with the skin-test data, they gave us the footing we needed to move into the final phase of the investigation. We knew the nature of the problem. We knew the general focus of infection. In spite of the two positive controls, it was somewhere around the elementary school. A couple of outside cases had no epidemiological significance. They could be rationalized in various ways—this was, after all, an endemic area. And we knew the size of the outbreak. The thirty-six clinical cases had been only a hint—like the minaret of an iceberg. On the basis of the blood and X-ray studies, the actual number of recent and cu
rrent histo cases was four times that. When all the data had been analyzed and all overlaps accounted for, it added up to a hundred and forty-six children. And Miss Smith.
"So we had a really champion outbreak to explain. As a matter of fact, it is still by far the biggest of its kind on record, and I doubt very much if it will even be equaled for a long time to come. It was also, in my experience, epidemiologically unique. The deeper into it we went, the more painfully apparent that became. Most outbreaks of histoplasmosis are puzzling, but only up to a certain point—only until the diagnosis is established. Once that is determined, it seldom requires much exertion to find and confirm the source of infection. A couple of questions will generally reveal that a couple of weeks before the victims got sick—the incubation period in histo is around ten to fourteen days—they had spent a day cleaning out an old chicken house. Or exploring a cave. Or cutting brush in a creek bottom. Or, often enough, just visiting somebody's farm. Samples of soil are then collected at the site for laboratory examination. The usual result is isolation of H. capsulatum. And that closes the case. Mountain Home was a maverick. The approximate date of exposure was easy enough to determine. The clinical case histories and the school attendance records placed it in the neighborhood of February 1. But there the pattern broke. As Chin and Paxton had already found, the usual questions didn't yield the usual answers. There wasn't any cave or creek or chicken house. Not even a trip to a farm. There was only a school —a well-kept school—with a big, sunny lawn and a playground. Which meant that the children hadn't, in the usual way, exposed themselves to H. capsulatum. They hadn't gone to it. It had come to them.
The Medical Detectives Volume I Page 11