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Chapter II

Contents

CHAPTER II

Coccidioidomycosis

Roger O. Egeberg, M.D.

The full clinical picture of coccidioidomycosis had been put together only a short time before the entry of the United States into World War II, and the very name was unfamiliar to the majority of physicians in the United States as the country began to take action against the eventuality of war.

What, then, was known to students of the disease as the United States began to mobilize and to prepare for training? By 1940-41, the clinical picture was fairly clear. It was recognized that coccidioidomycosis was a disease with an acute, relatively benign initial phase, usually localized in the lungs, and frequently associated with erythema nodosum. This acute phase was followed in a few patients by a generalized spread throughout the body with death occurring in more than 50 percent of white patients and in almost all dark-skinned patients. The causative agent was a biphasic fungus, Coccidioides immitis, which had been recovered from the soil of certain arid regions and from rodents. There were obvious similarities to tuberculosis, but analogies here were in many respects misleading.

HISTORICAL NOTE

In 1892, Posada1 and, later in the same year, Wernicke2 described a round parasite found on section in the autopsies of patients dying of a disease not unlike tuberculosis. This work was done in Argentina, and the patients were seen at infrequent but fairly regular intervals. In California, in 1894, Rixford3 and, in 1896, Rixford and Gilchrist4 were impressed with the similarity of this round parasite, which they also had seen at the autopsy table, to coccidiosis, a parasitic disease of chickens, and accordingly called

1Posada, A.: Un Nuevo Caso de Micosis Fungoidea con Psorospermias. An. d. Circ. Med. Argent. 15: 585-597, 1892. Cited by Moore, M.: Blastomycosis, Coccidioidal Granuloma, and Paracoccidioidal Granuloma. Arch. Dermat. & Syph. 38: 163-190, August 1938.
2Wernicke, R.: Ueber einen Protozoenbefund bei Mycosis fungoides. Centralbl. f. Bakt. 12: 859-861, 28 Dec. 1892. Cited by Moore, M.: Blastomycosis, Coccidioidal Granuloma, and Paracoccioidal Granuloma. Arch. Dermat. & Syph. 38: 163-190, August 1938.
3Rixford, E.: A Case of Protozoic Dermatitis. Occidental M. Times 8: 704-707, December 1894. Cited by Smith, C. E.: The Epidemiology of Acute Coccidioidomycosis With Erythema Nodosum ("San Joaquin" or "Valley Fever"). Am. J. Pub. Health 30: 600-611, June 1940.
4Rixford, E., and Gilchrist, T. C.: Two Cases of Protozoan (Coccidioidal) Infection of the Skin and Other Organs. Johns Hopkins Hosp. Rep. 1: 209-268, 1896. Cited by Smith, C. E.: The Epidemiology of Acute Coccidioidomycosis With Erythema Nodosum ("San Joaquin" or "Valley Fever"). Am. J. Pub. Health 30: 600-611, June 1940.


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it Coccidioides. The disease, coccidioidal granuloma, was usually fatal and for years was described sporadically in the literature, almost always from post mortem examination. In 1900, Ophüls and Moffitt5 showed clearly in a simple experiment that the spherules recovered from diseased tissue could develop into a mycelial mat and that Coccidioides was therefore a "mould."

Early in the settling of the southern part of the San Joaquin Valley, Calif., people noted a nonrecurring, relatively mild disease, primarily respiratory in nature, with symptoms similar to a cold or la grippe and associated with red "bumps" on the legs or with a blotchy eruption. This illness was called "Valley Fever," was common, and was considered to be a mild local condition. These "two" diseases continued to make themselves felt, side by side, one common, more of a nuisance or discomfort, the other relatively rare, severe, wasting, and usually ending in death.

In 1935 and 1936, Gifford and Dickson began to relate the two clinical pictures and in 1937-38 published their very important papers showing that coccidioidal granuloma was a relatively rare spread of the early mild disease and never occurred without the other.6 This immediately focused more attention on the primary form with the grave threat overhanging it, in what Dr. Karl F. Meyer of The George Williams Hooper Foundation, University of California Medical Center, San Francisco, Calif., in discussion called "the renaissance of the disease." With this much fuller clinical picture, with the total number of patients infected with the fungus very much greater than previously thought, and with the great gaps of information still to be filled in, interest was aroused, cases were better described, symptomatology became better known, and the time relationship between the two stages became evident.

By 1940-41, it was possible to define the disease as an infection caused by the fungus C. immitis, characterized by an acute respiratory syndrome simulating a cold, influenza, or pneumonia and infrequently progressing to a generalized chronic infection of a granulomatous type fatal in well over 50 percent of the cases.

CAUSATIVE AGENT

Coccidioides immitis is a biphasic fungus growing as a mycelial mat with aerial hyphae in its saprophytic phase-as on culture media-and as spherules which multiply by endosporulation in the animal body.

5Ophüls, W., and Moffitt, H. C.: A New Pathogenic Mould. Phila. M. J. 5: 1471-1472, 30 Jan. 1900. Cited by Smith, C. E.: The Epidemiology of Acute Coccidioidomycosis With Erythema Nodosum ("San Joaquin" or "Valley Fever"). Am. J. Pub. Health 30: 600-611, June 1940.
6(1) Gifford, M. A.: San Joaquin Fever. In Annual Report, Kern County Health Department for Fiscal Year July 1, 1935, to June 30, 1936, pp. 22-23, and for Fiscal Year July 1, 1936, to June 30, 1937, pp. 39-54. (2) Dickson, E. C.: "Valley Fever" of San Joaquin Valley and Fungus Coccidioides. California & West. Med. 47: 151-155, September 1937. (3) Dickson, E. C.: Coccidioidomycosis. J.A.M.A. 111: 1362-1364, 8 Oct. 1938. (4) Dickson, E. C., and Gifford, M. A.: Coccidioides Infection (Coccidioidomycosis); II. The Primary Type of Infection. Arch. Int. Med. 62: 853-871, November 1938.


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In its mycelial phase, the micro-organism sustains itself under a wide variety of meager nutritional situations. It remains alive in dry soils, even washed beach sand, in moderate temperatures for at least 7 years. Its ability to withstand higher temperatures is related to humidity. It grows abundantly in a pH range of 2.02 to 12.13.

FIGURE 11.-Sputum culture of C. immitis on Sabouraud's medium, showing white, cottony fungus growth. 

FIGURE 12.-Microscopic appearance of old culture C. immitis, showing fragmented chlamydospores. This is the infective form of the fungus occurring in nature.

On modified Sabouraud's medium, the mycelial mat or phallus may vary in appearance, but most commonly it is white and fluffy from above, very slightly yellowed underneath, and frequently has a whiteness and translucence resembling a naphthalene mothball broken in two (fig. 11). A speck fished from a 10- to 20-day-old colony and teased in a drop of water on a slide has a very characteristic appearance when viewed under the dry high power of a microscope. In varying amounts scattered through the relatively dense mycelial mat are hyphae, with the following characteristics:

1. They branch at right angles.

2. They have swellings at irregular intervals best described as "racqueting."

3. They are segmented, and the more mature areas show an increasing difference between adjacent segments, so that every other one becomes barrel shaped while the ones in between atrophy. It is these barrel-shaped segments (arthrospores) that can infect animals or man or repeat the saprophytic cycle.

A culture of more than 10 days becomes increasingly dangerous as a source of laboratory infection, and a 4-week-old culture while showing the characteristics best is a menace (fig. 12).


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FIGURE 13.-Development of coccidioidal spherules. A. Chlamydospores in tissue. B. Chlamydospores rounding up to form spherules. C. Protoplasm appearing within the spherule. D. Protoplasm divides into endospores. E. Mature spherule ruptures, releasing endospores which are carried by lymphatics or by the bloodstream. Each endospore increases in size, becomes a mature spherule, and repeats stages C, D, and E.

The home of the mycelial or saprophytic phase of the fungus now appears to be the soil of the endemic areas, where it can be recovered in as high as 40 percent of soil samples collected from the surface in the early summer. In the parasitic phase, in the tissues of man or lower animal, the arthrospores quickly round out into spherules, usually from 20 to 40 microns in diameter, which have a very characteristic doubly refractile wall. As these mature septae form within them and gradually wall off, approximately


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70 small pieces, which round out to become endospores, grow to the size of mature spherules and in turn endosporulate (fig. 13). Not infrequently, growth in a pulmonary cavity may resemble the saprophytic stage with mycelia and formation of hyphae, but it is doubtful that these ripen. It is thus apparent that spread of this disease is not by contagion from man to man but from the environment to man by inhalation of the arthrospores.

SYMPTOMATOLOGY

The symptoms and signs of coccidioidomycosis, in its primary phase, are best described as mimicing a cold, influenza, or primary atypical pneumonia; in its disseminated phase, as a generalized tuberculosis. About 60 percent of those infected, as evidenced by changing skin reactivity to coccidioidin, have no symptoms. In that 40 percent of infected people who become ill, the onset of coccidioidomycosis may be acute or gradual, and the patients exhibit one or more, or a combination of, symptoms, as follows:

1. Fever is relatively mild and most common. Usually, the temperature is not above 102° F., but it may reach 105° F. The fever lasts a short time-from 4 to 5 days in most instances-but may continue as a low grade fever for several months in uncomplicated primary coccidioidomycosis.

2. Chest pain varies from a mild sense of constriction to a pain severe enough to be mistaken for a myocardial infarction or an acute abdominal condition.

3. Cough, although most frequently present, is not very annoying to the patient. It is more often dry than productive. The slight amount of mucoid or mucopurulent sputum commonly raised frequently grows C. immitis on culture.

4. Arthralgia in the back or the peripheral joints is similar to the aching common in mild influenza and responds readily to salicylates.

5. Headache is usually mild and transitory; sometimes very severe, almost neuralgic in character. It is most often frontal, or when very severe postorbital, like the headache associated with malarial chills.

The symptoms just described occur in more than two-thirds of the patients. Malaise, of varying degree, chills, night sweats, anorexia, and pharyngitis occur in about one-third of the patients. Erythema nodosum (the early trademark of the disease), erythema multiforme, and urticaria-all of good prognostic significance-are seen in less than one-fifth of the patients, erythema nodosum occurring three times as often in women as in men.

The findings on physical examination vary somewhat with the symptoms and range from a reddened throat without exudate to the dullness, rales and rubs of a frank pneumonia, and include the allergic manifestations of erythema, nodosum or multiforme, and urticaria. Conjunctivitis is not infrequent, and pleural effusion can occur.


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FIGURE 14.-Coverslip preparation showing a doubly contoured spherule without protoplasm, one with undifferentiated protoplasm, and a mature spherule with characteristic endospores.

LABORATORY EXAMINATIONS

Although the diagnostic proof of coccidioidomycosis could be said to depend on finding the spherule (fig. 14) in sputum, discharge or pleural fluid, or by growing out the saprophytic phase from such materials and identifying the spherule after animal passage, there are other tests that are most important. These are the coccidioidin skin test, the precipitin test, and the complement fixation test.

Coccidioidin test.-The intracutaneous test with coccidioidin, performed and read like the tuberculin test, is the means of determining whether a person has been infected with C. immitis. Of the greatest value in an epidemiologic survey, the coccidioidin test is also very useful as a diagnostic tool and in some cases indicates a degree of resistance. The reaction is almost always positive in a person who has been infected with the specific agent, although there is a slight cross-reactivity with histoplasmin or haplosporangin extract, and in an overwhelming disseminated case of coccidioidomycosis the reaction may be negative. Otherwise, this is a very dependable test; it can be repeated regularly without creating a positive reaction in a noninfected subject, while a reaction, once positive,


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will remain positive for many years, if not for life. The material for the test can be obtained commercially, but in the early days of its use it was usually obtained from Dr. Charles E. Smith, Department of Public Health and Preventive Medicine, Stanford University School of Medicine, Calif. The material is prepared by growing 10 strains of C. immitis on the same asparagin culture medium used for making tuberculin. Grown for 1 to 2 months, it is tested at intervals, and when shown to be potent the suspension and extract are filtered through a Berkefeld filter and diluted with aqueous Merthiolate (thimerosal) to a concentrate of 1: 10,000. This is standardized on infected and on normal individuals. This dilution is then referred to as undiluted coccidioidin and is very stable, keeping its potency at room temperature for at least 4 years. For testing purposes, it is diluted in normal saline to 1: 100 and to 1: 1,000. The 1: 100 dilution is used for routine testing. The reaction is read at 36 to 48 hours.

Knowledge was at first inadequate concerning the immunologic meaning of the coccidioidin test and, particularly, of its implications for the soldier newly arrived in endemic regions. Subsequently, the important observation was made that the disease might occur, but did not progress to the severe disseminated form, in those who were positive to coccidioidin on their arrival at their posts. Dissemination occurred only in those who arrived uninfected, acquired infection, and then disseminated.7 Furthermore, it was found that dissemination rarely occurred in patients with primary infection accompanied by erythema nodosum which was an early manifestation associated with high sensitivity to coccidioidin. The reaction was frequently weak or negative in cases of severe (anergic) disseminated disease. When negative personnel were retested, the incidence of change to a positive reaction indicated a higher incidence of the completely "inapparent" or asymptomatic than of the clinically recognizable disease.

Aronson and his associates,8 in studies of large population groups in various parts of the United States including Alaska, had provided evidence that "clinched"9 the question of the specificity of the coccidioidin test, in proper dosage. Within their wider field of inquiry, they found a significant incidence, notably in a highly endemic region of Arizona, of calcified pulmonary nodules in persons negative to tuberculin, positive to coccidioidin. Forbus and Bestebreurtje10 found little evidence of calcifi-

7Smith, C. E., Beard, R. R., and Saito, M. T.: Pathogenesis of Coccidioidomycosis With Special Reference to Pulmonary Cavitation. Ann. Int. Med. 29: 623-655, October 1948.
8Aronson, J. D., Saylor, R. M., and Parr, E. I.: Relationship of Coccidioidomycosis to Calcified Pulmonary Nodules. Arch. Path. 34: 31-48, July 1942.
9Smith, C. E., Whiting, E. G., Baker, E. E., Rosenberger, H. G., Beard, R. R., and Saito, M. T.: The Use of Coccidioidin. Am. Rev. Tuberc 57: 330-360, April 1948. (Studies supported from 1937 to 1941 by the Rosenberg Foundation, subsequently an activity of the Commission on Acute Respiratory Diseases, Army Epidemiological Board, Office of The Surgeon General, carried out by the Department of Public Health and Preventive Medicine, Stanford University School of Medicine.)
10Forbus, W. D., and Bestebreurtje, A. M.: Coccidioidomycosis; A Study of 95 Cases of the Disseminated Type With Special Reference to the Pathogenesis of the Disease. Mil. Surgeon 99: 653-719, November 1946.


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cation in their autopsy material which was, however, derived from fatal disseminated cases. Studying the primary disease in persons who, positive to coccidioidin, died of other causes, Butt and Hoffman11 found calcified nodules interpreted as residua of healed or arrested coccidioidomycosis. Cox and Smith12 identified arrested lesions, some of them calcified which had been mistaken for tuberculosis in roentgenograms and at autopsy, and, from one such calcified lesion, Smith13 reported recovery of viable Coccidioides.

Precipitin test-The precipitin test becomes positive within the first month of the disease, and, no matter what the course of the disease is, it becomes negative again in 3 months. Its value lies in establishing the fact that a given symptom picture represents the acute phase of coccidioidomycosis. In the presence of nonspecific symptoms and a positive cutaneous reaction to coccidioidin, a positive precipitin reaction would indicate that the patient has a recently acquired case of coccidioidomycosis. This test is of no prognostic significance.

Complement fixation test-The complement fixation test is of both diagnostic and prognostic significance. Its titer rises with the severity of the infection, also beginning in the first month but continuing, and persisting possibly, for months or many years. In general, complement fixation in titers above 1-6 indicates disseminated disease. Except in a severe disseminated case with anergy, the complement fixation and precipitin tests will give negative results when the cutaneous reaction to coccidioidin is negative.

Erythrocyte sedimentation rate-Elevation of the erythrocyte sedimentation rate in acute primary infection is of prognostic significance and useful in following the course of primary or disseminated coccidioidomycosis.

CLINICAL COURSE

The benign primary form of the disease may occur without symptoms, its only evidence being the change from a negative to a positive reaction to coccidioidin. The course of a clinically apparent but uncomplicated case of primary coccidioidomycosis varies from a mild picture resembling a cold to a moderately severe case of bronchopneumonia with fever, cough, chest pain, headache, generalized aching, and malaise. The duration is related to the severity and may be for 2 or 3 days, or may last for 4 or 5 weeks with low grade fever.

11Butt, E. M., and Hoffman, A. M.: Healed or Arrested Coccidioidomycosis; Correlation of Coccidioidin Skin Tests With Autopsy Findings. Am. J. Path. 21: 485-505, May 1945.
12Cox, A. J., and Smith, C. E.: Arrested Pulmonary Coccidioidal Granuloma. Arch. Path. 27: 717-735, 1939.
13Smith, C. E.: Parallelism of Coccidioidal and Tuberculous Infections. Radiology 38: 643-648, June 1942.


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A number of complications may be associated with the primary phase, and these should not be confused with dissemination. Excavation may occur in a pneumonia area or, more frequently, may appear as a tension cavity with little surrounding infiltration. It does not have the worrisome connotation of a tuberculous cavity but usually heals in from 4 to 8 months with or without bed rest. Excavation, as observed for years, has not resulted in dissemination nor has it been a source of infection in others.14 Hemorrhage may be associated with the cavity, and this is occasionally severe. A bronchopleural fistula may result from the cavity and this in turn may lead to empyema or pyopneumothorax. All of these may occur and the patient be quite ill but still with a primary coccidioidomycosis and with an excellent prognosis. If troublesome, these manifestations may be relieved by surgery.

Not until the disease passes through the hilar lymph glands and leaves the chest, most frequently causing an abscess in the left supraclavicular area, has dissemination occurred. When this happens, the prognosis has suddenly changed, and what was a benign disease with virtually no mortality has now become a malignant disease with a mortality of 50 percent for white patients and up to 85 percent in the dark-skinned races. Dissemination occurs in a little over 1 percent of the clinically diagnosed white patients, in from 3 to 4 percent of clinically diagnosed Spanish-American patients, from 12 to 14 percent of clinically diagnosed Negroes, and in almost all Filipinos clinically diagnosed.

The disseminated disease is protean in its manifestations. Abscesses may form anywhere in the body (fig. 15), including the subcutaneous tissues, muscle, bone, organs, and the central nervous system. The pericardium and the myocardium may be affected, and meningitis is a common cause of death. Bony lesions (fig. 16) are usually multiple and are cystlike, sharply circumscribed lesions with minimal surrounding reaction. They occur most commonly in the prominences of cancellous bones. In the long bones, they are more frequently formed near the ends of, and may extend into, the joints.

The course of disseminated coccidioidomycosis may be steadily and rapidly downhill with meningitis and death occurring in 3 to 4 months from the onset of the primary disease, or it may follow a very slow course with remissions and exacerbations (figs. 17 through 20). There may even be periods of a year or two when the disease is apparently gone, only to return with the opening up of a fistulous tract from some active bony lesion.

14The possibility of spread from person to person cannot be completely dismissed in view of the demonstration, in a few postwar cases, of the mycelial form of Coccidioides in pulmonary cavities (see footnote 7, p. 55. Reported also by (1) Greer, S. J., Forsee, J. H., and Mahon, H. W.: Surgical Management of Pulmonary Coccidioidomycosis in Focalized Lesions. J. Thoracic Surg. 18: 589-601, October 1949; (2) Weisel, W., and Owen, G. C.: Pulmonary Resection for Coccidioidomycosis: Report of a Case. J. Thoracic Surg. 18: 678, October 1949). Nevertheless, Schwarz and Muth (Schwarz, J., and Muth, J.: Coccidioidomycosis: A Review. Am. J.M. Sc. 221: 89-107, January 1951), in their review, could still say "secondary infections in families of patients have never been demonstrated."


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FIGURE 15.-Characteristic skin granulomata on the forehead. This patient also had a smaller skin lesion on the trunk and had roentgenographic evidence of pulmonary infiltration with hilar gland involvement.

The course may be associated with a minimum of temperature elevation or the temperature may be high. Increasing weakness, lassitude, anorexia, and loss of weight are typical. Individual abscesses may heal spontaneously in from 4 to 6 months or faster when irrigated, but new ones come. Bony lesions show healing and new bone formation, but new lesions form. Meningitis is like a tuberculous meningitis with the major

FIGURE 16.-Cystlike areas of destruction in the distal tibia, malleoli, and talus.


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FIGURE 17.-Progressive coccidioidomycosis (coccidioidal granuloma). Massive mediastinal lymphadenopathy simulating lymphoblastoma. General dissemination with fatal termination 4 months after onset.

FIGURE 18.-Progressive coccidioidomycosis (coccidioidal granuloma). Dense shadow projecting from the right mediastinal border consisting of mediastinal lymphadenopathy with suppuration and associated parenchymal infiltration. Terminal miliary dissemination.


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FIGURE 19.-Progressive coccidioidomycosis (coccidioidal granuloma). Diffuse pneumonia-like infiltration radiating from the right hilum. Broad mediastinum due to associated lymphadenopathy.

FIGURE 20.-Progressive coccidioidomycosis (coccidioidal granuloma). Extensive diffuse nodular infiltration through both lungs. Confluent zone of consolidation at the left apex. Mediastinal lymphadenopathy.


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danger from loculation, obstruction, and increased intracranial pressure. It is almost always fatal.

The course of disseminated coccidioidomycosis is best followed by careful observation of the changing clinical picture and by the use of the complement fixation test, the latter being the best index of course and prognosis. A rising titer of complement fixation is definitely indicative of a spreading infection. A rising titer in the presence of a weakening coccidioidin skin reaction is a matter of very grave concern, usually followed by death in a month or two.

In Army experience, the disseminated phase, when it occurred, followed close upon the heels of the primary phase. A study15 of the autopsy and biopsy material from cases in military personnel, including all fatal cases, suggested that the danger of dissemination (endogenous spread) would remain, long after the war, in persons who had been exposed in endemic areas. Clinical observations, however, confirmed by the passage of time, does not indicate that this danger exists in those who did not promptly show themselves, by dissemination, to be "immunologically defective" with respect to this disease.16

OBSERVATION AND EXPERIENCE

As knowledge of the disease gradually increased during some 50 years, roentgenographic studies lagged behind clinical investigation until the war provided opportunity to make serial studies of suitable patients in considerable numbers (figs. 21 through 30). It was generally agreed that the diagnosis could not be made from roentgenograms alone. Carter,17 in 1931, noted that the pulmonary lesions might resemble tuberculosis or might even more closely resemble blastomycosis. Rosenberg and his associates,18 in a study at the Mayo Clinic, Rochester, Minn., in 1942, noted that differential diagnosis between blastomycosis, coccidioidomycosis, and torulosis from roentgenographic appearances was difficult or, in some cases, impossible. Carter,19 in 1942, commented, as follows:

15See footnote 10, p. 55.
16"Army experience * * * has indicated that dissemination occurs soon after the first infection * * * frequently within a matter of weeks and infrequently after months. It rarely occurs in the second year after infection * * *. Once dissemination ensues, the risk of continued dissemination is great though remission may occur. * * * none of our military coccidioidal patients, of whom we had records of thousands, has ever been reported to us as having undergone a postwar dissemination. * * * We have never seen dissemination occur in a patient with coccidioidal excavation. Recently Kurz and Loud have reported one [a postwar case, with recovery, of granulomatous cutaneous lesion developing at the site of a trauma, published in the 23 October 1947 issue of the New England Journal of Medicine], a very unusual case." (Cited from report by Smith and his associates, footnote 7, p. 55.)
17Carter, R. A.: Coccidioidal Granuloma: Roentgen Diagnosis. Am. J. Roentgenol. 25: 715-738, June 1931.
18Rosenberg, E. F., Dockerty, M. D., and Meyerding, H. W.: Coccidioidal Arthritis. Arch. Int. Med. 69: 238-250, February 1942.
19Carter, R. A.: Roentgen Diagnosis of Fungous Infections of Lungs With Special Reference to Coccidioidomycosis. Radiology 38: 639-659, June 1942.


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Fungus diseases of the lungs share with tuberculosis the characteristics to be expected when there is organized cellular response to infection. These include involvement of the lymph nodes; persistent parenchymal lesions of many forms, massive, nodular and miliary; variously appearing diffuse infiltrations, none of them characteristic of any specific disease. The predilections of these differ somewhat from disease to disease.

Carter noted that cases showing in the late stage of dissemination a miliary lesion in the lungs associated with meningitis were especially likely to be mistaken for tuberculosis. Such late pulmonary involvement often occurred as a result of hematogenous spread.

The Army control program, with its coccidioidin tests and repeated roentgenographic examinations, discovered several hundred clinical and several thousand subclinical cases. Observation of cases in hospital showed the short, self-limited course in the majority, while a small percentage persisted for many weeks or months, and a few ended fatally. Colburn20 studied 75 cases in Army personnel roentgenographically, with careful followup observations; the clinical details were reported by Goldstein and Louie.21 The pulmonary changes cleared completely within 3 or 4 months, and all 75 patients were eventually returned to duty, although dissemination did occur in one case.22 At the Regional Hospital, Santa Ana Army Air Base, Calif., to which most of the severe or prolonged cases were transferred, another study was made by Jamison23 of 96 such cases observed closely in roentgenograms for periods of from 2 to 21 months.

Among these, there was a group of 23 cases with nodular parenchymal lesions, situated most frequently in the midpart of the lung, less often in the lower part, least often in the apical and subapical regions. In a second group of 35 cases, there were thin-walled, cystlike cavities, occurring less often in the upper than in the middle field of the lung and least often in the lower. In a third group, there was persistent pneumonitis, ranging from lesions occupying a third of the lung to small foci in the hilum. These were primary infections that had "failed to resolve or focalize as nodular or cystic lesions." In the 12 cases of disseminated disease, there was conspicuous involvement of lymph nodes and, finally, a rapidly developing miliary spread, becoming confluent. The roentgenographic appearances as described were often not dissimilar to tuberculosis but differed widely from tuberculosis in their clinical and epidemiologic significance.

Cavities, as has been noted, may go entirely unnoticed clinically, or may cause some inconvenience, but present no serious threat to life or to public health, persisting sometimes for months, or for years,24 and finally

20Colburn, J. R.: Roentgenological Types of Pulmonary Lesions in Primary Coccidioidomycosis. Am. J. Roentgenol. 51: 1-8, January 1944.
21Goldstein, D. M., and Louie, S.: Primary Pulmonary Coccidioidomycosis; Report of an Epidemic of 75 Cases. War Med. 4: 299-317, September 1943.
22Extended studies have shown a more favorable course in disseminations occurring at a considerable interval after the initial infection.
23Jamison, H. W.: A Roentgen Study of Chronic Pulmonary Coccidioidomycosis. Am. J. Roentgenol. 55: 396-412, April 1946.
24See footnote 7, p. 55.


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FIGURE 21.-Primary coccidioidomycosis. Left hilar thickening. Slight prominence of right mediastinal border due to moderate lymphadenopathy.

FIGURE 22.-Primary coccidioidomycosis. Fuzzy peribronchial right hilar thickening.


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FIGURE 23.-Primary coccidioidomycosis. Pneumonia-like infiltration in the right lower lung field, which practically cleared after an interval of 1 week.

FIGURE 24.-Primary coccidioidomycosis. Patchy and strandlike infiltrations resembling tuberculosis at both apices and subapices. Note the thin-walled cavities just below the clavicles on each side.


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FIGURE 25.-Primary coccidioidomycosis. Small amount of infiltration at the left base associated with slight pleural effusion.

FIGURE 26.-Primary coccidioidomycosis. An unusual case, showing multiple nodular foci simulating metastatic carcinoma or multiple septic emboli. Central cavitation is visible in some of the nodules. The patient has shown progressive improvement both clinically and radiographically without evidence of extra thoracic dissemination.


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FIGURE 27.-Primary coccidioidomycosis. The massive hilar and mediastinal lymphadenopathy is unusual in primary infections. Observe the local zone of consolidation in the right lower lobe and compare with figure 28.

FIGURE 28.-Primary coccidioidomycosis. The mediastinal and hilar lymphadenopathy shown in figure 27 has regressed after a period of 6 weeks; the local zone of infiltration at the right base has been replaced by an isolated ringlike cavity.


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FIGURE 29.-Primary coccidioidomycosis. The mediastinal and hilar lymphadenopathy shown in figure 28 has further regressed after a period of 10 weeks; the cavity previously present has disappeared leaving a residual nodule.

FIGURE 30.-Primary coccidioidomycosis. Ringlike cavity in the right subclavicular region simulating tuberculosis. The wall of the cavity became pencil thin after a 3 months' interval, resembling that of a congenital cyst. The outlines of this cystlike lesion then gradually "melted away" after a 6 months' interval.


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closing without rest or other treatment. Some provoke cough and hemoptysis, some are associated with chest pain or weakness, and in these cases surgery may be done. Experience during and immediately following World War II showed that there was no danger of endogenous spread following surgery and that other complications can now be prevented by the use of chemotherapy.25 The typical coccidioidal cavity, repeatedly observed in Army studies,26 is thin walled, cystlike, not surrounded by infiltration, often fluctuating, sometimes widely. Cavities developing as central excavation of nodular foci are smaller and their walls are thicker.

In studies of the bones and joints, it was again found difficult or impossible to make the diagnosis on the roentgenographic evidence alone (fig. 31).27 From the investigation at the Mayo Clinic are drawn the following comments on the arthritic changes observed in roentgenograms:

Early lesions are characterized by regions of destruction in articular surfaces, often with evidence of swelling of overlying soft tissues. Cartilage may be destroyed and joint spaces narrowed * * *. Later lesions in joints may cause complete disappearance of joint spaces, more extensive zones of destruction in articular spaces and, in some instances, ankylosis. These lesions have been commonly mistaken for those of tuberculous arthritis. Carter pointed out that arthritis both in coccidioidal granuloma and in tuberculosis * * * shows little tendency to heal by production of bone * * *. Taylor found the destructive process in bones, as shown by roentgenograms, to be distinguished by an intensity and rapidity of development not often noted in the presence of tuberculosis.

Such lesions, Rosenberg and his associates stated:

* * * are fairly commonly encountered [in the chronic granulomatous phase of coccidioidomycosis]. Among 256 cases tabulated in the report of the California Department of Public Health in 1931, involvement of joints was noted in 79 * * *. Often, several joints are involved at one time. Affected joints have in this particular phase of the disease first the appearance of acute, later of chronic, arthritis. Early, the joints are swollen and red; later, fluctuation may appear. Nodular lesions may develop in the skin overlying affected joints * * * may ulcerate and discharge pus containing C. immitis. McMaster and Gilfillan expressed the opinion that joints may be primarily affected by direct involvement of the synovial membrane or infection may extend to joints from adjacent foci of coccidioidal osteomyelitis.

Similarly, in 1942, Benninghoven and Miller28 described joint involvement as of- 

Two distinctly different types: (a) purely synovial, (b) synovial with subarticular destruction indistinguishable from tuberculosis. Usually synovial involvement is seen as a large swelling of the joint capsule. Occasionally there is periosteal new bone formation on adjacent bone. This is thought to be a reactive rather than an infective process. In the

25See footnote 21, p. 62.
26(1) Winn, W. A.: Pulmonary Cavitation Associated With Coccidioidal Infection. Arch. Int. Med. 68: 1179-1214, 1941. (2) Winn, W. A., and Johnson, G. H.: Primary Coccidioidomycosis; Roentgenographic Study of 40 Cases. Ann. Int. Med. 17: 407-422, September 1942. (3) Sweigert, C. F., Turner, J. W., and Gillespie, J. B.: Clinical and Roentgenological Aspects of Coccidioidomycosis. Am. J.M. Sc. 212: 652-673, December 1946.
27(1) Benninghoven, C. D., and Miller, E. R.: Coccidioidal Infection in Bone. Radiology 38: 663-668, June 1942. (2) Carter, R. A.: Infectious Granulomas of Bones and Joints, With Special Reference to Coccidioidal Granuloma. Radiology 23: 1-16, July 1934.
28See footnote 27 (1).


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FIGURE 31.-Progressive coccidioidomycosis (coccidioidal granuloma). A and B. Destructive arthritis involving non-weight-bearing portions of joint. C. Proliferative periostitis at anterior surface of patella.


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lesions that are indistinguishable from tuberculosis there is capsular swelling, marked periarticular osteoporosis, with cartilage and subarticular destruction of bone on both sides of the joint.

The investigators at the Mayo Clinic, turning to the benign primary disease, the "valley fever" of earlier writers, refer to its acute onset, with malaise, general aches and pains, "toxic erythema," sore throat, fever, and occasionally signs of bronchopneumonia. From 8 to 15 days after onset, at a time when there appears to be a general improvement of the patient's condition, lesions typical of erythema nodosum may appear, mainly on the shins, occasionally elsewhere. Roentgenographic examination of the thorax at this time usually discloses opaque regions that suggest the diagnosis of tuberculosis. Signs of acute arthritis develop in about one-third of these patients, usually appearing simultaneously with the erythema nodosum.29 Joints are tender to pressure, painful on motion, and sometimes slightly swollen. Effusion and suppuration are not observed. Sometimes arthritis, conjunctivitis, and erythema nodosum appear together, persist about a month, and disappear at approximately the same time. In these cases, with their characteristically uneventful clearing, there is no residual damage or deformity of joints. Among older people, the arthritis was said to be more prolonged.

PATHOLOGY

Thus, knowledge of coccidioidomycosis, during little more than the half century since the problem was recognized, has necessarily been derived chiefly from clinical studies with, increasingly, roentgenographic observation. The anatomic changes seen in the severe disseminated form of the disease in material collected at the Army Institute of Pathology, Washington, D.C. (50 cases with autopsy, 45 with biopsy only), were reported and illustrated in detail at the close of World War II.30 Anatomic changes in the mild uneventful case, or in the asymptomatic cases, could not be so studied except in the rarer event of observations made on persons known to have been positive to coccidioidin, negative to tuberculin (without tuberculous anergy), and coming to autopsy by reason of other causes.31

The pathologic picture of the primary coccidioidal infection as seen in infected animals is that of an interstitial pneumonia, and the response may be leukocytic. Disseminated coccidioidomycosis as seen in man at the autopsy table is as its earlier named indicated-a granulomatous disease, and strikingly similar to tuberculosis-with the spherule to be seen in the tubercle. The spread at first is probably lymphatic to the supraclavic-

29Faber, H. K., Smith, C. E., and Dickson, E. C.: Acute Coccidioidomycosis With Erythema Nodosum in Children. J. Pediat. 15: 153-171, August 1939.
30See footnote 10, p. 55.
31See footnote 11, p. 56.


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FIGURE 32.-Tissue section of coccidioidal granuloma showing a characteristic mature endosporulation spherule within a giant cell.

ular area, but after this first extrapulmonary abscess it spreads to the rest of the body through the bloodstream. No system, organ, or tissue seems immune, and the lesions are seen everywhere. Suppuration is characteristic of the bone involvement which otherwise resembles osteomyelitis. The typical elementary lesion of disseminated coccidioidomycosis is a small tubercle, granulomatous, with proliferation of epithelioid cells (fig. 32) and with giant cells containing spherules scattered in the caseous material. In the lungs, there may be areas of focal suppuration with thickening of the alveolar wall, together with fibroblastic proliferation, edema, and infiltration of plasma cells and neutrophiles in the interstitial tissues.

Diagnosis

The diagnosis of primary coccidioidomycosis is made on the basis of the clinical picture, following opportunity for infection, in conjunction with a changing (negative to positive) coccidioidin skin test and a positive precipitin test. Its corroboration depends on culturing C. immitis from


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the sputum, gastric washings, or pleural fluid and by identifying the doubly refractile walled spherule in mice or guinea pigs inoculated with the culture.

The diagnosis of disseminated coccidioidomycosis depends on the development of its protean clinical picture and the increasing titer of complement fixation, 1-16 usually being taken as the differential point. In the disseminated disease, the fungus may be grown from sinus discharge, biopsies, pleural effusion, or spinal fluid. Roentgenographic evidence of bony or soft-tissue lesions are of definite assistance in making a diagnosis of disseminated disease. Pulmonary infiltrations of coccidioidomycosis cannot be differentiated from other diseases of the lungs by roentgenographic evidence alone.

Treatment

The treatment of primary coccidioidomycosis during World War II was essentially symptomatic, aspirin being the most useful single drug, but the possibility of dissemination was never forgotten and, if symptoms persisted or there was a rising complement fixation titer, conservative handling consisting primarily of bed rest and good diet was considered important. Temperature, leukocyte count, and sedimentation rates were useful guides in determining how much activity should be allowed. In general, with a slight elevation of temperature, an elevated white blood count, an elevated sedimentation rate, and a rising titer of complement fixation, the patient was kept in bed to lessen the possibility of dissemination.

Many methods of therapy have been hopefully instituted in an effort to cure disseminated coccidioidomycosis. Few have been of any specific value, until recently, in the treatment of this phase of the disease.32 Of all, effective results have been obtained with one basic regimen; namely, bed rest and supportive measures-the only real treatment of tuberculosis of a few decades ago. Many are the patients who have seemed moribund, with complement fixation in titers about 1:256, with numerous draining sinuses, with continual elevations of temperature, and with extreme loss of weight, who on bed rest plus a high-protein, high-caloric diet, and supplemental vitamins have improved clinically and serologically and have left the hospital apparently cured.

32The advent of the antibiotic Amphotericin B, related to streptomycin, and its effective use in the care of coccidioidomycosis patients, took place subsequent to submission of this chapter for publication. Amphotericin B is, apparently, the only effective drug thus far. Results are reported as excellent in early infections and encouraging even in chronic cases, although not as dramatic as those obtained in chronic blastomycosis with the drug.-A.L.A.


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COCCIDIOIDOMYCOSIS IN THE ARMY AIR FORCES33

In 1940-41, the Army Air Forces began establishing airfields in the San Joaquin Valley as a first step in its training program. The high percentage of days with good flying weather and the unlimited space for emergency landing fields made this country very desirable for training. This region was part of the Ninth Corps Area (later the Ninth Service Command). Dr. Walter T. Harrison, the U.S. Public Health Service liaison officer in the Office of the Surgeon, Ninth Corps Area, alerted both the surgeon of the corps area and the headquarters staff of the West Coast Training Center to the environmental health hazard-coccidioidomycosis.

Dr. Smith, professor of public health at Stanford University School of Medicine, had just published (June 1940) in the American Journal of Public Health his study of the epidemiology of acute coccidioidomycosis with erythema nodosum in the San Joaquin Valley. This was a broad, 17-month study in Kern and Tulare Counties of 432 patients with the disease called San Joaquin Valley fever (with erythema nodosum), or valley fever, or desert rheumatism, and frequently confused with influenza, pneumonia, tuberculosis, measles, smallpox, poliomyelitis, typhoid fever, and syphilis. Dr. Smith observed that the incubation period was from 1 to 3 weeks, most frequently 2, and that coccidioidin sensitivity was established about 2 weeks after onset of symptoms with a variation of 2 to 17 days. He learned that erythema nodosum was associated with the hypersensitivity of a freshly acquired coccidioidin reaction and that this reaction, like tuberculin sensitivity, was of long duration. His study also indicated that the disease was acquired by inhalation of chlamydospores, that spherules or endospores did not pass the disease from host to host, and that the seasonal incidence of the disease was related to the climate and agricultural activities with a peak in the dusty windy fall and an ebb in the wet winter. The benign "valley fever," as measured by patients with erythema nodosum, was shown to be most common in white females while the coccidioidal granuloma, or disseminated form, was most common in dark-skinned males. Approximately 50 percent of patients acquiring the disease had lived in the Valley less than 1 year and only one-ninth over 10 years. This led to the conclusion that most residents of the region were infected eventually, with 5 percent or less developing erythema nodosum. Therefore, these 432 patients with erythema nodosum represent 8 to 10,000 patients with coccidioidomycosis.

Of the ecology of the micro-organism, little was known. It had been isolated from soil, though with difficulty, and it was known to be a bi-

33For information to supplement the discussion of coccidioidomycosis in the Army Air Forces, Army Ground Forces (pp. 81-85), and prisoners of war (pp. 85-89), as presented in this volume, reference is made to Smith, Charles Edward: Coccidioidomycosis. In Medical Department, United States Army. Preventive Medicine in World War II. Volume IV. Communicable Diseases. Washington: U.S. Government Printing Office, 1958, pp. 285-316.


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phasic fungus. The prevailing theory, based on animal trapping, considered rodents (particularly pocket mice and kangaroo rats) as the reservoir hosts of the disease.

The timely publication of this well-studied series helped to lessen the impact of the unfamiliar disease on the Armed Forces and provided a broad scientific basis for further study.

Because of his knowledge of the disease, Dr. Smith was brought into the problem as it concerned the command active in the area. A meeting was arranged for Dr. Smith to discuss the matter with the headquarters staff of the West Coast Training Center-Brig. Gen. Henry W. Harms, Commanding General; Lt. Col. (later Brig. Gen.) Charles R. Glenn, MC, Senior Flight Surgeon; and Maj. Otis B. Schreuder, MC. After consultation, it was decided that a detailed study, clinical and epidemiologic, should be made.

Early Planning

On 24 February 1941, Col. H. R. Beery, MC, Surgeon, Ninth Corps Area, wrote to Col. (later Brig. Gen.) Charles C. Hillman, MC, Assistant to The Surgeon General, enclosing a copy of Smith's paper on epidemiology. In his letter, Colonel Beery pointed out that the weather, which elsewhere had been bad for flying, was excellent where the San Joaquin Valley flying fields were being built. He further advised:

* * * J. P. Leake, Medical Director, U.S. Public Health, on duty in Office of The Surgeon General of that Service is familiar with the condition existing in the Valley. * * * Colonel [(later Brig. Gen.) Condon C.] McCornack, Surgeon 4th Army, is familiar with the situation and will see that no Army Maneuvers are held in the affected area * * *. The Board appointed by this headquarters for the purpose of locating new camp sites will leave the San Joaquin Valley out of the picture.

The Surgeon General's Office concurred in the thought that the Air Corps was justified in developing flying fields in the Valley and also with Colonel McCornack's decision not to hold Army maneuvers there.

At the same time that this problem was being approached and studied through the normal Army channels, it also became the subject of interest to the Commission on Epidemiological Survey, Board for the Investigation of Epidemic Diseases in the Army, Preventive Medicine Division, Office of The Surgeon General. This body, wisely created under the leadership of Dr. Francis Blake and Dr. Stanhope Bayne-Jones for the purposes that the name implies, established a division in the Ninth Corps Area with Dr. Edwin W. Schultz, as director, and Dr. Edward B. Shaw and Dr. Smith, as members. A program was planned that would minimize coccidioidal infection in the San Joaquin Valley and at the same time carry on research into its epidemiology. This plan of study was worked out by Drs. Smith, Bayne-Jones, and Blake and approved on


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21 June 1941 by the Commission on Epidemiological Survey. Less orthodox channels, more sensitive to time and based on need and friendship, were also established between the Office of The Surgeon General (Col. (later Brig. Gen.) James S. Simmons, MC) and the West Coast Training Center.

Dr. Smith had been working on a grant from the Rosenberg Foundation. This grant was generously continued and supported the work at the airfields for the first 4 months, until more logical support could be obtained from the Army. Whether one wants to call this private injection into the great war machinery of the nation "pump priming" or "fusing," it served a great and helpful purpose and brought about a considerable speeding up of the work at a time when many decisions involving large masses of troops were being made every day.

It was planned through the coccidioidin test to learn who had or had not had the disease before coming to stations in the infected areas and, by repeated testing of "negatives" until they changed to "positives," to determine the proportion of those infected who really became ill with definite symptoms. The investigators expected to learn the variation in infection rate at different times of the year, and what influenced that rate. And it was hoped that they might evaluate the early and conservative treatment of the disease, and any other treatment that might shorten its course or save life in the disseminated disease. The study was in fact to throw important light on the meaning of the coccidioidin reaction and on the nature of resistance in this disease (pp. 54-56).

Institution of Program, West Coast Training Center

As this study got underway, it did so against a background familiar to most people going through Army training; namely, dust (four plus) or mud (four plus). When the program was started in July 1941 at Minter Field, Bakersfield, Calif., the background and the foreground were dust, with tents, informal equipment, and a frontier atmosphere of something great about to happen. The permanent staff of the Minter Field and the Gardner Field at Taft, Calif., was skin tested with coccidioidin, and 20 percent of those not already infected were found to convert from a negative to a positive reaction in the next 6 weeks.

It was soon apparent that the infection rate for coccidioidomycosis was highest at the two airfields nearest Bakersfield; namely, Gardner and Minter. (It is also apparent from the correspondence that more than one person in Washington, D.C., thought "Bakersfield" was yet another flying field.) The airfield at Lemoore, Calif., 50 miles to the north, had a lower rate, and the one at Merced in the northern part of the San Joaquin Valley, less than 150 miles from Gardner, had no coccidioidomycosis that was indubitably incurred at that field.


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The study showed a seasonal variation in infection rate with a high in the latter part of the summer toward the end of the dry season and a low in the wet winter and spring. During the period when much building was in progress, the dust or mud was terrific, and in the dusty month of August 1941 over 5 percent of the susceptible personnel at Minter Field were infected. With the tapering off of construction, the planting of lawns, the paving of roads and airstrips, the change from field to aquatic sports and, of course, possible other factors, the incidence of coccidioidal infections was halved.

At a later period during the war, Dr. Smith noted one other possible factor influencing the infection rate; namely, that the 2 years with the highest incidence were preceded by the wettest winters. This extra rain, he thought, might help the growth of the fungus in nature (wherever that might be). Subsequent work would indicate that he was right.

On 20 October 1941, Dr. Smith wrote to Dr. Bayne-Jones, Department of Bacteriology, Yale University School of Medicine, New Haven, Conn., and director of the Commission on Epidemiological Survey, briefly outlining the progress of the coccidioidomycosis study up to that time. In this letter, as in others, Dr. Smith emphasized the intense interest and enthusiastic cooperation given the study by Colonel Glenn. Colonel Glenn, being a personal friend of Colonel Simmons, also was frequently able to shorten the line of communication without giving offense. Again, as in other letters, Dr. Smith spoke appreciatively of the great contributions made, both administratively and professionally, by Major Schreuder and by the flight surgeons of the two basic training centers (Maj. (later Lt. Col.) John E. Roberts, MC, and Maj. (later Lt. Col.) Robert R. Estill, MC) and their staffs, and praised the warm cooperation of the numerous doctors, aidmen, and others who made this work possible.

Dr. Smith reported that more than 2,000 men had been tested with coccidioidin. Handicapped by their irregular arrivals at camp and the frequent shifts of men from organization, the investigators concentrated on skin testing the recent arrivals. Until the population of the camps could be stabilized, it was thought useless to attempt to retest any who did not have clinical symptoms. Under these difficult conditions, some significant observations were nonetheless made as follows:

The men from the east and midwest are all negative to coccidioidin. Quite a few from central and western Texas, New Mexico, and Arizona and, of course, the San Joaquin Valley of California react to the material. Besides these areas we have had a few reactors from Nevada, Southern Utah, Idaho and Montana, indicating the possibility of these areas as previously unrecognized endemic foci. However, the numbers from these sparsely settled regions are still too small and only when we have the camps fully tested should we have a sufficiently large group from which to draw any deductions. Thus any comments at the present time on the distribution of the positive reactors of the "control" test would seem to me premature.

When we were down in the middle of September there had been a recent sharp increase in the number of cases of coccidioidal infection and during the week we saw ten


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active cases at the Bakersfield Camp. As we hoped, the fact that the men had been tested with the coccidioidin proved a very great practical use in establishing diagnosis, for all that was necessary was to repeat the test and when it was positive, in view of previous negative record a copy of which is on file at the camp, a diagnosis was established.

The work of testing, tabulating, evaluating symptoms and treatment, and pointing up new areas of endemicity continued. This was not easy and was opportunist work as the Army moved personnel in and out. Dr. Smith continued to supply the coccidioidin and to perform the serology in his laboratory at Stanford University. In July 1942, the Commission on Epidemiological Survey took over the financial responsibility for the work being done by him and his coworkers under Contract W709 md-294.

On 2 January 1942, Dr. Schultz forwarded through Dr. Bayne-Jones, to Dr. Blake, President, Board for the Investigation of Epidemic Diseases, U.S. Army, a report prepared by Dr. Smith on the investigation of coccidioidomycosis in the Kern County, Calif., Air Corps Basic Flying Schools, West Coast Training Center, July through November 1941. In this complete report of the work so far accomplished, Dr. Smith brought out the method by which the coccidioidin-testing program was carried out, this being the basis for study of the epidemiology of this disease.

Following visits made solely for the purpose of educating medical officers on coccidioidomycosis, coccidioidin testing had been started on the Bakersfield group (Minter Field) on 13 July and on the Taft group (Gardner Field) on 20 July. The patients sick with the disease were seen in consultation. Lists of all nonreactor's were kept at the station hospitals, and, if a man with a negative skin reaction appeared at sick call with specific symptoms, a retest with coccidioidin usually established the diagnosis (by a positive reaction) or ruled it out (by continued negative reaction). Skin-testing surveys being done for epidemiologic reasons thus became a very important part in the laboratory diagnosis of coccidioidomycosis.

The correlation between the positive skin reactions and residence at the time of entry into the Army indicated that Arizona and California had heavily infected populations, with Texas showing 12 percent of its men positive. In striking contrast were the consistently negative results found in men coming from the Eastern or Mideastern States, bearing out other evidence that the distribution of C. immitis is restricted to arid, dusty regions. The study also, and very importantly, indicated a high degree of specificity of the coccidioidin skin test, and, because relatively few reactors could recall any specific illness suggesting their primary infection, it brought out the relative infrequency with which the infection is recognized. The diagnosis of primary coccidioidomycosis was made in 66 cases, of which 44 required hospitalization with an average stay of 14 days.

Because it was still not feasible to do repeat testing in an organized way, it was thought that many "converters" were missed, having changed over without being sick. October was the peak of the season and with the onset of winter rains the incidence dropped very markedly. Over half of


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those who became ill with the disease had been in camp less than 2 months. Smith suggested that, because of the immunity conferred by a single infection, the personnel in these endemic areas be stabilized, including the medical personnel for the additional purpose that they become increasingly expert in recognizing and handling the disease. He recommended that the disease be treated with respect because of the possibility of dissemination. He reiterated that except for the Air Corps training fields large concentrations of soldiers should avoid the San Joaquin Valley and finally advised that Dr. Harrison (p. 73) should continue to be consulted regarding any plans or problems that might have to do with coccidioidomycosis.

On 6 February 1942, Colonel Simmons, through Lt. (later Lt. Col.) Douglass W. Walker, MC, asked Dr. Smith if he could furnish more up-to-date information concerning the areas of endemicity of coccidioidomycosis and what hazards there might be in having concentrations of troops stationed in such areas, particularly in California, Arizona, New Mexico, and Texas.

On 2 March 1942, Dr. Smith answered that coccidioidomycosis was present in the southern half of the San Joaquin Valley and in Stanislaus, Merced, Madera, San Benito, Fresno, Kings, Tulare, and Kern Counties-being most intense in the last three (the south end of the San Joaquin Valley). He stated further that coccidioidin testing at the San Joaquin Valley airfields had shown occasional cases from the eastern half of Monterey, San Luis Obispo, Santa Barbara, and Ventura Counties, and further south and east in the northern part of Los Angeles County and in San Bernardino, Riverside, Imperial, and San Diego Counties. With reference to all the endemic areas he recommended that except for aviation training, which made the need very great, the following areas should be avoided for large encampments: (1) The San Joaquin Valley of California, (2) the southern half of Arizona, (3) the southern tip of Nevada, (4) the vicinity of St. George, Utah, (5) the southern half of New Mexico, and (6) Texas, the region from San Angelo, west and south. He ended his letter by saying: "We are still in quest of why the fungus is found where it is, what restricts its distribution and where it actually grows in nature."

The Syllabus

During the summer of 1942, a syllabus on coccidioidomycosis was prepared. It was published and distributed by Headquarters, West Coast Army Air Forces Training Center, in October of that year. It was revised in September 1943, and in March 1944 the publication of a third edition was made possible by the Josiah Macy, Jr. Foundation. Originally prepared by the surgeon of the command (Colonel Glenn and later Col. Michael G. Healey, MC), it was enlarged in scope and detail by Maj. (later Lt. Col.) Norman Nixon, MC. It was well illustrated by plates showing cultural


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characteristics of the fungus and by roentgenograms credited to Dr. R. A. Carter at the Los Angeles County Hospital, Los Angeles, Calif., and to Maj. Horace W. Jamison, MC. A map showed endemic areas. A graph indicated seasonal incidence. There was an extensive bibliography.

In substance, the syllabus was an excellent handbook on the disease, covering symptoms, diagnostic procedures, course, and criteria for discharge from hospital. It also pointed out the military significance of coccidioidomycosis; namely, that the total number of deaths would be low, the morbidity would be high, and the period of hospitalization, rather prolonged. All enlisted personnel and officers were to be tested with coccidioidin on their arrival at a station and twice yearly thereafter, and the reactions recorded on the individual's service record and his immunization register MD Form 81. The responsibility for reporting and control was placed on the medical officer specifically assigned to the coccidioidomycosis problem at each of the fields, and he in turn was to be responsible to the coccidioidomycosis control officer of the West Coast Army Air Forces Training Center, at the Santa Ana Air Base. By the time of issue of the second edition, the term "Coccidioidomycosis Control Officer" was as generally accepted in the endemic areas as "V. D. Control Officer."

The authors described the two clinical forms as (1) primary coccidioidomycosis, the acute, benign, self-limited respiratory infection and (2) progressive coccidioidomycosis, the chronic, disseminated, usually fatal illness, manifested by cutaneous, subcutaneous, visceral, and osseous lesions, occurring in certain individuals as one continuous progressive disease, although the serious form may not be recognized as such until several weeks or months have elapsed. Continued spread of infiltration suggests the progressive form, and the discovery of extrapulmonary foci confirms it. Death usually occurs in such cases after a course of many weeks' to 6 months' duration. Rarely, a patient will focalize his disseminating disease, usually after prolonged rest in bed, and make a complete recovery. The great majority of primary infiltrations, however, do not go on to dissemination but will disappear completely in 5 or 6 weeks. In some of these cases, residual cavities will persist, but the benign nature of these is indicated by their clinical course and low sedimentation rate.

They noted, on the other hand, the high susceptibility of dark-skinned persons to disseminating disease, advising against the use of Negro troops. They noted how infection is acquired by inhalation of dust containing the tiny live chlamydospores coming from the soil in endemic areas, and that some 90 percent of persons who have been resident in heavily endemic regions will react to coccidioidin. They summarized the important points, from the point of view of the military surgeon, to be (1) the recognition of the disease, (2) the prompt hospitalization of all clinical cases until the sedimentation rate becomes normal, and (3) the ability to distinguish this condition from tuberculosis, which it so closely resembles.


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There are many aids to differentiation from tuberculosis once the essential differences have been clearly established. First is the difference in epidemiology as this disease spreads from environment to man rather than from man to man. There is the striking immunologic difference in that the initial infection with the fungus confers permanent resistance against subsequent infection. Although people living in endemic areas (the San Joaquin Valley and southern Arizona) are repeatedly exposed to contaminated dust throughout their lives, the incidence of serious disease is low, probably not more than 1 case of the progressive form to 500 of the benign primary form.

By March 1943, there had been 253 clinical cases of coccidioidomycosis at the Minter, Gardner, and Lemoore Fields. There had been none at Merced. There were 125 cases in personnel of the Air Forces at Minter between July 1941 and March 1943, 61 at Gardner, and 67 at Lemoore. There were three cases of disseminated coccidioidomycosis with two deaths. The big months for coccidioidomycosis were from June through November with the emphasis in September and October. The infection rate at the three fields was approximately 20 percent per year, Minter and Gardner having the highest. It was observed that recruits from Merced County rarely showed evidence of having had coccidioidal infection; no clinical infections occurred at Merced Army Air Field and only seven changeovers.

Dr. Smith gave great credit to the persistence and cooperation of the following medical officers in carrying out the coccidioidomycosis-control program-Lt. Col. John E. Roberts, Lt. Col. A. L. Jennings, and Maj. Edward C. Donohoe, all successively at Minter Field; Lt. Col. Robert R. Estill, Lt. Col. Albert Phillips, successively at Gardner Field; Lt. Col. Edward Padden, at Lemoore; Lt. Col. M. U. Prescott and Lt. Col. Neil Johnson, at Merced. The designated coccidioidomycosis-control officers who took a leading part in the program were Maj. Russell W. Mapes, at Minter; Lt. David L. Thurman, at Gardner; Maj. J. Murray Kinsman, at Lemoore; and Capt. Harvey A. Woods, at Merced. All these medical officers, themselves subject to rapid turnover, were quick to grasp the problems before them and persistent in carrying out the work.

Again on 1 June 1943, Maj. Forrest M. Willet, MC, chief of the medical service at the Station Hospital, March Field, near Riverside, Calif., replying, through the Air Surgeon, to an inquiry from the Office of The Surgeon General, told of a recent increase in cases in connection with construction of an airfield at Banning, Calif., where Company B of the 856th Engineer Battalion (Aviation) had joined Company C on 24 April. These were Negro troops. Three weeks later, several patients with clinical coccidioidomycosis were admitted to the station hospital. The medical staff thereupon tested all members of the 856th Engineer Battalion with coccidioidin, finding a large number of positive reactors, all of whom had been in endemic areas before coming to March Field.


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A number of soldiers from Company B who had failed to react to coccidioidin entered the hospital later with the clinical disease. Company A of that battalion did not go to Banning and coccidioidomycosis developed in only one of its personnel, a man who had gone to Banning on a visit. A new outfit, 198 soldiers, moved in to replace the 856th Engineers. They were given the cutaneous test and there were three positive reactors, all of whom had previously been in endemic areas. It was planned to repeat such skin tests twice for the purpose of definitely proving Banning an endemic area.

With so much interest, widened by the experience of the Army, in a disease local by nature, many papers appeared in medical journals. These various publications34 helped alert the physicians of the country to the disease-its epidemiology, diagnosis, clinical course, and hazards.

COCCIDIOIDOMYCOSIS IN THE ARMY GROUND FORCES

Early Cases

On 1 December 1941, a report was forwarded to the Office of The Surgeon General through channels from Camp Roberts, Calif. It was written by Lt. Robert M. Shelton, MC, and later formed the basis of an excellent paper.35 The first case had been discovered in April 1941 among the troops there, whose training was in large part carried on in the area east of U.S. Highway 101, which included some of the rather dry country of the Coast Range. A number of other cases were seen in the Station Hospital, and a skin-testing survey was begun in June 1941. In all, 888 men were tested; 3 months later 736 of the negative reactors were retested, and of these 14 were found to react to coccidioidin. Allowing for those who might have been exposed elsewhere, the result pointed to an annual incidence of approximately 6 or 8 percent, indicating that 1,000 men would become infected annually at Camp Roberts. This report prompted a continuation of the survey.

During 1942 and the first half of 1943, coccidioidomycosis appeared sporadically in ground force units bordering the endemic areas and most

34Many of these reports and studies have been cited in this chapter. Among others appearing in 1943-44 were (1) Smith. C. E.: Coccidioidomycosis. M. Clin. North America 27: 790-807, May 1943; (2) Colburn, J. R.: Roentgenological Types of Pulmonary Lesions in Primary Coccidioidomycosis. Am. J. Roentgenol. 51: 1-8, January 1944; (3) Goldstein, D. M., and McDonald, J. B.: Primary Pulmonary Coccidioidomycosis; Follow-Up of 75 Cases, With 10 More Cases From New Endemic Areas. J.A.M.A. 124: 557-561, 26 Feb. 1944; (4) Lee, R. V.: Coccidioidomycosis in Western Flying Training Command. California & West. Med. 61: 133-134, September 1944; (5) Quill, L. M., and Burch, J. C.: Surgical Manifestations of Coccidioidomycosis. Ann. Surg. 120: 670-679, October 1944; and (6) Denenholz, E. J., and Cheney, G.: Diagnosis and Treatment of Chronic Coccidioidomycosis. Arch. Int. Med. 74: 311-330, November 1944.
In July 1943, Colonel Bayne-Jones prepared an excellent chapter on "Coccidioidomycosis" for General Simmons' revision of "Laboratory Methods of the United States Army." This chapter included exposition of the initial or primary infection, the progressive or disseminated infection, the distribution, and the mode of spread, with fairly detailed laboratory instructions covering techniques from the growth of the fungus to the preparation of coccidioidin and the performance of the precipitin and complement fixation tests.
35Shelton, R. M.: Survey of Coccidioidomycosis at Camp Roberts, California. J.A.M.A. 118: 1186-1190, 4 Apr. 1942.


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probably associated with travel through them by individuals or small groups.

Desert Training

In the latter part of 1942 and early 1943, a desert training center was created for the purpose of preparing troops for the terrain and the extremes of heat and dryness which they might encounter if fighting continued in North Africa. This area was a large one in the lower Mojave Desert west of Blythe and northeast of the Salton Sea. It included the Pallen Mountains, the Granite Mountains, and the Iron Mountains, and all the dry springs and dry lake beds in an area 3 or 4 thousand square miles in extent. With such an assignment and such country, the trainees were really put through their paces. As more and more troops came in, ultimately reaching 80,000 and including at least one Negro division, it was obvious to those interested in coccidioidomycosis that parts of this region were highly endemic for the disease, particularly certain camps near Yuma and the area near Pallen Pass west of Blythe. The distribution would indeed seem to be very spotty but intense where it existed, thus offering opportunities to avoid small heavily infested areas.

On 26 March 1943, the following communication went from the Office of The Surgeon General to the Surgeon, Army Ground Forces:

1. This office has recently been informed that a number of cases of acute coccidioidomycosis (Valley Fever) have recently occurred in troops maneuvering in the Desert Training area in Southern California. This area is somewhat beyond the highly endemic San Joaquin Valley, and while cases have been reported in this region, it has not hitherto been considered that coccidioidomycosis constitutes a serious threat to persons living within this area.

2. In view of the above, it is requested that full information as to the extent of any recent outbreak of coccidioidomycosis among troops in this area be obtained. It is believed that Major Roswell K. Brown, M.C., Desert Warfare Board, Camp Young, California, is acquainted with this situation.

The first action in this was apparently taken in December of that year, according to a memorandum for file on a conference with the Ground Surgeon, Col. William E. Shambora, MC, on 23 December 1943, to determine the policy of his office with respect to coccidioidomycosis control in Ground Forces organizations. For the conferees, including Maj. (later Lt. Col.) Aims C. McGuinness, MC, Colonel Shambora obtained the following information from Col. Frank S. Matlack, Surgeon, Headquarters, Communications Zone, California-Arizona Maneuver Area, Banning, Calif.:

a. All pertinent information furnished the Ground Surgeon by the S.G.O. has been forwarded to units maneuvering in the endemic legions.

b. A meeting of all battalion and regimental surgeons, and hospital medical officers of troops on maneuvers in this region was held. Full details on the endemicity and recognition of coccidioidomycosis were present at this meeting. The services of Dr. Charles E. Smith have been utilized.


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c. Information about the disease has also been furnished to line officers.

d. A large number of cases of coccidioidomycosis have recently occurred in troops in the vicinity of Yuma, Arizona. Efforts are being made to locate this source of infection more accurately.

e. Commanding officers responsible for the selection of maneuvers sites will be advised concerning the avoidance of endemic regions. There is no doubt that such advice will be followed so far as it is consistent with military necessity.

It was agreed that an exchange of all pertinent information on this subject reaching either the Surgeon General's Office or the Ground Surgeon's office should be kept up.

Coccidioidomycosis-control programs were instituted in the Communications Zone of the California-Arizona Maneuver Area in the summer of 1943, but efforts to institute it in the real desert training center were refused, and, except for the information given physicians in this area, no real cooperation was established.

Coccidioidomycosis was picked up from New Jersey to the western Pacific in troops who had been in this area. One of the most significant reports came from Fort Bragg, N.C., in the following letter from Dr. Theodore J. Abernathy to Dr. Smith, in early 1944:

Recently, a case of coccidioidomycosis was discovered on the wards of the Station Hospital at Fort Bragg. This patient was suffering from the primary form of the disease, characterized by a circumscribed pneumonic lesion in which cavitation was demonstrated roentgenographically. A skin test with Coccidioidin, 1-100 dilution, done at the height of the disease, was positive. * * * [Other tests not completed.]

Checking back on this patient's army experience it was learned that he was one of a group of Field Artillery trainees, recruited largely from Michigan, Ohio and Illinois, who had spent three months (22 August to 24 November) at Camp Iron Mountain, California, participating in desert maneuvers. Further investigation of 35 additional patients from this same group, now stationed at Fort Bragg and admitted within the past week because of various medical and surgical complaints, has disclosed five positive reactors to Coccidioidin (14.2 percent). One patient who gave the strongest positive reaction was admitted with a presumptive diagnosis of rheumatic fever, and the test was exceedingly valuable in pointing toward the true nature of the disease.

Available information which we have at our disposal is that Camp Iron Mountain is located in the extreme south-easterly portion of California close to the Arizona border. According to the syllabus on coccidioidomycosis (AAFWFTC), this area is in close proximity to an endemic focus of the disease in Arizona. Do you have any reports indicating that cases of coccidioidomycosis may have originated in Camp Iron Mountain or in the desert maneuver area? Have you any information regarding a control program in this camp and the results of same, if attempted?

We are considering enlarging the present study to include the skin testing of a large number of men who were at Camp Iron Mountain * * *.

Cases were picked up also at Camp Dix, N.J., in Hawaii, and in the western Pacific in members of the 77th Infantry Division who had gone through the desert maneuvers. Further testing reported in a later letter from Dr. Abernathy showed that over 15 percent of 555 men from one field artillery battalion coming from the desert maneuver area reacted positively to coccidioidin. By 16 March, Dr. Abernathy reported to Colonel


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(later Brigadier General) Bayne-Jones on cavalry units that had been stationed in the California-Arizona Maneuver Area at Camp Hyder (halfway between Yuma and Phoenix), Camp Laguna (27 miles north of Yuma), and Camp Pilot Knob. Positive skin reactors in these groups were as follows: 28.6 percent of 70 men in the 11th Group; 23.8 percent of 736 men in the 36th Squadron; and 20.6 percent of 786 men of the 44th Squadron. Plans to examine by roentgenogram the 337 positive reactors dissolved when the three organizations were sent to four different places.

A letter from Maj. (later Lt. Col.) George A. Young, Jr., MC, Consultant, Headquarters, Communications Zone, California-Arizona Maneuver Area, to Dr. Smith is quoted at length as indicating the efforts so many of us made for months and years to open the ears of the fire-eating trainers to our message.

Your letter of 12 Jan. 44 to Lt. Col. Manjos has been forwarded to this headquarters for reply. Following my letter to you of 29 July 43, we initiated a program for the study of coccidioidomycosis in the Desert Training Center * * *. Unfortunately this headquarters has jurisdiction only over Communications Zone installations and when we attempted to extend the program to the entire desert we were informed by the Desert Training Center that: "1. Not favorably considered. 2. There is not sufficient data to indicate an urgent need of this work and with the present shortage of Medical Officers in DTC it is not considered that this diversion of personnel is practical. 3. If research and investigation of special problems in DTC are indicated, it should be done under the direction of the Surgeon General by especially trained and assigned personnel." The foregoing required us to continue our project in an unofficial status and limit our activities to the Communications Zone. Within the past month we succeeded in convincing the DTC as to the importance of the problem of coccidioidomycosis and it will now be possible to more thoroughly approach the problem. What factual information we have accumulated from the present study was forwarded to the Army Ground Forces, 3 Jan 44 * * *. To this can be added the following statements which are considered to be sound, but which are, as yet, unsupported by sufficient factual data:

a. The maneuver area proper, indicated on map * * *, is highly endemic. Supporting this statement is the fact that a division of Negro troops was stationed at Camp Clipper for three (3) months without experiencing significant coccidioidal infection; then, beginning three weeks after they participated in exercises in the maneuver area proper thirty (30) cases of coccidioidomycosis were admitted to one of our hospitals. These soldiers were acutely ill and were admitted with transfer diagnoses such as atypical pneumonia, lobar pneumonia, bronchitis, etc. Obviously many hundreds of milder cases are going unrecognized. It would appear most reasonable that the cases described by Dr. Abernathy represent troops recently in the formal maneuver area, and that the maneuver area and not their camp site was the endemic legion. It is my personal belief that a great many soldiers are leaving this area with unrecognized smouldering infections which become manifest at a new station. Not every medical installation will be as alert as the Ft. Bragg group and recognize the disease.

b. The entire area between Yuma and Hyder, Arizona is heavily endemic. Over two hundred cases of the disease occurred in troops stationed at Camp Hyder. These cases were diagnosed by the 32nd Evacuation Hospital; but because they were a combat zone unit, we received no data and could not include them in any official report. * * * [however there is] a more satisfactory liaison now established between the two zones * * *. Incidentally eight (8) nurses of the 32d Evacuation Hospital developed coccidioidomycosis. The hospital was located between Horn and Hyder, Arizona.


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c. Pomona, Camp Young, Thermal and San Bernardino are areas of very low or no endemicity. This statement is based on the absence of changeover's after serial skin tests (3, 6, 9, and 12 weeks) and is supported by the absence of any proven cases from the areas noted.

d. Supporting the belief that Desert Center, Granite, Coxcomb, and Camp Young are innocuous areas is the experience of the Station Hospital SCU 1925 which hospitalized soldiers from the areas mentioned during the period 15 July 42 to 15 Feb 43. After receipt of some coccidioidin we requested from you, Capt. Elmer Brock, our radiologist, skin tested in all cases showing pulmonary pathology-no positive reactions were demonstrated.

At the present time our general hospitals are functioning under a 45 day evacuation policy, this has necessitated the evacuation of coccidioidomycosis patients to hospitals outside of our supervision. In an attempt to centralize these patients, we have established a policy wherein all such cases are evacuated to the Camp Haan [Calif.] Station Hospital. Reports from your laboratory are then forwarded to Camp Haan. Dr. Rutherford and Mr. Copper from USC visited us frequently in Banning collecting rodents and plants from the area of Banning airstrip. A recent conversation with Dr. Kessel indicates as yet they have grown no coccidioides. It is Dr. Rutherford's plan to carry out his rodent survey in all proven endemic areas.

The preceding paragraphs contain the pertinent data and impressions we have obtained. I feel certain that much of this is unknown to the Surgeon General's Office; however any official communication by us is precluded [by the disapproval by the Desert Training Center] * * *.

* * * This office will continue to supervise the program which, however, it is felt will now continue under its own momentum. We have purposely made each hospital and laboratory feel this was their program and that all data at this office are available to them. I believe that many will publish articles on the subject. We have requested an informal summary from each general hospital and the mobile laboratory, a copy of which will be furnished you.

It is my belief that the medico-military aspects of coccidioidomycosis in this area are now obvious and appropriate steps should soon follow. It would appear wise to consider the transition of this study into State Health channels as it is possible that the present laboratory facilities will not always exist * * *.

May I express the deep appreciation we all feel for the generous manner in which you have aided us. We regret exceedingly that the suggestions included in your letter of July could not be carried out for the entire desert. I feel that we have finally hacked out some data instead of obtaining the clean cut results that might have been accomplished.

A plan was projected for continuation of the work if necessary by the use of mobile laboratories, but none were to be assigned to the Communications Zone, as the whole desert training program was being given up and the area was to be completely evacuated by 1 May 1944.

COCCIDIOIDOMYCOSIS IN PRISONERS OF WAR

In a report dated 4 February 1944, Col. Verne R. Mason, MC, medical consultant to the Ninth Service Command, brought to The Surgeon General's attention the fact that there was a large number of patients with coccidioidomycosis among the prisoners of war at Florence, Ariz. He noted, in part, as follows:

There are 89 patients with tuberculosis in the hospital. Of these, 2 are Japanese, a number are German, and the remainder are Italian. In addition to these patients, there


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are a large number with primary pulmonary coccidioidomycosis. A number of patients have both active tuberculosis and coccidioidomycosis. Some have developed coccidioidomycosis of pulmonary type while in the hospital under treatment for active tuberculosis. A recent survey of 557 enlisted men of this SCU [Service Command Unit] was made. Of this number 54 percent had a positive coccidioidin test. The percent with positive tests varies directly with the length of time at this camp. The effects of co-incidental or contemporary coccidioidomycosis on the course of active tuberculosis may be studied well at this station. At present one Italian prisoner has the rapidly fatal acute disseminating type of coccidioidomycosis with miliary pulmonary lesions and pustular dermal lesions.

By 23 February, Dr. Smith was in Florence, at the request of the Preventive Medicine Service of the Surgeon General's Office, and, on 3 March 1944, made a report to The Surgeon General through Colonel Bayne-Jones. After careful study of the patients in the Station Hospital at Florence and a review of the many relevant factors, he made the following comments and recommendations:

Probably two-thirds to three-quarters of new arrivals from non-endemic areas can be expected to become infected during a year. Had this fact been realized prior to the location of the Camp, another choice might have been made. However, * * * my personal recommendation would be to continue the Camp but to develop a Control Program based upon repeated coccidioidin testing, detection of clinical coccidioidomycosis and prompt treatment. This is the plan which was developed as part of the work of the Commission on Epidemiological Survey in the San Joaquin Valley and which was expanded and applied by the entire Western Flying Training Command. The plan has been discussed with Lieutenant Colonel Bernadine and his medical personnel and they will welcome it * * *. The Station Hospital laboratory is already prepared to carry on its part, with sedimentation tests * * * culturing * * * and proper collection of blood specimens * * * in case of diagnostic doubt. Arrangements have been made to send us positive cultures for animal confirmation as well as blood for the serological testing. It is most important that sufficient medical personnel be available so the Camp Surgeon can designate one man to be in charge of the Program. It should not take more than one-third of his time * * *. The Camp Hospital is developing into an important tuberculosis sanitarium with enthusiastic chest specialists experienced in survey work * * *.

[It seems not improbable, and because of the climate not illogical] that the Florence Station Hospital is destined to be made the tuberculosis sanitarium for Prisoners-of-war. However, coccidioidomycosis poses two complicating considerations. First, can people acquire coccidioidomycosis when merely staying indoors in the hospital ward? Second, if they should acquire a coccidioidal infection, would it adversely affect their "cure" for tuberculosis?

The decision made shortly thereafter in the Office of The Surgeon General was announced in a memorandum from the Medicine Division to the Hospital Division, on 24 March 1944, as follows:

A conference was called by Brigadier Generals Bayne-Jones and Morgan for the purpose of considering the removal of the tuberculosis center for prisoners-of-war from the Station Hospital at Florence, Arizona, to another location. Evidence has been acquired recently which indicates that the incidence of coccidioidal infection at Florence, Arizona, is high. It has been shown that patients in the Station Hospital there have acquired the infection in residence. It was agreed that prisoner-of-war patients with tuberculosis should be protected from this additional health hazard. Therefore, the conference unanimously recommends that the tuberculosis center for prisoners-of-war be moved from the Florence, Arizona, Station Hospital and located elsewhere.


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In May 1945, the incidence of coccidioidomycosis at Camp Cooke, Prisoner of War Center (San Luis Obispo County, Calif.), began to rise, 162 cases occurring. In the subsequent 3 months, investigation by Dr. Smith for the Surgeon General's Office, and by others, determined that these cases were incurred by prisoners working near Shafter in the San Joaquin Valley in one of the subsidiary prisoner-of-war camps. These prisoners and those at Lamont were digging potatoes and working cotton and other crops. Similar conditions obtained at some of the subsidiary camps around Florence. Dr. Smith, consulted from the field, explained the difficulty and the amount of personnel necessary to set up a coccidioidomycosis-control program among these scattered installations. When it was pointed out to the commanding officers of the prisoner-of-war camps that the rate at Camp Cooke alone was higher than for all the rest of the Army, the prisoners of war were withdrawn from work in the Shafter and Lamont areas.

The war was now drawing to a close and with it the immediate concern of the Army with this disease of arid regions. The time was approaching when we could all "go back to hoeing our own potatoes" and allow the search for a living to bring fresh divisions of civilians into the endemic areas-but of their own volition.

On 31 August 1944, Capt. Louis Schneider, MC, radiologist at the Separation Center, Fort Dix, N.J., wrote Dr. Smith a letter which is a good preamble to the conclusion of the story of coccidioidomycosis in World War II. The letter follows.

As you know, routine chest films will be taken on all service men and women who will be demobilized through these centers. In the course of these examinations, we have come across and will continue to come across soldiers who months ago recovered from a case of Primary Coccidioidomycosis and now have residual pulmonary lesions which are undoubtedly not active, and though they have not regressed by comparison of serial roentgenograms, the pulmonary shadows have neither broken down or extended. From my present knowledge it would appear safe to discharge these individuals, appreciating that they may therefore go out into any civil employment with little fear of reactivation. Of course it would be wise, it seems to me, to follow these cases with serial chest radiographs at Veterans Hospitals' out-patient departments much as we do with arrested cases of pulmonary tuberculosis. In this connection, your advice and comment in regard to the handling and after-handling of such separatees will be appreciated.

This letter, as concerned with a matter of policy regarding the separation of Army personnel with roentgenographic evidence of residual coccidioidal lesions, was referred by Dr. Smith to Generals Morgan and Bayne-Jones of the Office of The Surgeon General, and to Dr. Blake as President of the Board for the investigation of Epidemic Diseases, U.S. Army. In his reply of 6 September 1944 to Captain Schneider, Dr. Smith gave his personal opinion, as follows:

First, may I express great pleasure and congratulate you upon your discernment in your evaluation of the pathogenesis of coccidioidal infection. Unfortunately, even in the newly revised edition of Cecil's text the opinion is expressed that many soldiers who acquired coccidioidomycosis in the Service will break down with a disseminated infection


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in civilian life. Such an expression is ill founded and very damaging. As you indicated, even with coccidioidal nummular lesions remaining, men can be discharged without fear of disseminating coccidioidal infection. There does remain the very slight possibility of a cavity developing. This complication is so rare, generally developing within a few months after the infection, while the nummular lesions may continue so long (many years), that it would be impractical to continue the man in the Service until the roentgenogram is clear. The one safeguard I would recommend is that suggested by you, serial chest roentgenograms at Veterans Hospitals, say every six months. There should be no question of compensation or pension, as these lesions are not incapacitating. Particular pains should be taken to reassure these men not only for their peace of mind but also to keep them out of the hands of shyster lawyers or even misinformed medical men who * * * may try to make invalids out of these utterly healthy veterans. If any specific problems arise, please feel free to write me. I do feel quite certain that the Fort Dix separatees will be handled wisely.

General Bayne-Jones referred Dr. Smith's letter with its enclosures to Col. Esmond R. Long, MC, Deputy Chief, Professional Service, Office of The Surgeon General. Colonel Long, visiting the Fort Dix separation center, primarily to look over the chest X-ray work, spent some time with Captain Schneider, who again raised the same question. Colonel Long concurred in the general opinion that no public health problem was involved and was inclined to think also that the medical problem would not be serious. "The Army is not going to discharge men with active coccidioidomycosis, and men with scarred lesions are not likely to break down," He observed that the Army could not insure followup examinations although each separatee, being informed of his right to medical care under the Veterans' Administration, might be advised to have periodic checkups for appropriate conditions, of which coccidioidomycosis was only one in several.

On that sensible note, the experience of the Army with coccidioidomycosis was brought to a close. There remains only to summarize statistics before bringing to its close this historical sketch. During the years 1942-45, the admission rate per 1,000 troops per year (based on the total number of cases reported in the Army in the continental United States and the strength of the Ninth Service Command) ranged from 0.2 to 2.8 per month, being greater than 1 in 22 months and greater than 2 in 6 months of the span of 37 months. The Marines, in the small detachments scattered through the endemic areas, and specifically those reported by Lt. Cdr. E. F. Pfanner, MC, USNR, at Mojave, Calif., and by the U.S. Navy, in some of its inland installations, such as Inyokern, Calif., encountered the disease but in number's insufficient to warrant very active countermeasures.

We have thus again one of the few unequivocally good things that sometimes come out of modern war, more knowledge of a disease process. In this instance, a gradual accumulation of knowledge, accelerated by work done shortly before the war, was further accelerated as a medical problem of local interest affecting the Army. It has been suggested36 that general interest may continue as the modern habit of travel brings into endemic

36Jamison, H. W., and Carter, R. A.: Roentgen Findings in Early Coccidioidomycosis. Radiology 48: 323-332, April 1947.


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regions increasing numbers of people who, like the young soldiers negative to coccidioidin, are highly susceptible. However that may be, better understanding has been achieved of one of the diseases that attack the lungs, with the immediate gain of increased clinical competence and with wider implications for comparative research.

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