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Gastrointestinal histoplasmosis in children
Gastrointestinal Histoplasmosis in Children By ROBERT T. SOPER, DAVID L. SILBER AND GEORGE W. HOLCOMB, JR.
H
ISTOPLASMOSIS is a fungal infection with virtually worldwide distribution. It is relatively common in the central portion of the United States, where as many as 30 million people are estimated to have at one time acquired histoplasmosis. Specific skin tests are positive in from one per cent of residents of coastal areas to 80 per cent of those living in the drainage basins of the midcontinental rivers1 Schwarz and Baum? have outlined the historical background of the disorder, beginning with Darling’s description” of the organism (Histoplasma capsdatum) which he recovered from a terminally ill man in 1906. The diagnosis of histoplasmosis was first established in a living child by Dodd and Thompkins4 in 1934, and from this patient, Demonbreun” first cultured the organism to prove that it was a fungus rather than a protozoan. Christie and PetersonG were among the first investigators to recognize a benign form of pulmonary histoplasmosis, and to distinguish it from tuberculosis. Histoplasma capsdatum is a diphasic organism which exists as a small round yeast at body temperature, and in a mold form at lower temperatures or when it occurs in nature. Only the mycelial (mold) form has the typical rounded spores which are so characteristic of the organism. Histoplasmosis is thought to be not communicable from man to man, or from animals or birds to man. The yeast grows in soil under rather sharply defined optimal conditions of temperature and humidity, and probably is transmitted directly to man via inhalation of spores. Birds have no direct connection with histoplasmosis aside from furnishing guano for a favorable growth environment. Most investigators indict the lung as the common portal of entry in humans. Pulmonary histoplasmosis usually is manifested as a benign and self-limiting atypical pneumonia. Occasionally it occurs as a chronic calcifying or cavitary disease which resembles tuberculosis. Disseminated histoplasmosis is rare, and may run either an acute or chronic course. Patients with advanced, untreated systemic involvement often die. The reticuloendothelial systems are preferentially involved in extrapulmonary histoplasmosis, lymph nodes, liver and spleen being most commonly attacked; however, any body system may be involved. Histoplasmosis has been reported to involve all levels of the gastrointestinal tract from the oral cavity to the anus,4*7*8vQ but there seems to be a predilection for small bowel and colon. A diagnostic skin test for histoplasmosis was first described in 1941 by Van From University of Iowa, College of Medicine, Iowa City, Iowa. ROBERT T. SOPER, M.D.: Professor of Surgery, University of Zowa, College of Medicine, Iowa City, Iowa. DAVID L. SILBER, M.D.: Assistant Professor of Pediatrics, University of Iowa, College of Medicine, Iowa City, Zowa. GEORGE W. HOLCOMB, JR., M.D.: Clinical University, School of Medicine, Nashville, Assistant Professor of Surgery, Vanderbilt Tennessee. 32
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1 (FEBRUARY), 1970
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Pernis and colleagues.t(’ The skin test was further refined by the Public Health Service”,‘” and has been used in mass screening studies.‘.l” A positive skin test indicates a sensitivity to histoplasmin but does not necessarily signify infection occur to cocwith the fungus Histoplasma capsdatum, since cross reactions cidiomycoSiS, polio virus, and other agents. Furthermore, false-negative skin tests occur in patients with overwhelming histoplasmosis. Histoplasma complement-fixation antibody titers are of some help in determining infection. Rising titers support the diagnosis of active histoplasmosis and decreasing titers often are associated with improvement. Cross reactions and nonspecificity limit this test, however. Biopsy and culture of the organism are needed to make a specific diagnosis of histoplasmosis. The purpose of this paper is to call attention to the problem of gastrointestinal histoplasmosis in children with three illustrative patients who have been treated by the authors during the past few years. Each is sufficiently unique in its clinical manifestations to warrant review. CASE REPORTS Case No. I (C.E.H.), a white male. was 2-I l/12 years old when admitted to Baptist Hospital, Nashville, Tennessee, because of lethargy, fever and night sweats. Physical examination revealed a listless, pallid child with moderate abdominal distention and percussion tympany, but no organomegaly or masses. and PPD skin tests. Routine laboratory studies were normal, as were Histoplasmin X-rays revealed a fine infiltrate throughout both lung fields. Culture of the blood, throat, gastric washings and stool grew no pathogens. Barium enema was normal. The bone marrow culture eventually yielded Hisfoplasma capsrclntum. revealed mild myeloid hyperplasia; after the diagnosis was established in other ways. During this workup his condition gradually deteriorated with increasing abdominal pain and distention, bloody stools and fever dominating the picture. On the eighth hospital day roentgenograms revealed an air-fluid level in the peritoneal cavity with free air under the diaphragm. A tentative diagnosis of a perforated duodenal ulcer was made and exploratory laparotomy was carried out. The duodenum and appendix were normal. A S-mm. perforation was found in the distal ileum, and in addition, there were several areas of circular scarring of the serosal surface of the small intestine with apparent ulceration through the entire thickness of the bowel except for the serosa; these areas were imbricated to prevent perforation. The site of perforation was resected and the bowel was anastomosed. A mesenteric node showed intracytoplasmic organisms having the morphologic characteristics of Histoplrrsmrr CNJ).YII/aturn. The ileum at the site of perforation had a granulomatous inflammatory reaction. At one point in the subserosa, phagocytic cells containing structures resembling Hi.vtop/!c.rnrrr were found. Penicillin and streptomycin were given; later, when culture and histologic evidence of histoplasmosis was found, Amphotericin B was given intravenously for a period of seven days. The postoperative course was stormy with persistent temperature elevation until 72 hours after Amphotericin was begun. The child was maintained on intravenous fluids for the first ten postoperative days. On the 16th postoperative day abdominal wound dehiscence required surgical closure. At the same time a feeding gastrostomy was performed. A mesenteric lymph node on microscopy showed yeasts with the morphology of Hisfophmcc capsulafum. Culture of a portion of the stomach grew Histoplasma capsulatum. The child then began to improve. Body weight increased from 31 lb. (14 Kg.) to 35 lb. ( 16 Kg.). A second eight-day course of Amphotericin was administered. Three weeks before discharge, triple sulfa suspension was begun. Total hospitalization was 60 days. At discharge he was clinically improved, active and eating well. X-rays of the chest showed no change but all other laboratory studies were normal.
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During the subsequent three years, repeated episodes of bacterial furunculosis have been treated by drainage and antibiotics. Studies have not incriminated histoplasmosis in these abscesses, nor is there evidence of an impaired immunological response. Thirteen months after operation he was admitted with symptoms suggesting recurrence of his intestinal problems: fever, malaise, loss of appetite and abdominal distention. His abdominal complaints disappeared with therapy for constipation; however, on X-rays of the chest there was an increase in pulmonary infiltrate and another course of Amphotericin was administered. He showed progressive improvement and to date has done well with the exception of the furunculosis. Case No. 2 (T.M.F.), a white male, was 10 years old when first seen at the University of Iowa Hospitals in 1962 because of fever, adenopathy, chest pain and cough. Chest X-rays showed bilateral hilar adenopathy with a right lower lobe infiltrate. Coccidiomycosis was proven by cervical lymph node biopsy and a specific complement-fixation antibody titer of 1:4096. After intravenous Amphotericin B was given, he became afebrile and the lung X-rays improved, He was readmitted in July 1966, because of abdominal pain and tenderness, constipation, and shotty lymphadenopathy. Constipation was alleviated with medications, after which his abdominal pain decreased somewhat. Upper GI X-rays were normal, but chest X-rays showed some increase in hilar adenopathy. A diagnosis of systemic histoplasmosis was made by remarkably elevated and rising complement-fixing antibodies, and a seven-month course of triple sulfa was begun. In June 1968, he developed periumbilical pain with radiation to the back. Because eating sometimes triggered the pain, he had reduced his food intake and lost weight. He denied vomiting or diarrhea. He was a thin, withdrawn lW’z-year-old boy with palpable cervical lymph nodes. The abdomen was tender and guarded with no masses. Hemogram, urinalysis, chest and plain abdominal X-rays, IVP, and lumbar puncture were negative or normal. Histoplasmosis antibody titers were 1: 1024, and the coccidiomycosis titer was 1:64. Complete GI barium studies showed narrowing of the terminal ileum (Fig. 1) with irregular mucosa and some fixation of the surrounding bowel loops. This prompted the radiographic diagnosis of regional ileitis (Crohn’s disease). Sigmoidoscopy was unremarkable. Biopsy of a right cervical lymph node showed coccidioides organisms as well as ovoid budding fungal cells compatible with Histoplasma capsdatum. Laparotomy was performed to pinpoint the cause of the ileal narrowing. Mesenteric lymph nodes as large as 5-7 cm. in diameter were found, most prominent in the mesentery draining the terminal ileum and there was subacute enteritis involving a segment of jejunum
Fig. l.Spot film of barium enema in case #2 showing narrowed distal ileum with ragged mucosa suggestive of Crohn’s disease.
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and proximal ileum. The distal 10 cm. of ileum was indurated, thickened, injected and adherent to the posterior peritoneum suggestive grossly of Crohn’s disease. Biopsy of the liver and a mesenteric lymph node showed non-caseating granulomas with giant cells and mononuclear cells; intracellular Histoplasma organisms were demonstrated by PAS and Grocott stains. Histoplasmn capsdatum was grown from sputum and urine. as well as from the mesenteric lymph node and the liver. Amphotericin B was given by intravenous infusions for 40 days. The abdominal pain gradually improved. Repeat gastrointestinal barium studies showed improvement of the involved ileum. Four months postoperatively, the urine, sputum and blood cultures were negative. He was 13-Kg. heavier than at operation, had no adenopathy or abdominal pain. and was purusing normal school activities. Physical examination and routine blood studies were normal. Case No. 3 (V.L.O.), a white female, was nine years old when fever, lymphadenopathy and a questionable abdominal mass developed. Cervical lymph node biopsy showed Hisfoplasma cnpsulatum. She was treated with sulfa and Amphotericin B and did well for three years. Recurrent histoplasmosis was heralded by cervical lymphadenopathy, fever, weight loss and elevation of complement-fixation antibody titers. Triple sulfa was given for six months with improvement. At 13 years, abdominal pain, bilious vomiting, weight loss and fever prompted referral to the University of Iowa Hospitals. She was a thin, alert female with enlarged cervical lymph nodes bilaterally. There was chemical and X-ray evidence of partial mechanical obstruction of the jejunum. An upper GI study showed dilatation of the duodenum and a few loops of jejunum with prominence of the mucosal pattern and segmentation of the barium (Fig. 2a). Barium enema was normal. Laparotomy revealed partial obstruction proximal to an 18-cm. segment of midjejunum which showed thickening, edema, induration, injection of the subserosal vessels (Fig. 2b). and enlargement of the adjacent mesenteric lymph nodes resembling Crohn’s disease. There were four other areas from 7 to 30 cm. in length similarly involved with intervening normal bowel. The proximal area of obstructing jejunitis was excised and a mesenteric lymph node was biopsied. The resected bowel wall was thickened and the mucosa had a cobblestone appearance. Histologically. there was granulomatous inflammation involving the mucosa, submucosa and muscularis (Fig. 2~). Numerous Histoplusma capsulatum organisms were identified, mostly in extracellular clusters (Fig. 2d). There was granulomatous involvement submucosally at both of the resection margins, where the bowel appeared grossly normal. The mesenteric lymph nodes showed fibrosis and small amounts of chronic granulomatous inflammation with numerous Histoplnsma capsdatum organisms. Cultures of bowel and mesenteric lymph nodes ultimately grew Histoplusmu capsdatum. The patient’s postoperative course was unremarkable; she tolerated well a course of intravenous Amphotericin B. and she remains free of gastrointestinal symptoms to date. DISCUSSION In 1945, Iams and co-workersI reported 21 cases of histoplasmosis in children. They stressed the lack of specificity of symptoms in the very young patient with histoplasmosis. Eleven of their patients had gross gastrointestinal tract lesions, and histologic evidence of gastrointestinal histoplasmosis was present in 13 cases. Morse and Schultzl” reported 30 children with histoplasmosis in 1962. They emphasized the gravity of the disease in the young patient, with a mortality rate of 40 per cent in their patients under the age of four years. None of these children had documented involvement of the gastrointestinal system, although two had abdominal pain as presenting complaints.
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obstructed loop of Fig. Za.- Late motor meal X-ray showing dilated, partially jejunum with ragged, edematous mucosa. Much barium has passed into colon. Fig. 2b.-Gross appearance at operation of acute jejunitis due to histoplasmosis, producing bowel obstruction. Fig, 2c.-Acute granulomatous jejunitis, low-power view (H&E). Submucosa especially thickened and inflamed. Fig. 2d.-High-power view of jejunal wall, Grocott’s stain; silver stain taken up by Histupk~sma capsulutum organisms, some within giant cells.
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Most investigators feel that the reticuloendothelial tissue of the gastrointestinal tract and mesenteric nodes are secondarily involved from a primary pulmonary site of entry. Gastrointestinal entry of Histoplasma capsdatum has Whether hubeen experimentally demonstrated by Allenl” and Demonbreun.l? mans acquire gastrointestinal histoplasmosis by ingestion of the organisms is unknown, Histologically, the lesions of gastrointestinal histoplasmosis are characterized by noncaseating granulomatous inflammation, similar to that seen in Crohn’s disease. The organisms generally lie within macrophages and giant cells, and are best seen with Grocott stain. Submucosal lymphoid tissue and mesenteric lymph nodes seem to be the earliest and most commonly involved structures. Raftery lx~l!’ has reported finding the organisms and characteristic inflammation in the appendix and mesenteric lymph nodes as the only manifestation of histoplasmosis. He found such evidence in 10 per cent of 436 appendices surgically removed in children 16 years of age and under, and in 40 per cent of nodes excised from patients with the clinical diagnosis of mesenteric adenitis. Culture confirmation is lacking in these cases, and is necessary for definitive, specific diagnosis. Only the surgeon can provide tissue for appropriate culture. Collins”‘-“” has pointed out an alarmingly high percentage of patients with a variety of gastrointestinal tract lesions which may be due to histoplasmosis. He found histologic, cultural or serologic evidence of histoplasmosis in 52.6 per cent of patients with juvenile mesenteric lymphadenitis, 37.5 per cent of patients with chronic ulcerative colitis, 1 I .5 per cent of patients with nonspecific anorectal inflammatory diseases, and 9.8 per cent of patients with other inflammatory colonic disease. He also found evidence of histoplasmosis in 7.X per cent of 50,000 consecutive unselected specimens of the vermiform appendix. In 151 patients with juvenile mesenteric adenitis, Collins found positive histoplasmin skin tests in 85 per cent and typical diffuse “birdshot” calcifications in the lung parenchyma compatible with pulmonary histoplasmosis in 61 per cent. He makes an impassioned plea for specific histologic and cultural search for histoplasmosis in patients with these gastrointestinal diseases. Again, it is the surgeon’s responsibility to request these studies on biopsy material. With these exceptions, most authors describe gastrointestinal histoplasmosis in association with widespread and serious systemic histoplasmosis. Fever, weight loss, anorexia, and cramping abdominal discomfort are common nonspecific complaints in these patients. Dysphagia, diarrhea, constipation, vomiting, and protein-losing enteropathy”” are also described. Acute abdominal complaints may dominate the picture, such as hemorrhage, perforation (our Case No. I ) and mechanical obstruction (our Case No. 3). Gastrointestinal histoplasmosis may be suspected in patients with digestive complaints who are known to have pulmonary or systemic histoplasmosis. On occasion, rectal or oral mucosal lesions or accessible lymph nodes provide histologic and cultural confirmation of diagnosis, eliminating the need for laparotomy. Gastrointestinal X-rays are not specific. The intestinal ulcerations often are small and superficial, and may not be seen radiographically. Either ulcerating or constricting lesions can be found. A “cobblestone” mucosal appearance.
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pseudopolypoid irregularity, puddling, and spasm all have been described. Free intraperitoneal air or mechanical obstruction are dramatic, but nonspecific, findings. Radiographic changes typical for chronic ulcerative colitis and Crohn’s disease (our Case No. 2) also have been reported in patients with gastrointestinal histoplasmosis. It is interesting to speculate what proportion of patients with ulcerative colitis or Crohn’s disease actually have histoplasmosis colitis or enteritis. Laparotomy is justified for confirmation of gastrointestinal histoplasmosis when a specific diagnosis cannot otherwise be made (our Case No. 2), in view of the prolonged and somewhat dangerous nature of medical treatment. Of course, surgical complications (massive hemorrhage, intestinal obstruction, free perforation) demand surgical therapy, and provide an opportunity for precise diagnosis if the surgeon is aware that histoplasmosis may provoke these dramatic surgical misadventures (our Cases No. 1 and 3). The surgeon must request special (Grocott) stains and appropriate culture of biopsied tissue to pinpoint diagnosis and direct proper definitive treatment. The primary treatment for systemic as well as gastrointestinal histoplasmosis is Amphotericin B.* The drug is given intravenously in five per cent dextrose in distilled water to a total dosage of at least 25 mg./Kg. body weight. One should begin with a low dose of 5-10 mg. daily to determine the patient’s tolerance. Dosage is increased daily to the highest dosage tolerated, up to 50 mg./day. This drug has supplanted triple sulfa, which may be of value in minor forms of the disease or mild recrudescences. Renal function must be serially monitored to guard against renal toxicity. Major recrudescences deserve additional full courses of Amphotericin B. SUMMARY
Three children with documented gastrointestinal histoplasmosis are presented and the pertinent literature reviewed. One of the patients had coexistent active histoplasmosis and coccidiomycosis. In each case operation was necessary for management of emergent complications. In two of the patients, the enteritis resembled Crohn’s disease both grossly and radiographically. These cases demonstrate the need for considering histoplasmosis as a cause of abdominal complaints, especially in endemic areas. They also document the effectiveness of Amphotericin B in treatment of gastrointestinal histoplasmosis. REFERENCES 1. Edwards, P. Q., and Palmer, C. E.: Nationwide histoplasmin sensitivity and histoplasmal infection. U.S. Pub. Health Rep. 78:241, 1963. 2. Schwarz, J. and Baum, G. L.: The history of histoplasmosis. New Eng. J. Med. 256:253, 1957. 3. Darling, S. T.: Protozoan general infection producing pseudotubercles in lungs and focal necroses in liver, spleen and lymph *Squibb,
Fungizone@
Intravenous.
nodes. JAMA 46: 1283, 1906. 4. Dodd, K., and Thompkins, E. H.: A case of histoplasmosis of Darling in an infant. Amer. J. Trop. Med. 14:127, 1934. 5. Demonbreun, W. A.: The cultivation and cultural characteristics of Darling’s histoplasma capsulatum. Amer. J. Trop. Med. 14:93, 1934. 6. Christie, A., and Peterson, J. D.: Pulmonary calcification in negative reactors to
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IN CHILDREN
tuberculin. Amer. J. Public Health 35: 1131, 1945. 7. Henderson, R. G., Pinkerton, H., and Moore, L. T.: Histoplasma capsulatum as cause of chronic ulcerative colitis. JAMA 11X:885, 1942. 8. Parsons, R. J., and Zarafonetis, C. J. D.: Histoplasmosis in man: Report of 7 cases and review of 71 cases. Arch. Int. Med. 75:l. 1945. 9. Shull, H. J.: Human histoplasmosis: Disease with protean manifestations often with digestive system involvement. Gastroenterology 25:582, 1953. 10. Van Pernis, P. A., Benson, M. E., and Hollinger, P. H.: Specific cutaneous reactions with histoplasmosis. JAMA 117:436, 1941. 11. Shaw, L. W.. Howell, A., Jr., and Weiss, E. S.: Biological assay of lots of histoplasmin and the selection of a new working lot. Pub. Health Rep. 65:583, 1950. 12. Workman, W. G., and Hottle, G. A.: Standardization of histoplasmin. Proceedings of the Conference on Histoplasmosis, 1952. Pub. No. 465, Washington, DC., U.S. Gov. Printing Office. 13. Palmer. C. E., and Edwards, P. Q.: The dose of histoplasmin H-42 for skin testing. Amer. Rev. Tuberc. 77:546, 1958. 14. lams. A. M., Tenen, M. M., and Flanagan, H. F.: Histoplasmosis in children. Amer. J. Dis. Child. 70:229, 1945. 15. Morse, T. S.. and Schultz, L.: Histoplasmosis in children. Ohio St. Med. J.
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58:429, 1962. 16. Allen, R. M.: Experimental histoplasmosis: Portal of entry of the fungus. Amer. J. Trop. Med. 28:857, 1948. 17. Demonbreun, W. A.: Infection of dog by the gastrointestinal tract. Amer. J. Trop. Med. 19:565, 1939. 18. Raftery, A.: Subclinical histoplasmosis: Gastrointestinal histoplasmosis of children. JAMA 145:216, 1951. 19. Raftery, A., Trafas, P. C.. and McClure, R. D.: Histoplasmosis: A common cause of appendicitis and mesenteric adenitis. Ann. Surg. 132:720, 1950. 20. Bank. S., Trey, C., Cans, I.. Marks. I. N.. and Groll. A.: Histoplasmosis of the small bowel with “giant” intestinal villi and secondary protein-losing enteropathy. Amer. J. Med. 39:492, 1965. 21. Collins, D. C.: The role of histoplasmosis in colonic disease. Southwest. Med. 37: 104, 1956. 22. Collins, D. C.: Histoplasmosis and the cola-proctologist. Amer. J. Proct. 7:379. 1956. 23. Collins, D. C.: Histoplasmosis and the gastroenterologist. Amer. J. Gastroenterology 27~251. 1957. 24. Collins. D. C.: Histoplasmosis: The present status in the west. Amer. J. Proct. 8:220. 1957. 25. Collins. D. C.: Histoplasmosis is a common disease of the cola-rectum. Amer. J. Proct. 16:219. 1965.
H
ISTOPLASMOSIS is a fungal infection with virtually worldwide distribution. It is relatively common in the central portion of the United States, where as many as 30 million people are estimated to have at one time acquired histoplasmosis. Specific skin tests are positive in from one per cent of residents of coastal areas to 80 per cent of those living in the drainage basins of the midcontinental rivers1 Schwarz and Baum? have outlined the historical background of the disorder, beginning with Darling’s description” of the organism (Histoplasma capsdatum) which he recovered from a terminally ill man in 1906. The diagnosis of histoplasmosis was first established in a living child by Dodd and Thompkins4 in 1934, and from this patient, Demonbreun” first cultured the organism to prove that it was a fungus rather than a protozoan. Christie and PetersonG were among the first investigators to recognize a benign form of pulmonary histoplasmosis, and to distinguish it from tuberculosis. Histoplasma capsdatum is a diphasic organism which exists as a small round yeast at body temperature, and in a mold form at lower temperatures or when it occurs in nature. Only the mycelial (mold) form has the typical rounded spores which are so characteristic of the organism. Histoplasmosis is thought to be not communicable from man to man, or from animals or birds to man. The yeast grows in soil under rather sharply defined optimal conditions of temperature and humidity, and probably is transmitted directly to man via inhalation of spores. Birds have no direct connection with histoplasmosis aside from furnishing guano for a favorable growth environment. Most investigators indict the lung as the common portal of entry in humans. Pulmonary histoplasmosis usually is manifested as a benign and self-limiting atypical pneumonia. Occasionally it occurs as a chronic calcifying or cavitary disease which resembles tuberculosis. Disseminated histoplasmosis is rare, and may run either an acute or chronic course. Patients with advanced, untreated systemic involvement often die. The reticuloendothelial systems are preferentially involved in extrapulmonary histoplasmosis, lymph nodes, liver and spleen being most commonly attacked; however, any body system may be involved. Histoplasmosis has been reported to involve all levels of the gastrointestinal tract from the oral cavity to the anus,4*7*8vQ but there seems to be a predilection for small bowel and colon. A diagnostic skin test for histoplasmosis was first described in 1941 by Van From University of Iowa, College of Medicine, Iowa City, Iowa. ROBERT T. SOPER, M.D.: Professor of Surgery, University of Zowa, College of Medicine, Iowa City, Iowa. DAVID L. SILBER, M.D.: Assistant Professor of Pediatrics, University of Iowa, College of Medicine, Iowa City, Zowa. GEORGE W. HOLCOMB, JR., M.D.: Clinical University, School of Medicine, Nashville, Assistant Professor of Surgery, Vanderbilt Tennessee. 32
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Pernis and colleagues.t(’ The skin test was further refined by the Public Health Service”,‘” and has been used in mass screening studies.‘.l” A positive skin test indicates a sensitivity to histoplasmin but does not necessarily signify infection occur to cocwith the fungus Histoplasma capsdatum, since cross reactions cidiomycoSiS, polio virus, and other agents. Furthermore, false-negative skin tests occur in patients with overwhelming histoplasmosis. Histoplasma complement-fixation antibody titers are of some help in determining infection. Rising titers support the diagnosis of active histoplasmosis and decreasing titers often are associated with improvement. Cross reactions and nonspecificity limit this test, however. Biopsy and culture of the organism are needed to make a specific diagnosis of histoplasmosis. The purpose of this paper is to call attention to the problem of gastrointestinal histoplasmosis in children with three illustrative patients who have been treated by the authors during the past few years. Each is sufficiently unique in its clinical manifestations to warrant review. CASE REPORTS Case No. I (C.E.H.), a white male. was 2-I l/12 years old when admitted to Baptist Hospital, Nashville, Tennessee, because of lethargy, fever and night sweats. Physical examination revealed a listless, pallid child with moderate abdominal distention and percussion tympany, but no organomegaly or masses. and PPD skin tests. Routine laboratory studies were normal, as were Histoplasmin X-rays revealed a fine infiltrate throughout both lung fields. Culture of the blood, throat, gastric washings and stool grew no pathogens. Barium enema was normal. The bone marrow culture eventually yielded Hisfoplasma capsrclntum. revealed mild myeloid hyperplasia; after the diagnosis was established in other ways. During this workup his condition gradually deteriorated with increasing abdominal pain and distention, bloody stools and fever dominating the picture. On the eighth hospital day roentgenograms revealed an air-fluid level in the peritoneal cavity with free air under the diaphragm. A tentative diagnosis of a perforated duodenal ulcer was made and exploratory laparotomy was carried out. The duodenum and appendix were normal. A S-mm. perforation was found in the distal ileum, and in addition, there were several areas of circular scarring of the serosal surface of the small intestine with apparent ulceration through the entire thickness of the bowel except for the serosa; these areas were imbricated to prevent perforation. The site of perforation was resected and the bowel was anastomosed. A mesenteric node showed intracytoplasmic organisms having the morphologic characteristics of Histoplrrsmrr CNJ).YII/aturn. The ileum at the site of perforation had a granulomatous inflammatory reaction. At one point in the subserosa, phagocytic cells containing structures resembling Hi.vtop/!c.rnrrr were found. Penicillin and streptomycin were given; later, when culture and histologic evidence of histoplasmosis was found, Amphotericin B was given intravenously for a period of seven days. The postoperative course was stormy with persistent temperature elevation until 72 hours after Amphotericin was begun. The child was maintained on intravenous fluids for the first ten postoperative days. On the 16th postoperative day abdominal wound dehiscence required surgical closure. At the same time a feeding gastrostomy was performed. A mesenteric lymph node on microscopy showed yeasts with the morphology of Hisfophmcc capsulafum. Culture of a portion of the stomach grew Histoplasma capsulatum. The child then began to improve. Body weight increased from 31 lb. (14 Kg.) to 35 lb. ( 16 Kg.). A second eight-day course of Amphotericin was administered. Three weeks before discharge, triple sulfa suspension was begun. Total hospitalization was 60 days. At discharge he was clinically improved, active and eating well. X-rays of the chest showed no change but all other laboratory studies were normal.
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During the subsequent three years, repeated episodes of bacterial furunculosis have been treated by drainage and antibiotics. Studies have not incriminated histoplasmosis in these abscesses, nor is there evidence of an impaired immunological response. Thirteen months after operation he was admitted with symptoms suggesting recurrence of his intestinal problems: fever, malaise, loss of appetite and abdominal distention. His abdominal complaints disappeared with therapy for constipation; however, on X-rays of the chest there was an increase in pulmonary infiltrate and another course of Amphotericin was administered. He showed progressive improvement and to date has done well with the exception of the furunculosis. Case No. 2 (T.M.F.), a white male, was 10 years old when first seen at the University of Iowa Hospitals in 1962 because of fever, adenopathy, chest pain and cough. Chest X-rays showed bilateral hilar adenopathy with a right lower lobe infiltrate. Coccidiomycosis was proven by cervical lymph node biopsy and a specific complement-fixation antibody titer of 1:4096. After intravenous Amphotericin B was given, he became afebrile and the lung X-rays improved, He was readmitted in July 1966, because of abdominal pain and tenderness, constipation, and shotty lymphadenopathy. Constipation was alleviated with medications, after which his abdominal pain decreased somewhat. Upper GI X-rays were normal, but chest X-rays showed some increase in hilar adenopathy. A diagnosis of systemic histoplasmosis was made by remarkably elevated and rising complement-fixing antibodies, and a seven-month course of triple sulfa was begun. In June 1968, he developed periumbilical pain with radiation to the back. Because eating sometimes triggered the pain, he had reduced his food intake and lost weight. He denied vomiting or diarrhea. He was a thin, withdrawn lW’z-year-old boy with palpable cervical lymph nodes. The abdomen was tender and guarded with no masses. Hemogram, urinalysis, chest and plain abdominal X-rays, IVP, and lumbar puncture were negative or normal. Histoplasmosis antibody titers were 1: 1024, and the coccidiomycosis titer was 1:64. Complete GI barium studies showed narrowing of the terminal ileum (Fig. 1) with irregular mucosa and some fixation of the surrounding bowel loops. This prompted the radiographic diagnosis of regional ileitis (Crohn’s disease). Sigmoidoscopy was unremarkable. Biopsy of a right cervical lymph node showed coccidioides organisms as well as ovoid budding fungal cells compatible with Histoplasma capsdatum. Laparotomy was performed to pinpoint the cause of the ileal narrowing. Mesenteric lymph nodes as large as 5-7 cm. in diameter were found, most prominent in the mesentery draining the terminal ileum and there was subacute enteritis involving a segment of jejunum
Fig. l.Spot film of barium enema in case #2 showing narrowed distal ileum with ragged mucosa suggestive of Crohn’s disease.
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and proximal ileum. The distal 10 cm. of ileum was indurated, thickened, injected and adherent to the posterior peritoneum suggestive grossly of Crohn’s disease. Biopsy of the liver and a mesenteric lymph node showed non-caseating granulomas with giant cells and mononuclear cells; intracellular Histoplasma organisms were demonstrated by PAS and Grocott stains. Histoplasmn capsdatum was grown from sputum and urine. as well as from the mesenteric lymph node and the liver. Amphotericin B was given by intravenous infusions for 40 days. The abdominal pain gradually improved. Repeat gastrointestinal barium studies showed improvement of the involved ileum. Four months postoperatively, the urine, sputum and blood cultures were negative. He was 13-Kg. heavier than at operation, had no adenopathy or abdominal pain. and was purusing normal school activities. Physical examination and routine blood studies were normal. Case No. 3 (V.L.O.), a white female, was nine years old when fever, lymphadenopathy and a questionable abdominal mass developed. Cervical lymph node biopsy showed Hisfoplasma cnpsulatum. She was treated with sulfa and Amphotericin B and did well for three years. Recurrent histoplasmosis was heralded by cervical lymphadenopathy, fever, weight loss and elevation of complement-fixation antibody titers. Triple sulfa was given for six months with improvement. At 13 years, abdominal pain, bilious vomiting, weight loss and fever prompted referral to the University of Iowa Hospitals. She was a thin, alert female with enlarged cervical lymph nodes bilaterally. There was chemical and X-ray evidence of partial mechanical obstruction of the jejunum. An upper GI study showed dilatation of the duodenum and a few loops of jejunum with prominence of the mucosal pattern and segmentation of the barium (Fig. 2a). Barium enema was normal. Laparotomy revealed partial obstruction proximal to an 18-cm. segment of midjejunum which showed thickening, edema, induration, injection of the subserosal vessels (Fig. 2b). and enlargement of the adjacent mesenteric lymph nodes resembling Crohn’s disease. There were four other areas from 7 to 30 cm. in length similarly involved with intervening normal bowel. The proximal area of obstructing jejunitis was excised and a mesenteric lymph node was biopsied. The resected bowel wall was thickened and the mucosa had a cobblestone appearance. Histologically. there was granulomatous inflammation involving the mucosa, submucosa and muscularis (Fig. 2~). Numerous Histoplusma capsulatum organisms were identified, mostly in extracellular clusters (Fig. 2d). There was granulomatous involvement submucosally at both of the resection margins, where the bowel appeared grossly normal. The mesenteric lymph nodes showed fibrosis and small amounts of chronic granulomatous inflammation with numerous Histoplnsma capsdatum organisms. Cultures of bowel and mesenteric lymph nodes ultimately grew Histoplusmu capsdatum. The patient’s postoperative course was unremarkable; she tolerated well a course of intravenous Amphotericin B. and she remains free of gastrointestinal symptoms to date. DISCUSSION In 1945, Iams and co-workersI reported 21 cases of histoplasmosis in children. They stressed the lack of specificity of symptoms in the very young patient with histoplasmosis. Eleven of their patients had gross gastrointestinal tract lesions, and histologic evidence of gastrointestinal histoplasmosis was present in 13 cases. Morse and Schultzl” reported 30 children with histoplasmosis in 1962. They emphasized the gravity of the disease in the young patient, with a mortality rate of 40 per cent in their patients under the age of four years. None of these children had documented involvement of the gastrointestinal system, although two had abdominal pain as presenting complaints.
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obstructed loop of Fig. Za.- Late motor meal X-ray showing dilated, partially jejunum with ragged, edematous mucosa. Much barium has passed into colon. Fig. 2b.-Gross appearance at operation of acute jejunitis due to histoplasmosis, producing bowel obstruction. Fig, 2c.-Acute granulomatous jejunitis, low-power view (H&E). Submucosa especially thickened and inflamed. Fig. 2d.-High-power view of jejunal wall, Grocott’s stain; silver stain taken up by Histupk~sma capsulutum organisms, some within giant cells.
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Most investigators feel that the reticuloendothelial tissue of the gastrointestinal tract and mesenteric nodes are secondarily involved from a primary pulmonary site of entry. Gastrointestinal entry of Histoplasma capsdatum has Whether hubeen experimentally demonstrated by Allenl” and Demonbreun.l? mans acquire gastrointestinal histoplasmosis by ingestion of the organisms is unknown, Histologically, the lesions of gastrointestinal histoplasmosis are characterized by noncaseating granulomatous inflammation, similar to that seen in Crohn’s disease. The organisms generally lie within macrophages and giant cells, and are best seen with Grocott stain. Submucosal lymphoid tissue and mesenteric lymph nodes seem to be the earliest and most commonly involved structures. Raftery lx~l!’ has reported finding the organisms and characteristic inflammation in the appendix and mesenteric lymph nodes as the only manifestation of histoplasmosis. He found such evidence in 10 per cent of 436 appendices surgically removed in children 16 years of age and under, and in 40 per cent of nodes excised from patients with the clinical diagnosis of mesenteric adenitis. Culture confirmation is lacking in these cases, and is necessary for definitive, specific diagnosis. Only the surgeon can provide tissue for appropriate culture. Collins”‘-“” has pointed out an alarmingly high percentage of patients with a variety of gastrointestinal tract lesions which may be due to histoplasmosis. He found histologic, cultural or serologic evidence of histoplasmosis in 52.6 per cent of patients with juvenile mesenteric lymphadenitis, 37.5 per cent of patients with chronic ulcerative colitis, 1 I .5 per cent of patients with nonspecific anorectal inflammatory diseases, and 9.8 per cent of patients with other inflammatory colonic disease. He also found evidence of histoplasmosis in 7.X per cent of 50,000 consecutive unselected specimens of the vermiform appendix. In 151 patients with juvenile mesenteric adenitis, Collins found positive histoplasmin skin tests in 85 per cent and typical diffuse “birdshot” calcifications in the lung parenchyma compatible with pulmonary histoplasmosis in 61 per cent. He makes an impassioned plea for specific histologic and cultural search for histoplasmosis in patients with these gastrointestinal diseases. Again, it is the surgeon’s responsibility to request these studies on biopsy material. With these exceptions, most authors describe gastrointestinal histoplasmosis in association with widespread and serious systemic histoplasmosis. Fever, weight loss, anorexia, and cramping abdominal discomfort are common nonspecific complaints in these patients. Dysphagia, diarrhea, constipation, vomiting, and protein-losing enteropathy”” are also described. Acute abdominal complaints may dominate the picture, such as hemorrhage, perforation (our Case No. I ) and mechanical obstruction (our Case No. 3). Gastrointestinal histoplasmosis may be suspected in patients with digestive complaints who are known to have pulmonary or systemic histoplasmosis. On occasion, rectal or oral mucosal lesions or accessible lymph nodes provide histologic and cultural confirmation of diagnosis, eliminating the need for laparotomy. Gastrointestinal X-rays are not specific. The intestinal ulcerations often are small and superficial, and may not be seen radiographically. Either ulcerating or constricting lesions can be found. A “cobblestone” mucosal appearance.
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pseudopolypoid irregularity, puddling, and spasm all have been described. Free intraperitoneal air or mechanical obstruction are dramatic, but nonspecific, findings. Radiographic changes typical for chronic ulcerative colitis and Crohn’s disease (our Case No. 2) also have been reported in patients with gastrointestinal histoplasmosis. It is interesting to speculate what proportion of patients with ulcerative colitis or Crohn’s disease actually have histoplasmosis colitis or enteritis. Laparotomy is justified for confirmation of gastrointestinal histoplasmosis when a specific diagnosis cannot otherwise be made (our Case No. 2), in view of the prolonged and somewhat dangerous nature of medical treatment. Of course, surgical complications (massive hemorrhage, intestinal obstruction, free perforation) demand surgical therapy, and provide an opportunity for precise diagnosis if the surgeon is aware that histoplasmosis may provoke these dramatic surgical misadventures (our Cases No. 1 and 3). The surgeon must request special (Grocott) stains and appropriate culture of biopsied tissue to pinpoint diagnosis and direct proper definitive treatment. The primary treatment for systemic as well as gastrointestinal histoplasmosis is Amphotericin B.* The drug is given intravenously in five per cent dextrose in distilled water to a total dosage of at least 25 mg./Kg. body weight. One should begin with a low dose of 5-10 mg. daily to determine the patient’s tolerance. Dosage is increased daily to the highest dosage tolerated, up to 50 mg./day. This drug has supplanted triple sulfa, which may be of value in minor forms of the disease or mild recrudescences. Renal function must be serially monitored to guard against renal toxicity. Major recrudescences deserve additional full courses of Amphotericin B. SUMMARY
Three children with documented gastrointestinal histoplasmosis are presented and the pertinent literature reviewed. One of the patients had coexistent active histoplasmosis and coccidiomycosis. In each case operation was necessary for management of emergent complications. In two of the patients, the enteritis resembled Crohn’s disease both grossly and radiographically. These cases demonstrate the need for considering histoplasmosis as a cause of abdominal complaints, especially in endemic areas. They also document the effectiveness of Amphotericin B in treatment of gastrointestinal histoplasmosis. REFERENCES 1. Edwards, P. Q., and Palmer, C. E.: Nationwide histoplasmin sensitivity and histoplasmal infection. U.S. Pub. Health Rep. 78:241, 1963. 2. Schwarz, J. and Baum, G. L.: The history of histoplasmosis. New Eng. J. Med. 256:253, 1957. 3. Darling, S. T.: Protozoan general infection producing pseudotubercles in lungs and focal necroses in liver, spleen and lymph *Squibb,
Fungizone@
Intravenous.
nodes. JAMA 46: 1283, 1906. 4. Dodd, K., and Thompkins, E. H.: A case of histoplasmosis of Darling in an infant. Amer. J. Trop. Med. 14:127, 1934. 5. Demonbreun, W. A.: The cultivation and cultural characteristics of Darling’s histoplasma capsulatum. Amer. J. Trop. Med. 14:93, 1934. 6. Christie, A., and Peterson, J. D.: Pulmonary calcification in negative reactors to
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tuberculin. Amer. J. Public Health 35: 1131, 1945. 7. Henderson, R. G., Pinkerton, H., and Moore, L. T.: Histoplasma capsulatum as cause of chronic ulcerative colitis. JAMA 11X:885, 1942. 8. Parsons, R. J., and Zarafonetis, C. J. D.: Histoplasmosis in man: Report of 7 cases and review of 71 cases. Arch. Int. Med. 75:l. 1945. 9. Shull, H. J.: Human histoplasmosis: Disease with protean manifestations often with digestive system involvement. Gastroenterology 25:582, 1953. 10. Van Pernis, P. A., Benson, M. E., and Hollinger, P. H.: Specific cutaneous reactions with histoplasmosis. JAMA 117:436, 1941. 11. Shaw, L. W.. Howell, A., Jr., and Weiss, E. S.: Biological assay of lots of histoplasmin and the selection of a new working lot. Pub. Health Rep. 65:583, 1950. 12. Workman, W. G., and Hottle, G. A.: Standardization of histoplasmin. Proceedings of the Conference on Histoplasmosis, 1952. Pub. No. 465, Washington, DC., U.S. Gov. Printing Office. 13. Palmer. C. E., and Edwards, P. Q.: The dose of histoplasmin H-42 for skin testing. Amer. Rev. Tuberc. 77:546, 1958. 14. lams. A. M., Tenen, M. M., and Flanagan, H. F.: Histoplasmosis in children. Amer. J. Dis. Child. 70:229, 1945. 15. Morse, T. S.. and Schultz, L.: Histoplasmosis in children. Ohio St. Med. J.
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58:429, 1962. 16. Allen, R. M.: Experimental histoplasmosis: Portal of entry of the fungus. Amer. J. Trop. Med. 28:857, 1948. 17. Demonbreun, W. A.: Infection of dog by the gastrointestinal tract. Amer. J. Trop. Med. 19:565, 1939. 18. Raftery, A.: Subclinical histoplasmosis: Gastrointestinal histoplasmosis of children. JAMA 145:216, 1951. 19. Raftery, A., Trafas, P. C.. and McClure, R. D.: Histoplasmosis: A common cause of appendicitis and mesenteric adenitis. Ann. Surg. 132:720, 1950. 20. Bank. S., Trey, C., Cans, I.. Marks. I. N.. and Groll. A.: Histoplasmosis of the small bowel with “giant” intestinal villi and secondary protein-losing enteropathy. Amer. J. Med. 39:492, 1965. 21. Collins, D. C.: The role of histoplasmosis in colonic disease. Southwest. Med. 37: 104, 1956. 22. Collins, D. C.: Histoplasmosis and the cola-proctologist. Amer. J. Proct. 7:379. 1956. 23. Collins, D. C.: Histoplasmosis and the gastroenterologist. Amer. J. Gastroenterology 27~251. 1957. 24. Collins. D. C.: Histoplasmosis: The present status in the west. Amer. J. Proct. 8:220. 1957. 25. Collins. D. C.: Histoplasmosis is a common disease of the cola-rectum. Amer. J. Proct. 16:219. 1965.