Disseminated histoplasmosis with an oral lesion

Disseminatedhistoplasmosiswith an oral lesion Report

of a case

Robert A. Boden, D.D.S.,’ Danbury, Conn. FEDERAL

CORRECTIONAL

INSTITUTION

S

tudies by Furcolow and other investigators during the past decade have shown that the prevalence of histoplasmosis is more widespread’? 2 than once realized. It was not until 1945 that the concept of histoplasmosis as a rare and fatal disease changed to that of a widespread a,nd mild one. Ten years later it was estimated that 30,000,OOOpersons were infected in the United States alone.3 Extensive epidemiologic studies in endemic areas show a positive histoplasmin skin test in more than 75 per cent of the population. Histoplasmosis usually occurs as a benign, self-limited, pulmonary disease. It is a difficult condition to diagnose because the disease spectrum may vary from an asymptomatic or mild infection to an acute fulminating disease to a chronic cavitary disease of long duration. Its progressive course involves not only the lungs but multiple organ systems of the body. Pneumonitis, endocarditiq4 pericarditis5 erythema nodosum, erythema multiforme,6 and oral mucocutaneous lesions’~ * have all been described. In the majority of reported cases, patients with mucous membrane lesions have been over 40 years of age. According to Rubin and associates,gmucocutaneous lesions usually indicate disseminated disease, but occasionally patients present seemingly isolated mucocutaneous lesions with no apparent active disease elsewhere. Such casesmay have a prolonged course, however, and the prognosis, in general, is poor,lO the mortality rate currently being at least 83 per cent.ll At present the treatment of disseminated histoplasmosis is limited to amphotericin B, an effective but highly toxic drug.lz AS should be evident, it is important that the general practitioner, in medi*Dental Surgeon, United States Public Health Service.

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eine as well a,s in dentistry, be familiar with this disease and be a\varc of the skin tests, serologic testing, and special stains (for ident3ication of the organism) that are a,vailable. Awareness is especially important, brca~s~, for the first time. promising therapeubic agents a,re being developed that. are effective against the mycoses. CASE REPORT History

A 61.year-old white man had lived in New York City most of his life, There was a past history of syphilis in 1925, which was treated with salvarsan. A subtotal gastrectomy was performed in 1960 for treatment of an ulcer. In July, 1962, the patient complained of swollen ankles; this was attributed to a heart condition which improved with bed rest. Ho was admitted to the United States Public Health Service Hospital in Lexington, Kentucky, in May, 1963, for treatment of heroin addiction. He admitted that he had smoked opium siince he was 18 years of age and that in 1961 he began using heroin. On Dec. 16, 1963, the patient developed an acute respiratory infection. A chest roentgenogram revealed a right upper lobe infiltrate which spread within one week’s time to the left upper lobe. He was treated with a course of tetracycline and prostaphlin, without significant benefit. Sputum cultures for bacteria, acid-fast organisms, and fungi failed tom disclose any significant pathogens. Complement-fixation tests for Bistoplmm capwlatum on Dec. 31, 1963, revealed a titer of 1:16 with both the mycelial and yeast phase antigens. Tuberculin and histoplasmin skin tests were negative on Dee. 26, 1963, and positive 5 weeks later. Symptoms gradually resolved over a period of 3 weeks. A chest film taken 4 months later was interpreted as showing fibrotic reaction with cystic changes throughout both upper lobes. The patient was transferred to the Federal Correctional Institution at Danbury, Connecticut, April 9, 1964. While he was at Danbury, his chest films remained stable and numerous sputum examinations for acid-fast organisms were nega,tive. Jn early August, 1965, the patient developed a painful ulcerated lesion on the right lateral surface of the tongue’ (Fig. 7). A cytological smear was t,aken and read as Class II. In the succeeding months there was progressive enlargement of the ulcer (Fig. Z), and the patient developed malaise, weight loss, hoarseness, and anemia. A biopsy of the lesion on Sept. 11, 7965, was consistent with a Histoplasma ca~s&t~ infection. On Oct. 1, 1965, the patient was transferred to the United States Public Health Service Hospital at St,aten Island, New York, for evaluation and treatment. Physical

examination

Physical examination revealed a thin, chronically ill white man who spoke in a hoarse voice. The blood pressure was 110/60; the pulse rate was 88 and regular; the temperature was 99” F.; and the respiration rate was 18. The patient was 5 feet 6 inches tall a,nd weighed 128 pounds. A 10 by 20 mm. indurated area was noted on the right lateral surface of the tongue. The lesion was erythematous, with scattered areas of pale discoloration. A central and severe tenderness irregular ulceration, measuring 2 by 3 mm., was present. Induration extended to the base of the tongue, alveolar ridge, and submandibular area on the right side. Auscultation of the chest revealed coarse breath sounds and rhonchi in both upper lung fields. A Grade II/VI systolic murmur was heard at the apex. The pulmonic second sound was accentuated. There was no hepatosplenomegaly, significant lymphadenopathy, cyanosis, clubbing, or edema, and no skin lesions were noted. The hematocrit was 29 per cent, and the white blood count was 7,200, with a normal differential and a platelet count of 490,000. The peripheral blood smear revealed marked anisocytosis and hypochromia. The urine had a specific gravity of 3.025, and was, negative for sugar and albumin. Microscopic study of the urine showed 6 to 8 red blood cells and 4 to 7 white blood cells per high-power field, The sedimentation rate was 24 mm.; blood urea nitrogen was 23 mg. per cent; fasting blood sugar was 90 mg. per cent; and VDRL was nonreaotive. Multiple urine and sputum cultures were negative for acid-fast organisms. Total

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Fig.

Fig. 2. Lesion on right lateral aspect of tongue on Aug. 10, 1965, one week after first symptoms appeared. Fig. 8. Sept. 30, 1965. Lesion involves entire right side of tongue and extends to floor of mouth. Fig. 3. April 5, 1966. Right lateral aspect of tongue after Amphotericin B treatment, showing complete resolution.

protein was 7.2 Gm. per cent; albumin, 3.8 Gm. per cent; alkaline phosphatase, 2.3 BesseyLowry units. Total serum bilirubin was less than 1 mg. per cent; thymol turbidity was 9.7 units. Serum creatinine ranged from 1.65 to 2.5 mg. per cent before the onset of treatment. Prothrombin time was 55 per cent of the control. Blood and bone marrow cultures were negative for fungi. Cultures of the tongue lesion and the urine were positive for Histophma capsdatum. An electrocardiogram, an intravenous pyelogram, and a skeletal x-ray survey were all negative. Chest films revealed bilateral apical fibrosis. Tuberculin and histoplasmin skin tests were negative. On two occasions complement-fixation tests for H&&ma cqwulatum were positive in a dilution of 1:16. Hospital

course

A biopsy of the tongue on Oct. 8, 1965, revealed a marked granulomatous formation with many plasma cells, giant cells of the Langhans type, and epithelioid cells. Special stains revealed small, round, intracellular organisms consistent with Htitq&wma caps~~%m. Indirect laryngoscopy demonstrated erythema of the ventricular bands. No discrete laryngeal

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lesions were noted. Cystoscopic examination revealed no specific lesions other than increased vascularity and trabeculation of the bladder mucosa. Prior to therapy, the patient experienced intermittent temperat,urc elevat,ions up to 100.5” F. and the pain involving the tongue increased progressively. On Sov. 3, 1965, therapy with amphotericin B was started. The initial dose was 10 mg. diluted in 500 C.C. of 5 per cent dextrose and water, given intravenously over a 6 hour period. The patient was given Benadryl (100 mg.) orally one hour before each infusion. He tolerated the initial dose of amphotericin B with no side effects. Subsequent doses were administered every 48 hours and were increased by 5 mg. unt.il a maintenance dose of 35 mg. every 48 hours was reached. On Nov. 3, 1965, the patient was started on dexamethasone, 1 mg. by mouth daily, because of transient episodes of hypotension. This steroid was continued and gradually tapered in the ensuing 5 months. Within 9 days after the start of therapy, the pain and hoarseness decreased and there was an improvement in the appetite and general well-being. The patient was afebrile within 5 days after the initiation of therapy. Within 2 weeks following the onset of therapy the tongue lesion began to resolve visibly, and within 6 weeks the lesion was healed (Fig. 3). During therapy the blood urea nit,rogen ranged between 24 and 29 mg. per cent. Serum creatinine after 5 month8 of therapy was 2.4 per cent. The hematocrit increased from 23 per cent at the onset to 29 per cent after 5 months of therapy. The hematuria entirely resolved. During therapy, serum potassium levels ranged from 2.9 to 3.6 mEq. per liter, while urinary excretion of potassium ranged between 35 and 53 mEq. per liter. The hypokalemia was promptly corrected with supplemental oral potassium. By March 8, 1966, the patient had received a total of 2,180 mg. of amphotericin B, and he felt entirely well. On July 15, 1966, the patient was still free of disease.

DISCUSSION Lexington, Kentucky, is in the center of the western Appalachian slope. Histoplasmosis is highly endemic in this a.rea, and the fungus has frequently been cultured from the soil.13 It is following the contamination of the soil, as by bats or starlings, that man acquires the infection by ingestion or inhalation of spore-containing dust. The patient recalled spending considerable time sitting under trees frequented by starlings and pigeons while in Lexington. Since the patient had no history of travel into regions endemic for histcplasmosis prior to his assignment at Lexington, Kentucky, it is highly probable that the pneumonic process in 1963 was secondary to recently acquired histoplasmosis. This belief is supported by the histoplasmosis skin test conversion and the positive complement-fixation tests to both histoplasmin mycelial antigen and to whole yeast phase organisms. Each of these strongly supports the Histoplasma capsulatum organism as the etiologic agent. basically responsiblc. Approximately 20 months following this episode of acute pulmonary histoplasmosis, the patient noted a progressive ulceration of the tongue. Biopsy revealed yeastlike intracellular organisms, and1 the cultures grew Histoplasma capsulatum in both mycelial and yeast phases (Figs. 4, 5, and 6). Bone marrow, blood, and sputum cultures were negative, but urine cultures grew the organism in the mycelial phase and it was converted to the yeast phase. Histoplasma capsdatum is a small yeastlike oval intracellular fungus in the tissues and is yeastlike on blood agar slants at 37’ C. In culture at room temperature on Sabouraud’s agar, a mycelial form is assumed; colonies are moldlike, white, and cottony with aerial mycelium. The organism is verified by the

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‘ig. 6

Fig. 4. Multinucleate giant cells of Langhans type located within granulomatous infiltrate. Small clear areas in cytoplasm are Histoplasrrca oaps%latm. Larger dark-staining bodies are nuclei within giant cell. (Hematoxylin and eosin stain.) Fig. 5. Smear taken directly from tongue shows macrophage containing Histoplasma mpsuhtwm (small cells surrounded by clear halo). Dark-staining material is debris and nuclei of inflammatory white blood cells which have been engulfed by macrophage. (Giemsa stain.) Fig. 6. Gomori’s silver methenamine stain (oil emersion). This is the best possible stain for the tissue (yeast) phase of the organism. The nucleus and the cell wall stain darker; the cytoplasm picks up a minimal amount of stain, There is TW capszde; Hi-stopEasma c~ps~~t~ is a misnomer.

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Fig. 7. Mycelial form of fungus on Xabouraud’s agar at room temperature (lactophenol cotton blue stain) is distinguished from other pathogenic fungi by formation of large chlamydospores.

morphologic characteristics of the colonies and the presence of distinctive tuberculate spores (Fig. 7). In conjunction with culturing procedures, the diagnosis can be verified by the inoculation of laboratory animals. Almost any laboratory animal is susceptible to either the yeast or the mycelial phase of Hi&optima capsdatum, mice being most useful for diagnosis. In order to prevent death from contaminating bacteria,14 a broad-spectrum antibiotic should be given several days before the suspected material is administered to mice. The histoplasmin skin test, qualitatively and quantitatively, is no reflectio’n of the state of activity of the infection. I5 Conversion or development in the very young indicates active disease. Sensitivity appears 2 to 3 weeks after the infection begins and persists for years. Massive progressive infection may suppress the humoral antibody titer and, with it, the skin sensitivity. The skin test, particularly when used concurrently with tuberculin, coccidioidin, and blastomycin skin tests, is important in diagnosis. It enables one to differentiate histoplasmosis from tuberculosis, coccidioidomycosis, and North American blastomycosis, and it is also an epidemiologic tool in determining whether a person has had subclinical histoplasmosis. The serologic studies must be made before the second week following the skin test. In approximately one out of five subjects there is a change from negative to positive complement-fixation following a single histoplasmin skin test.13, I6 Fungi are considered weak antigens because concentrations of circulating antibody are usually low. Antigens for the mycoses show varying degrees of cross reaction, especially in the histoplasmosis-blastomycosis-coccidioidomycosis group. The precipitin test, the complement-fixation test, the agar gel diffusion test, and the agglutination test are the usual serologic indicators of circulating antibody. The precipitating antibodies appear first, but the complement-fixation antibodies persist longer and are better for both diagnostic and prognostic purposes.

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Acute pulmonary histoplasmosis is almost always a benign infection and is associated with a geographical point source. The severity of the infection is proportional to the time and intensity of exposure. Blood-borne dissemination probably does occur at the time of the primary infection, since calcification of the spleen and liver is often seen. In some persons (possibly those with defective immune mechanisms), definite foci of disease ase established in other than the pulmonary tissues. These may be evidenced clinically as an acute septicemic type (usually in younger persons), as a histoplasmic meningitis, or, in older persons, as a chronic granulomatous type with adrenal involvement, accompanied by ulceration of the mucous membranes. To date, the treatment of choice is amphotericin B (Squibb), which was used in this case. This comparatively new antibiotic is derived from a species of Streptomyces and has been shown to be an extremely good fungicidal agent. Amphotericin B is available today in microcrystalline and colloidal preparations. The microcrystalline form is well tolerated orally but is not absorbed from the gastrointestinal tract. In the colloidal form, amphotericin B is combined with sodium desoxycholate in a sodium chloride buffer. Adequate blood levels are achieved when the drug is administered parenterally, but the untoward effects of the desoxycholate include nausea, abdominal cramps, and diarrhea. The toxic symptoms following the parenteral administration of amphotericin B include fever, chills, headache, nausea, vomiting, and phlebitis.17 The drug acts on the cytoplasmic membra,ne of the yeasts, causing inhibition of metabolic activity and’ a loss of intracellular contents.18 Anemia following amphotericin B administration is caused by bone marrow suppression, which is reversible. Brandriss19 reports that the mean hematocrit was 41 per cent before and 27 per cent during amphotericin B therapy. The hematocrit returned to normal in twenty-seven out of thirty patients after cessation of therapy. The anemia was normocytic and normochromic. There was a decreased rate of plasma iron utilization and clearance. There was no correlation between the dose of amphotericin B and the degree of anemia. Electrolyte abnormalities occurring during amphotericin B therapy include hypokalemia and hypomagnesemia. 2o This patient exhibited hypokalemia but had normal urinary potassium excretion. Abnormalities in renal function are found in 80 per cent of patients treated with amphotericin B and include a decreased renal plasma flow and a decreased glomernlar filtration rate.*lv 22 Renal biopsy specimens show renal tubular abnormalities consisting of amorphous material containing calcium and phosphate in the lumen of the convoluted tubules. If the dose of amphotericin B is 0.5 mg. per kilogram per day or less, the renal toxicity is decreased. SUMMARY

A ca’se of proved disseminated histoplasmosis presenting as a hi&plasma ulcer of the tongue has been reported. Treatment with relatively small doses of amphotericin B resulted in prompt regression of the granulomato;us lesion with a minimum of side effects. The epidemiology and clinical characteristics of disseminated histoplasmosis were discussed, a.s were the serologic and skin tests for

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HistopZasma caps&turn. therapy was presented.

O.S., O.M. & 0.1’. ;ipril, 1967

A review of the cuprent literature

011 anlphoteririn

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This report, in its present form, was in great part made possible by the valuable assistance and suggestions of James Fields, M.D., Chief, Dermatology, and P. Hiley, M.D., United States Public Health Service Hospital, Staten Island, New York. The knowledge and experience of Dr. Fields and Dr. Hiley have been drawn upon extensively, and fullest appreciation is here extended. REFERENCES

6.

7. 8. 9.

10. 11. 12.

13.

14. 15. 16. 17. 18.

19. 20.

21.

22.

Christie, A. : The Disease Spectrum of Histoplasmosis, Ann. Int. Med. 49: 544-555, 1958. Furcolow. M. D.: Emereing Pattern of Urban Histonlasmosis: Studies on an Enidemic I in Mexicb, Missouri, N& &gland J. Med. 264: 1226Fi232, 1961. Furcolow, M. D.: Histoplasmosis, GP 18: 117-127. 195& Korns. u. E.: Coincide&e of M&otic IHistot&&a CaDsulatum\ Vegetative Endocarditis of the’ Mitral Valve and the Lutkmbacier Sy&drome, Ci&ulation’32: 0589-592, 1965. Rosenbaum, A. E., Schweppe, H. I., and Rabin. E.: Constrictive Pericarditis, Pneumopericardium and iortic A&%&m D&e to Histopiasma Capsulatum, New England J. Med. 270: 935938. 1964. Medeirii, A. A;., Marty, S. ?., Tosh, F. E., and Chin, D. Y.: Erythema Nodosum and Erythema Multiforme &9 Clinical Manifestations of Histoplasmosis in a Community Outbreak, New England J. Med. 274: 415420, 1966. Baum, G. L., Schwartz, J., Slot, W. B.. and Straub. M.: Mucocutaneous Histoplasmosis, Arch.‘Dermat. 76: 4-8.‘1947. ’ Stiff, R. H.: Histopl&mosis, ORAL SURG., ORAL MED. & ORAL PATH. 16: 140-149, 1963. Rubin, H., Furcolow, M. L., Yates, J. L., and Brasher, C. A.: The Course and Prognosis of Histodasmosis. Am. J. Med. 27: 278-288. 1959. U.S.P.H.B. Coopektive Mycosis Study: Co&se and Prognosis of Untreated Histoplasmosis, J. A. M. A. 177: 292-296, 1961. Furcolow. M. L.: Comoarison of Treated and Untreated Severe Histodasmosis, J. A. M. A. 183: 823&29, 1963. Utz, J. P., Bennett, J. E., Brandriss, M. W., Butler, W. T., and Hill, G. J.: Amphotericin B Toxicity: Combined Clinical Staff Conference. National Institutes of Health. Ann. Int. Med. 61: -334-354. 1964. Sigrest, M. L., L&.mus, F. L., Campbell, G. O., Busey, J. F., and Allison, F.: Effect of Diagnostic Skin Testing on Antibody Levels for Histoplasmosis, New England J. Med. 269: 390-394, 1963. Nutman, N. N.: A Case of Histoplaamoeis With Oral Manifestations, ORAL SURG., ORAL MED. & ORAL P&TH. 2: 1562.1565. 1949. Salvin, S. B.: Current Concepts 04 Diagnostic Serology and Skin Hypersensitivity in the Mycoses, Am. J. Med. 27: 97-114, 1959. Nicholas, W. M., Weir, J. A., Kuhn, L. R., Campbell, C. C., Nolte, L. B., and Hill, G. B.: Serologic Effects of Histoplasmin Skin Testing, Am. Rev. I&p. Dia. 83: 276-279, 1961. Andriole, V. T., and Kravetz, H. M.: The Use of Amphotericin B in Man, J. A. M. A. 180: 269-272, 1962. Butler, W. T.: Pharmacology, Toxicity and Therapeutic Usefulness of Amphotericin B, J. A. M. A. 195: 127-131, 1966. Brandriss, M. W., Wolff, S. M., Moor+ R., and Stohlman, F.: Anemia Induced by Amphotericin B, J. A. M. A. 189: 663-666, 1964. Butler, W. T., Bennett, J. E., Hill, G. J., Szwed, C. F., and Cotlove, E.: Electroeardiographic and Electrolyte Abnormalities Caused by Amphotericin B in Dogs and Man, Proc. Sot. Exper. Biol. & Med. 116: 857-863, 1964. Butler, W. T., Bennett, J. E., Alling, D. W., Wertlake, P. T., Utz, J. P., and Hill, G. J.: Nephrotoxicity of Amphotericin B: Early and Late Effects in 81 Patients, Ann. Int. Med. 61: 175-187, 1964. Bell, N. H.,, Andriole, V. T., Sabesin, S. M., and Utz, J. P.: On the Nephrotoxicity of Amphoterlcm B in Man, Am. J. Med. 33: 64-69, 1962.