HISTOPLASMOSIS: TWENTY YEARS EXPERIENCE IN A GENERAL HOSPITAL RALPH TOMPSETT, M.D. AND (by invitation) LOUIS A. PORTERA, M.D. DALLAS
Histoplasma capsulatum is a fungus with worldwide distribution in the temperate zones. Infection with this organism occurs by way of inhalation of airborne spores sufficiently small to be deposited in the pulmonary alveoli. The fungus is found in the soil in endemic areas, and as is well known, its association with the excreta of fowl has been found to be a particularly favorable circumstance for propagation and aerosolization of spores.1 In the main, contact with the fungus results in asymptomatic infection ultimately manifested only by delayed skin reactivity.2 In a small proportion of patients, a variety of clinical syndromes develop and have been well described in several papers in the past decade.1 3 4. 5, 6 Our interest has been stimulated by personal experience with a number of diagnostic and therapeutic problems arising in this disease as seen in a general hospital on the periphery of the highly endemic area of the United States. These experiences, coupled with the fact that knowledge of the varied presentation of the most serious form of the disease, namely progressive disseminated histoplasmosis, is still limited, has prompted us to review our general experience with histoplasmosis. Accordingly we have reviewed the records of Baylor University Medical Center in Dallas for the past 20 years for all patients with the diagnosis of histoplasmosis. No pediatric patients are included. The overall experience will be reviewed briefly and details will be given on the patients with progressive disseminated disease. DIAGNOSTIC METHODS Three laboratory diagnostic methods are available in histoplasmosis. The organism grows well on artificial media as a dimorphic fungus, the mycelial form growing best at temperatures below 37 degrees C. Both a complement fixation test and a latex agglutination test (the so-called "acute histo test") are available.', 8. 9 Extremely valuable also are staining techniques of tissues, especially the methenamine silver stain. The typical lesion is a granuloma, and at times the organism can be identified in an ordinary hematoxylin and eosin stain. The advantages of the silver stain are readily apparent in scanning microscopic sections under low power, and at higher power reasonably certain identification of the yeasts may be made. The skin test is of limited value diagnostically but is an important epidemiologic tool.2 Figure 1 illustrates the unique distribu214
HISTOPLASMOSIS
215
tion of the disease in the United States as indicated by skin testing. It will be noted that the Dallas area is just outside of one of the most highly endemic areas. 1o COMPOSITION OF THE SERIES A total of 57 patients were found, of whom 38 were classified as primary pulmonary, 6 as a mixed group and 13 as progressive disseminated disease. This represents one case of disseminated disease in approximately 45,000 hospital admissions. Group I consisted essentially of asymptomatic patients with negative serologic tests, who had pulmonary lesions discovered on chest x-rays. These lesions were biopsied or removed for various reasons, usually because of the inability to exclude carcinoma. Some Group I patients presented as acute benign primary histoplasma pneumonia. Eight had chronic pulmonary histoplasmosis with positive complement fixation tests. Group II consisted of two patients who had positive liver biopsies discovered accidentially during exploratory laparotomy, one patient with fibrosing mediastinitis and three with pleural effusions. In the Group Ill cases the age and sex data u aIC To I a A euA &aa
_ .g, _,,,,
WIWiME" OMS1 COPiTvy RI$sE#-gis
FIG. 1. Map shows incidence of skin reactivity histoplasmin among naval recruits. (Courtesy of Edwards, L. B., Acquaviva, F. A., Livesay, V. T. and Palmer, C. E.: see reference 10.)
216
RALPH TOMPSETT AND LOUIS A. PORTERA
TABLE I Age and Sex Data in 57 Patients with Histoplasmosis Group I
Group IL
Group III
Totals
38 Primary Pulmon.
6 Mixed
13 Dissem.
Age Range
Mean = 47 13-74
Mean = 49 33-63
Mean = 62 49-84
21/17
2/4
11/2
Sex M/F
coincide well with other series. 1, 4, 5, 6 As noted in Table I, the average age of the patients with disseminated disease was 62, and there was a preponderance of males, 11 males and 2 females. Symptoms and signs are listed in Table II. Half of the patients in Group III had fever but in general the symptoms were relatively non-specific with the single exception that 11 Group III patients had mucocutaneous lesions. Ten of these were in the mouth, and one was perineal. As may be noted in Table III, 8 of the patients had diseases commonly associated with opportunistic infections. The usual mucocutaneous lesions were simply mass lesions located on the tongue, gingiva, and soft palate, and were thought to be carcinoma prior to biopsy. As indicated in Table IV the chest x-rays were uniformly abnormal in Group I and II. Pulmonary lesions were not prominent in the disseminated cases, being present in only 5 of 13 patients, and all were relatively small lesions. Anemia and abnormal liver and kidney function tests were present in approximately half of those Group III patients tested as outlined in Table V. Adrenal function has been reported often to be abnormal in other series.',l, 5, 6, 11 In Table VI it may be seen that there are data on 8 of 13 patients with disseminated disease. Three had clinical evidence of adrenal insufficiency and also abnormal adrenal function tests. One of these three died and at autopsy had lesions in the adrenal with microorganisms demonstrable. Of the remainder on whom we have data, five had no clinical signs of adrenal insufficiency, and in only 2 of these, were adrenal function studies done, which were normal. Three, however, showed organisms in the adrenals at autopsy, indicating the very frequent occurrence of this lesion. In all instances, it was possible to demonstrate granulomas with microorganisms visible on methenamine silver stains (Table VII). Positive cultures were obtained from several sites including blood, bone marrow, sputum, or lung tissue. As a rule the mucocutaneous lesions are
217
HISTOPLASMOSIS
TABLE II Signs and Symptoms in Histoplasmosis Signs & Symptoms
Group I
Group II
Group III
Total patients Fever Malaise Weakness Weight loss Cough Chest pain Sore throat Mucocutaneous lesions Rales Hepatomegaly
38 5 3 4 2 7 8 0 0 6 1 0 0 3
6 4 1 1 0 2 4 0 0 1 1 1 3 0
13 6 6 7 7 3 1 7 11 0 6 4 0 0
Splenomegaly Pleural effusion Wheezes
TABLE III Associated Diseases in Histoplasmosis Associated Diseases
Total patients
Diabetes Leukemia/Lymphoma Hypogammaglobulinemia Aplastic anemia
Group I
Group II
Group III
38 0 0 0 0
6 1 1 0 0
13 2 2 3 1
TABLE IV Chest X-Ray Results in Histoplasmosis Chest x-rays Abnormal Normal
Group I
Group II
Group III
38 38 0
6 6 0
13 5 8
TABLE V Admission Laboratory Data in 13 Patients with Disseminated Histoplasmosis Abnormal/Total tested
Chest x-rays Serum alkaline phosphatase Serum lactic dehydrogenase Blood urea nitrogen Serum creatinine Hematocrit
5/13
4/10 5/9 9/13 5/9
7/13
218
RALPH TOMPSETT AND LOUIS A. PORTERA
TABLE VI Adrenal Abnormalities in Patients with Disseminated Histoplasmosis (Data on 8 Patients) No. Patients
Clinical adrenal insufficiency Adrenal function abnormal Autopsy-adrenal lesions with organisms
3
3 1
No. Patients
No clinical adrenal
5
insufficiency Adrenal function normal Autopsy lesions with organisms
2
3
TABLE VII Histopathology and Culture Data in Histoplasmosis Total patients Granulomas Methenamine silver stain positive Cultures positive (number of patients) Mucocutaneous lesions Blood Bone marrow Sputum or lung Liver *
Group I
Group II
Group III
38 38 38 0 N.D.* N.D. N.D. N.D. N.D.
6 6 5 1 N.D. N.D. N.D. 1 N.D.
13 13 13 7 2 3 3 3 0
Not done
the easiest from which to recover organisms, but this series again points up the problem of failure to r,cognize the lesion before biopsy so that cultures frequently were not obtained. Despite the frequent presence of granulomas in the liver, culture of liver biopsies in this group were negative. Complement fixation tests were done on all of the patients and 8 of 13 were significantly abnormal (Table VIII). The latex agglutination test has been available for a shorter period of time and was done on only six patients. Three of these were positive. These results are in keeping with those of other series and again demonstrate the limitations of these serologic tests in disseminated disease. ' 5. 6 1 1 Skin tests were frequently not performed and in only two of the seven patients in whom the test was done was it positive. The exact significance of this is not known, but may be a manifestation of an underlying immunologic defect. All of the Group III patients were treated with amphotericin (Tables IX and X). The smallest dose given was approximately 500 mg. and the largest 11.8 gm. Follow-up data are given in Table XI. Aside from the patient in whom we have no follow-up, only one patient is known to have
219
HISTOPLASMOSIS
TABLE VIII Skin and Serologic Tests in Disseminated Histoplasmosis Abnormal/Total
Complement fixation > 1:8 Latex agglutination > 1:8 Skin tests
Treatment
8/13 3/6 2/7
TABLE IX Types of Treatment in Histoplasmosis Group I Group II
Total patients Amphotericin Surgery Both None
38 2
Group III
6 2 0 0 4
21 3 12
13 13 0 0 0
TABLE X Amphotericin Dosage in Histoplasmosis Amphotericin-B
Group III
Totals 1 gm.-2 gm. > 2 gm.-4 gm. >4gm.
13 3 4 4 2 TABLE XI
Follow-up Data in 13 Patients with Disseminated Histoplasmosis 6 mo- I
Alive Dead No follow-up
yr.
3 2 1
Causes of death Histoplasmosis Other infection
Subarachnoid hemorrhage Myocardial infarction
1-5 vrs.
5-10 yrs.
0 2
2 3
1 2 1 3
died of histoplasmosis. Myocardial infarction was responsible for 3 of the 7 deaths. Two cases were of special interest. The first was a 56 year old man who had severe hypogammaglobulinemia and who began treatment in 1961. Each time he was treated, he appeared to respond promptly, but always
220
RALPH TOMPSETT AND LOUIS A. PORTERA
relapsed when treatment was stopped. He had 5 different courses of treatment with a total of 11.8 gm of amphotericin. He ultimately died of multiple central nervous system granulomas. A second case of special interest was a 61 year old man admitted to the hospital in 1963 with the sudden onset of severe pain in the left leg and foot.12 He had evidence of femoral artery occlusion and was taken to surgery where an unusual appearing embolus was removed from the femoral artery. Unfortunately this was not cultured, but on tissue section, it showed budding yeasts and also showed branching septate mycelia. Although the presence of mycelia in tissue lesions is very unusual, it has been reported on rare occasions and has previously been reported in endocardial lesions."3 On the basis of the morphology of the yeast forms, the morphology of the mycelia, positive fluorescent antibody staining of the organisms, and strongly positive complement fixation tests, the diagnosis of histoplasma endocarditis seemed well established. The patient received a total of 4 gm of amphotericin and remained well for 11 years. He was admitted to the hospital 11 years after treatment with acute myocardial infarction and subsequently died suddenly at home. SUMMARY
This report summarizes the clinical and laboratory data on 57 patients with histoplasmosis, including 13 with progressive disseminated disease. The experience in general is supportive of that of others in that although infection with Histoplasma capsulatum is prevalent, clinical disease is uncommon and disseminated disease actually rare. The data again emphasize the limitations of diagnostic methods, and in particular point up the need to obtain cultures of biopsy material from mucocutaneous lesions. BIBLIOGRAPHY 1. DES PREZ, R. M. AND GOODWIN, R. A.: Pathogenesis and clinical spectrum of histoplasmosis. Southern Med. J. 66: 13-25, 1973. 2. Scientific Assembly Statement: The use of skin tests and serologic tests in histoplasmosis, coccidioidomycosis, and blastomycosis. Am. Rev. Resp. Dis. 108: 156-159, 1973. 3. REDDY, P. A.: Progressive disseminated histoplasmosis, in Histoplasmosis, Charles C Thomas. Springfield, Ill., 202-205, 1971. 4. SAROSI, G. A., VOTH, D. W., DAHL, B. A., DOTO, I. L., AND TOSH, F. E.: Disseminated histoplasmosis: results of long-term follow-up. Ann. Int. Med. 75: 511-516, 1971. 5. SMITH, J. W. AND UTZ, J. P.: Progressive disseminated histoplasmosis. Ann. Int. Med. 76: 557-565, 1972. 6. VANEK, J. AND SCHWARZ, J.: The gamut of histoplasmosis. Am. J. Med. 50: 89-104, 1971. 7. CARLISLE, H. N. AND SCHWARZ, J.: A histoplasmin latex agglutination test. I. Results of animal sera. J. Lab. and Clin. Med. 51: 793-801, 1958. 8. KAUFMAN, L.: Serological tests for histoplasmosis: Their use and interpretation, in Histoplasmosis, Charles C Thomas, Springfield, Ill. 321-326, 1971.
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221
9. SHUBERT, J. H. AND WIGGINS, G. L.: The evaluation of serologic tests for histoplasmosis in relation to the clinical diagnosis. Am. J. Hyg. 77: 240-249, 1963. 10. EDWARDS, L. B., AcQUAVIvA, F. A., LIVESAY, V. T., AND PALMER, C. E.: An atlas of sensitivity to tuberculin, PPD-B, and histoplasmin in the United States. Amer. Rev. Resp. Dis. 99: 1-132, 1969. 11. REDDY, P., GRELICK, D. F., BRASHER, C. A. AND LARSH, H.: Progressive disseminated histoplasmosis as seen in adults. Amer. J. Med. 48: 629-636, 1970. 12. SEGAL, C., WHEELER, C. G. AND ToMPsETT, R.: Histoplasma endocarditis cured with amphotericin. NFJM 280: 206-207, 1969. 13. HARTLEY, R. A., REMSBERG, J. R. AND SIMALY, N. P.: Histoplasma endocarditis. Arch. Int. Med. 119: 527-531, May 1967.
DISCUSSION DR. KENNETH CRISPELL (Charlottesville): I think this is an excellent summary. I would like to make a couple of points and then ask a question. Dr. Parson and I got interested in this disease when we were in New Orleans in 1947 when a patient was referred to us from the ENT Service with adrenal insufficiency and who was thought to have carcinoma of the larynx but which on biopsy proved to be histoplasmosis. We then saw in the next year another patient from the Mississippi area with hypoadrenalism. We then moved to Virginia. The first patient with adrenal insufficiency we saw in Charlottesville tumed out to have a lung lesion which turned out to be histoplasmosis. We were amazed (this was still in the 50's) that we should find such a patient there, but it turned out on careful history he had served in the Navy in the Memphis area. But then the fourth patient which we saw had never left Virginia. You have to remember that your map in the 50's wouldn't look like your map now. It turned out that he never left Loudon County, which is adjacent to Washington. We thought he was a liar probably, although there are no liars in that area. That's Mr. Byrd's County. But at this time the NIH ran out of dogs as you may know, and they went over to Loudon County to get their dogs, and as they tested them they found out that all the dogs they brought from Loudon County to Bethesda had histoplasmosis. So we were satisfied then that this man was a true Virginian. The question I have is about a young lady on the Dermatology Service who had a single lesion on her leg. They, being great detectives, discovered that she had changed a chicken house into a home, and there hadn't been any chickens in that building for ten years. She then got a puncture wound from a nail, and this apparently was the site of histoplasmosis. Our point was that these organisms will live forever in the old buildings. Have you seen a single lesion of the skin disseminate? We did not treat this lady with chemotherapy. She had a wide excision which healed completely. And for two years she has been perfectly all right, so we didn't go ahead with therapy. Would you advise therapy in somebody who had only a single lesion? DR. TOMPSETT: A very interesting question, and although I can't answer that question on the basis of personal experience, I think the literature on that would lead fairly convincingly to the idea that with such a patient with a clearly cutaneous lesion, it would be advisable, as you did, to watch the patient without treatment and follow them along. On the other hand if this is a mucocutaneous lesion or actually a mucosal lesion, I believe the evidence is very strong that this represents an important manifestation of disseminated disease. Now we have to make one very strong point here. If you noted, we very carefully used the term "progressive disseminated disease". Obviously this disease is at times disseminated and doesn't require treatment. For example, one of the patients that I reported to you who had a liver biopsy just incidentally, obviously had to have disseminated disease to involve the liver. If this patient had not been treated, and I think most people would agree, if you just find a coincidental lesion in the liver, not to treat the patient. DR. DAVID ROGERS (Princeton): Dr. Tompsett, I am delighted that another New York
222
RALPH TOMPSETT AND LOUIS A. PORTERA
transplant to the South has become interested in this fascinating disease. You mentioned the patient with endocarditis we treated with Amphotericin. She is now symptom free for some sixteen years after the onset of disseminated disease. I always call Histoplasmosis "Vanderbilt disease" because its entire history with the exception of Dr. Darling's first exposition of it (a University of Marylander). The development of our knowledge about it stems from Vanderbilt Faculty. Nashville sits in the endemic area, and my introduction to this disease was the patient we described. On my arrival as Professor of Medicine in '59, I was shown a young woman who clearly had endocarditis. She had a typical history of fever, progressive anemia and the development of painful nodules in the ends of her fingers. A massive femoral embolus brought her to the hospital. We had the same experience that Dr. Tompsett did. I was sure she had endocarditis. My Assistant Resident, who was from Vanderbilt, suggested that she might have histoplasmosis because of some remarkable mucus membrane lesions very similar to those that Dr. Tompsett has just shown you. She turned out to have both. And one of the typical massive vegetations which occur in this disease had embolized her artery. Just a few additional comments. The disseminated disease in the adult that I have seen certainly parallels that that Dr. Tompsett has described. It is worth pointing out, however, that the disease has a double age hump, and the disseminated disease in youngsters is quite different. Here one sees massive pulmonary lesions with marked involvement of the reticuoendothelial system. Thus it looks quite different in youngsters. We have had the same kinds of difficulties in culturing the organism from tissues and body fluids. However, I have found if one innoculates mice intraperitoneally with suspected material, the payoff is often very high. We have also seen about the same incidence of adrenal involvement, thirty to forty per cent in disseminated disease. Our experience in Tennessee was very similar to your's in Dallas. DR. TOMPSErr: I am glad you emphasized the point about the pediatric age group because your remarks are certainly well taken and very true. As I mentioned, we do not have any pediatric patients in this hospital and thus could not include those, but it is a different disease in children. DR. JOSEPH JOHNSON (Winston-Salem): I anticipated that Dr. Rogers would claim histoplasmosis as a Vanderbilt disease. Accordingly, I am prepared to defend the propriety of my comments by pointing out that I spent a number of years at Vanderbilt where I had the opportunity of becoming well acquainted with this disorder. Subsequently, in Baltimore, we encountered periodic patients who acquired histoplasmosis after cleaning out old chicken coops. More recently, my colleagues and I had the opportunity of identifying what we believe to have been the first case of histoplasmosis actively acquired in the state of Florida. The patient was a college student who was an avid spelunker and who acquired his disease while exploring bat caves. We subsequently proved the diagnosis in the patient and recovered the organisms from the bats in the cave. The question I have, Dr. Tompsett, is whether the patients you described showed evidence of defects in cell-mediated immunity. I recognize you may not have been able to study this in detail, but I wonder, for example, whether you had any studies of skin test reactivity in these patients. For example, did they show cutaneous anergy? DR. TOMPSETT: We do not have adequate information to make any positive statements about this, but we hope to get information on some of the later cases. DR. JOHN UTZ (Washington, D.C.): Ralph, may I add my compliments too on such a fine review of progressive disseminated histoplasmosis. You did allude to one particular cultural study which I would like to re-emphasize. It is one that is not commonly performed and, indeed, in some areas decried. Hematologists believe and can cite extensive series of bone marrows which were cultured with negative results. But in these instances it is important to
HISTOPLASMOSIS
223
remember the purposes for which the bone marrow specimens were obtained: virtually always for hematologic disease. On the other hand, the bone marrow examination is culturally positive in 75% of patients with severe, disseminated histoplasmosis. This is additionally important, since, as you described, it may be extremely difficult to obtain H capsulatum in any way, pure culture of otherwise from lesions in the mouth, which are so contaminated with commensals. DR. TOMPSETr: Thank you for your comment. It would appear that all potential sources of culture material should be explored in these cases.
Histoplasma capsulatum is a fungus with worldwide distribution in the temperate zones. Infection with this organism occurs by way of inhalation of airborne spores sufficiently small to be deposited in the pulmonary alveoli. The fungus is found in the soil in endemic areas, and as is well known, its association with the excreta of fowl has been found to be a particularly favorable circumstance for propagation and aerosolization of spores.1 In the main, contact with the fungus results in asymptomatic infection ultimately manifested only by delayed skin reactivity.2 In a small proportion of patients, a variety of clinical syndromes develop and have been well described in several papers in the past decade.1 3 4. 5, 6 Our interest has been stimulated by personal experience with a number of diagnostic and therapeutic problems arising in this disease as seen in a general hospital on the periphery of the highly endemic area of the United States. These experiences, coupled with the fact that knowledge of the varied presentation of the most serious form of the disease, namely progressive disseminated histoplasmosis, is still limited, has prompted us to review our general experience with histoplasmosis. Accordingly we have reviewed the records of Baylor University Medical Center in Dallas for the past 20 years for all patients with the diagnosis of histoplasmosis. No pediatric patients are included. The overall experience will be reviewed briefly and details will be given on the patients with progressive disseminated disease. DIAGNOSTIC METHODS Three laboratory diagnostic methods are available in histoplasmosis. The organism grows well on artificial media as a dimorphic fungus, the mycelial form growing best at temperatures below 37 degrees C. Both a complement fixation test and a latex agglutination test (the so-called "acute histo test") are available.', 8. 9 Extremely valuable also are staining techniques of tissues, especially the methenamine silver stain. The typical lesion is a granuloma, and at times the organism can be identified in an ordinary hematoxylin and eosin stain. The advantages of the silver stain are readily apparent in scanning microscopic sections under low power, and at higher power reasonably certain identification of the yeasts may be made. The skin test is of limited value diagnostically but is an important epidemiologic tool.2 Figure 1 illustrates the unique distribu214
HISTOPLASMOSIS
215
tion of the disease in the United States as indicated by skin testing. It will be noted that the Dallas area is just outside of one of the most highly endemic areas. 1o COMPOSITION OF THE SERIES A total of 57 patients were found, of whom 38 were classified as primary pulmonary, 6 as a mixed group and 13 as progressive disseminated disease. This represents one case of disseminated disease in approximately 45,000 hospital admissions. Group I consisted essentially of asymptomatic patients with negative serologic tests, who had pulmonary lesions discovered on chest x-rays. These lesions were biopsied or removed for various reasons, usually because of the inability to exclude carcinoma. Some Group I patients presented as acute benign primary histoplasma pneumonia. Eight had chronic pulmonary histoplasmosis with positive complement fixation tests. Group II consisted of two patients who had positive liver biopsies discovered accidentially during exploratory laparotomy, one patient with fibrosing mediastinitis and three with pleural effusions. In the Group Ill cases the age and sex data u aIC To I a A euA &aa
_ .g, _,,,,
WIWiME" OMS1 COPiTvy RI$sE#-gis
FIG. 1. Map shows incidence of skin reactivity histoplasmin among naval recruits. (Courtesy of Edwards, L. B., Acquaviva, F. A., Livesay, V. T. and Palmer, C. E.: see reference 10.)
216
RALPH TOMPSETT AND LOUIS A. PORTERA
TABLE I Age and Sex Data in 57 Patients with Histoplasmosis Group I
Group IL
Group III
Totals
38 Primary Pulmon.
6 Mixed
13 Dissem.
Age Range
Mean = 47 13-74
Mean = 49 33-63
Mean = 62 49-84
21/17
2/4
11/2
Sex M/F
coincide well with other series. 1, 4, 5, 6 As noted in Table I, the average age of the patients with disseminated disease was 62, and there was a preponderance of males, 11 males and 2 females. Symptoms and signs are listed in Table II. Half of the patients in Group III had fever but in general the symptoms were relatively non-specific with the single exception that 11 Group III patients had mucocutaneous lesions. Ten of these were in the mouth, and one was perineal. As may be noted in Table III, 8 of the patients had diseases commonly associated with opportunistic infections. The usual mucocutaneous lesions were simply mass lesions located on the tongue, gingiva, and soft palate, and were thought to be carcinoma prior to biopsy. As indicated in Table IV the chest x-rays were uniformly abnormal in Group I and II. Pulmonary lesions were not prominent in the disseminated cases, being present in only 5 of 13 patients, and all were relatively small lesions. Anemia and abnormal liver and kidney function tests were present in approximately half of those Group III patients tested as outlined in Table V. Adrenal function has been reported often to be abnormal in other series.',l, 5, 6, 11 In Table VI it may be seen that there are data on 8 of 13 patients with disseminated disease. Three had clinical evidence of adrenal insufficiency and also abnormal adrenal function tests. One of these three died and at autopsy had lesions in the adrenal with microorganisms demonstrable. Of the remainder on whom we have data, five had no clinical signs of adrenal insufficiency, and in only 2 of these, were adrenal function studies done, which were normal. Three, however, showed organisms in the adrenals at autopsy, indicating the very frequent occurrence of this lesion. In all instances, it was possible to demonstrate granulomas with microorganisms visible on methenamine silver stains (Table VII). Positive cultures were obtained from several sites including blood, bone marrow, sputum, or lung tissue. As a rule the mucocutaneous lesions are
217
HISTOPLASMOSIS
TABLE II Signs and Symptoms in Histoplasmosis Signs & Symptoms
Group I
Group II
Group III
Total patients Fever Malaise Weakness Weight loss Cough Chest pain Sore throat Mucocutaneous lesions Rales Hepatomegaly
38 5 3 4 2 7 8 0 0 6 1 0 0 3
6 4 1 1 0 2 4 0 0 1 1 1 3 0
13 6 6 7 7 3 1 7 11 0 6 4 0 0
Splenomegaly Pleural effusion Wheezes
TABLE III Associated Diseases in Histoplasmosis Associated Diseases
Total patients
Diabetes Leukemia/Lymphoma Hypogammaglobulinemia Aplastic anemia
Group I
Group II
Group III
38 0 0 0 0
6 1 1 0 0
13 2 2 3 1
TABLE IV Chest X-Ray Results in Histoplasmosis Chest x-rays Abnormal Normal
Group I
Group II
Group III
38 38 0
6 6 0
13 5 8
TABLE V Admission Laboratory Data in 13 Patients with Disseminated Histoplasmosis Abnormal/Total tested
Chest x-rays Serum alkaline phosphatase Serum lactic dehydrogenase Blood urea nitrogen Serum creatinine Hematocrit
5/13
4/10 5/9 9/13 5/9
7/13
218
RALPH TOMPSETT AND LOUIS A. PORTERA
TABLE VI Adrenal Abnormalities in Patients with Disseminated Histoplasmosis (Data on 8 Patients) No. Patients
Clinical adrenal insufficiency Adrenal function abnormal Autopsy-adrenal lesions with organisms
3
3 1
No. Patients
No clinical adrenal
5
insufficiency Adrenal function normal Autopsy lesions with organisms
2
3
TABLE VII Histopathology and Culture Data in Histoplasmosis Total patients Granulomas Methenamine silver stain positive Cultures positive (number of patients) Mucocutaneous lesions Blood Bone marrow Sputum or lung Liver *
Group I
Group II
Group III
38 38 38 0 N.D.* N.D. N.D. N.D. N.D.
6 6 5 1 N.D. N.D. N.D. 1 N.D.
13 13 13 7 2 3 3 3 0
Not done
the easiest from which to recover organisms, but this series again points up the problem of failure to r,cognize the lesion before biopsy so that cultures frequently were not obtained. Despite the frequent presence of granulomas in the liver, culture of liver biopsies in this group were negative. Complement fixation tests were done on all of the patients and 8 of 13 were significantly abnormal (Table VIII). The latex agglutination test has been available for a shorter period of time and was done on only six patients. Three of these were positive. These results are in keeping with those of other series and again demonstrate the limitations of these serologic tests in disseminated disease. ' 5. 6 1 1 Skin tests were frequently not performed and in only two of the seven patients in whom the test was done was it positive. The exact significance of this is not known, but may be a manifestation of an underlying immunologic defect. All of the Group III patients were treated with amphotericin (Tables IX and X). The smallest dose given was approximately 500 mg. and the largest 11.8 gm. Follow-up data are given in Table XI. Aside from the patient in whom we have no follow-up, only one patient is known to have
219
HISTOPLASMOSIS
TABLE VIII Skin and Serologic Tests in Disseminated Histoplasmosis Abnormal/Total
Complement fixation > 1:8 Latex agglutination > 1:8 Skin tests
Treatment
8/13 3/6 2/7
TABLE IX Types of Treatment in Histoplasmosis Group I Group II
Total patients Amphotericin Surgery Both None
38 2
Group III
6 2 0 0 4
21 3 12
13 13 0 0 0
TABLE X Amphotericin Dosage in Histoplasmosis Amphotericin-B
Group III
Totals 1 gm.-2 gm. > 2 gm.-4 gm. >4gm.
13 3 4 4 2 TABLE XI
Follow-up Data in 13 Patients with Disseminated Histoplasmosis 6 mo- I
Alive Dead No follow-up
yr.
3 2 1
Causes of death Histoplasmosis Other infection
Subarachnoid hemorrhage Myocardial infarction
1-5 vrs.
5-10 yrs.
0 2
2 3
1 2 1 3
died of histoplasmosis. Myocardial infarction was responsible for 3 of the 7 deaths. Two cases were of special interest. The first was a 56 year old man who had severe hypogammaglobulinemia and who began treatment in 1961. Each time he was treated, he appeared to respond promptly, but always
220
RALPH TOMPSETT AND LOUIS A. PORTERA
relapsed when treatment was stopped. He had 5 different courses of treatment with a total of 11.8 gm of amphotericin. He ultimately died of multiple central nervous system granulomas. A second case of special interest was a 61 year old man admitted to the hospital in 1963 with the sudden onset of severe pain in the left leg and foot.12 He had evidence of femoral artery occlusion and was taken to surgery where an unusual appearing embolus was removed from the femoral artery. Unfortunately this was not cultured, but on tissue section, it showed budding yeasts and also showed branching septate mycelia. Although the presence of mycelia in tissue lesions is very unusual, it has been reported on rare occasions and has previously been reported in endocardial lesions."3 On the basis of the morphology of the yeast forms, the morphology of the mycelia, positive fluorescent antibody staining of the organisms, and strongly positive complement fixation tests, the diagnosis of histoplasma endocarditis seemed well established. The patient received a total of 4 gm of amphotericin and remained well for 11 years. He was admitted to the hospital 11 years after treatment with acute myocardial infarction and subsequently died suddenly at home. SUMMARY
This report summarizes the clinical and laboratory data on 57 patients with histoplasmosis, including 13 with progressive disseminated disease. The experience in general is supportive of that of others in that although infection with Histoplasma capsulatum is prevalent, clinical disease is uncommon and disseminated disease actually rare. The data again emphasize the limitations of diagnostic methods, and in particular point up the need to obtain cultures of biopsy material from mucocutaneous lesions. BIBLIOGRAPHY 1. DES PREZ, R. M. AND GOODWIN, R. A.: Pathogenesis and clinical spectrum of histoplasmosis. Southern Med. J. 66: 13-25, 1973. 2. Scientific Assembly Statement: The use of skin tests and serologic tests in histoplasmosis, coccidioidomycosis, and blastomycosis. Am. Rev. Resp. Dis. 108: 156-159, 1973. 3. REDDY, P. A.: Progressive disseminated histoplasmosis, in Histoplasmosis, Charles C Thomas. Springfield, Ill., 202-205, 1971. 4. SAROSI, G. A., VOTH, D. W., DAHL, B. A., DOTO, I. L., AND TOSH, F. E.: Disseminated histoplasmosis: results of long-term follow-up. Ann. Int. Med. 75: 511-516, 1971. 5. SMITH, J. W. AND UTZ, J. P.: Progressive disseminated histoplasmosis. Ann. Int. Med. 76: 557-565, 1972. 6. VANEK, J. AND SCHWARZ, J.: The gamut of histoplasmosis. Am. J. Med. 50: 89-104, 1971. 7. CARLISLE, H. N. AND SCHWARZ, J.: A histoplasmin latex agglutination test. I. Results of animal sera. J. Lab. and Clin. Med. 51: 793-801, 1958. 8. KAUFMAN, L.: Serological tests for histoplasmosis: Their use and interpretation, in Histoplasmosis, Charles C Thomas, Springfield, Ill. 321-326, 1971.
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9. SHUBERT, J. H. AND WIGGINS, G. L.: The evaluation of serologic tests for histoplasmosis in relation to the clinical diagnosis. Am. J. Hyg. 77: 240-249, 1963. 10. EDWARDS, L. B., AcQUAVIvA, F. A., LIVESAY, V. T., AND PALMER, C. E.: An atlas of sensitivity to tuberculin, PPD-B, and histoplasmin in the United States. Amer. Rev. Resp. Dis. 99: 1-132, 1969. 11. REDDY, P., GRELICK, D. F., BRASHER, C. A. AND LARSH, H.: Progressive disseminated histoplasmosis as seen in adults. Amer. J. Med. 48: 629-636, 1970. 12. SEGAL, C., WHEELER, C. G. AND ToMPsETT, R.: Histoplasma endocarditis cured with amphotericin. NFJM 280: 206-207, 1969. 13. HARTLEY, R. A., REMSBERG, J. R. AND SIMALY, N. P.: Histoplasma endocarditis. Arch. Int. Med. 119: 527-531, May 1967.
DISCUSSION DR. KENNETH CRISPELL (Charlottesville): I think this is an excellent summary. I would like to make a couple of points and then ask a question. Dr. Parson and I got interested in this disease when we were in New Orleans in 1947 when a patient was referred to us from the ENT Service with adrenal insufficiency and who was thought to have carcinoma of the larynx but which on biopsy proved to be histoplasmosis. We then saw in the next year another patient from the Mississippi area with hypoadrenalism. We then moved to Virginia. The first patient with adrenal insufficiency we saw in Charlottesville tumed out to have a lung lesion which turned out to be histoplasmosis. We were amazed (this was still in the 50's) that we should find such a patient there, but it turned out on careful history he had served in the Navy in the Memphis area. But then the fourth patient which we saw had never left Virginia. You have to remember that your map in the 50's wouldn't look like your map now. It turned out that he never left Loudon County, which is adjacent to Washington. We thought he was a liar probably, although there are no liars in that area. That's Mr. Byrd's County. But at this time the NIH ran out of dogs as you may know, and they went over to Loudon County to get their dogs, and as they tested them they found out that all the dogs they brought from Loudon County to Bethesda had histoplasmosis. So we were satisfied then that this man was a true Virginian. The question I have is about a young lady on the Dermatology Service who had a single lesion on her leg. They, being great detectives, discovered that she had changed a chicken house into a home, and there hadn't been any chickens in that building for ten years. She then got a puncture wound from a nail, and this apparently was the site of histoplasmosis. Our point was that these organisms will live forever in the old buildings. Have you seen a single lesion of the skin disseminate? We did not treat this lady with chemotherapy. She had a wide excision which healed completely. And for two years she has been perfectly all right, so we didn't go ahead with therapy. Would you advise therapy in somebody who had only a single lesion? DR. TOMPSETT: A very interesting question, and although I can't answer that question on the basis of personal experience, I think the literature on that would lead fairly convincingly to the idea that with such a patient with a clearly cutaneous lesion, it would be advisable, as you did, to watch the patient without treatment and follow them along. On the other hand if this is a mucocutaneous lesion or actually a mucosal lesion, I believe the evidence is very strong that this represents an important manifestation of disseminated disease. Now we have to make one very strong point here. If you noted, we very carefully used the term "progressive disseminated disease". Obviously this disease is at times disseminated and doesn't require treatment. For example, one of the patients that I reported to you who had a liver biopsy just incidentally, obviously had to have disseminated disease to involve the liver. If this patient had not been treated, and I think most people would agree, if you just find a coincidental lesion in the liver, not to treat the patient. DR. DAVID ROGERS (Princeton): Dr. Tompsett, I am delighted that another New York
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transplant to the South has become interested in this fascinating disease. You mentioned the patient with endocarditis we treated with Amphotericin. She is now symptom free for some sixteen years after the onset of disseminated disease. I always call Histoplasmosis "Vanderbilt disease" because its entire history with the exception of Dr. Darling's first exposition of it (a University of Marylander). The development of our knowledge about it stems from Vanderbilt Faculty. Nashville sits in the endemic area, and my introduction to this disease was the patient we described. On my arrival as Professor of Medicine in '59, I was shown a young woman who clearly had endocarditis. She had a typical history of fever, progressive anemia and the development of painful nodules in the ends of her fingers. A massive femoral embolus brought her to the hospital. We had the same experience that Dr. Tompsett did. I was sure she had endocarditis. My Assistant Resident, who was from Vanderbilt, suggested that she might have histoplasmosis because of some remarkable mucus membrane lesions very similar to those that Dr. Tompsett has just shown you. She turned out to have both. And one of the typical massive vegetations which occur in this disease had embolized her artery. Just a few additional comments. The disseminated disease in the adult that I have seen certainly parallels that that Dr. Tompsett has described. It is worth pointing out, however, that the disease has a double age hump, and the disseminated disease in youngsters is quite different. Here one sees massive pulmonary lesions with marked involvement of the reticuoendothelial system. Thus it looks quite different in youngsters. We have had the same kinds of difficulties in culturing the organism from tissues and body fluids. However, I have found if one innoculates mice intraperitoneally with suspected material, the payoff is often very high. We have also seen about the same incidence of adrenal involvement, thirty to forty per cent in disseminated disease. Our experience in Tennessee was very similar to your's in Dallas. DR. TOMPSErr: I am glad you emphasized the point about the pediatric age group because your remarks are certainly well taken and very true. As I mentioned, we do not have any pediatric patients in this hospital and thus could not include those, but it is a different disease in children. DR. JOSEPH JOHNSON (Winston-Salem): I anticipated that Dr. Rogers would claim histoplasmosis as a Vanderbilt disease. Accordingly, I am prepared to defend the propriety of my comments by pointing out that I spent a number of years at Vanderbilt where I had the opportunity of becoming well acquainted with this disorder. Subsequently, in Baltimore, we encountered periodic patients who acquired histoplasmosis after cleaning out old chicken coops. More recently, my colleagues and I had the opportunity of identifying what we believe to have been the first case of histoplasmosis actively acquired in the state of Florida. The patient was a college student who was an avid spelunker and who acquired his disease while exploring bat caves. We subsequently proved the diagnosis in the patient and recovered the organisms from the bats in the cave. The question I have, Dr. Tompsett, is whether the patients you described showed evidence of defects in cell-mediated immunity. I recognize you may not have been able to study this in detail, but I wonder, for example, whether you had any studies of skin test reactivity in these patients. For example, did they show cutaneous anergy? DR. TOMPSETT: We do not have adequate information to make any positive statements about this, but we hope to get information on some of the later cases. DR. JOHN UTZ (Washington, D.C.): Ralph, may I add my compliments too on such a fine review of progressive disseminated histoplasmosis. You did allude to one particular cultural study which I would like to re-emphasize. It is one that is not commonly performed and, indeed, in some areas decried. Hematologists believe and can cite extensive series of bone marrows which were cultured with negative results. But in these instances it is important to
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remember the purposes for which the bone marrow specimens were obtained: virtually always for hematologic disease. On the other hand, the bone marrow examination is culturally positive in 75% of patients with severe, disseminated histoplasmosis. This is additionally important, since, as you described, it may be extremely difficult to obtain H capsulatum in any way, pure culture of otherwise from lesions in the mouth, which are so contaminated with commensals. DR. TOMPSETr: Thank you for your comment. It would appear that all potential sources of culture material should be explored in these cases.
