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Disseminated Mycobacterium aviumintracellulare Infection in Acquired Immunodeficiency Syndrome Mimicking Whipple's Disease
GASTROENTEROLOGY 1983;85:1187-91
Disseminated Mycobacterium aviumintracellulare Infection in Acquired Immunodeficiency Syndrome Mimicking Whipple's Disease J.
SCOTT GILLIN, CARLOS URMACHER, REARDON WEST, and MOSHE SHIKE
Departments of Medicine and Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
We report a patient with acquired immunodeficiency syndrome whose clinical presentation and histologic features resembled Whipple's disease. The unique feature of this case was the absence of Whipple's bacillus and the presence of Mycobacterium avium-intracellulare within macrophages infiltrating the smaIl intestinal lamina propria. In 1907, Whipple described a case initially believed to represent mesenteric tuberculosis but which at autopsy revealed large deposits of fat within the intestinal submucosa and mesenteric lymph nodes. An associated finding was the presence of 2-JLm-Iong rod-shaped structures "resembling the tubercle bacillus" contained within peculiar, foamy, mononuclear cells located within submucosa and lymph nodes (1). Not until the 1960s was the presence of rod-shaped structures in affected tissues confirmed and identified as bacterial in nature (2,3). With electron microscopy, these bacilli have been demonstrated to be small (0.25 JLm x 1.5-2.5 JLm), to be gram-positive, to possess a unique outer membrane external to their cell wall, to undergo binary fission , to exist in variable states of intracellular digestion, and to disappear after antibiotic therapy (4). It is believed that degenerating masses of these organisms represent the periodic acid-Schiff (PAS) positivity of the macrophages of Whipple's disease (2,3). Attempts to identify Whipple's bacilli have isolat-
Received December 3.1982 . Accepted May 17 , 1983. Address requests for reprints to: Moshe Shike, M.D., Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021. This work was supported by grants 1 P 30 CA-29502 and CA20449 from the National Institutes of Health. © 1983 by the American Gastro enterological Association 0016-5085/83/$3. 00
ed viridans streptococci, group D streptococci, Lforms of streptococci, anaerobic Corynebacteria, Listeria, Hemophilis, KlebsieIla, SalmoneIla, and Shigella (5-13). More recently, immunohistochemical examination of bacterial antigens has implicated streptococcal species in the pathogenesis of the disease (14-16). To date, however, the identity of Whipple's bacillus remains unclear. Recently, it has been found that patients with Whipple's disease may have a defect in cellular immunity (17). The following case is unique in that despite clinical, immunologic, and light microscopic features similar to Whipple's disease, the inciting organism is not Whipple's bacillus but Mycobacterium avium-intraceIIulare, a frequent opportunistic infection in acquired immunodeficiency syndrome.
Case Report A 39-yr-old white, homosexual male was admitted to Memorial Hospital for evaluation of chronic diarrhea. The patient, who averaged 80 different homosexual partners per year, was well until June 1981, when 10-15 watery, nonbloody bowel movements per day developed. He noted an associated low-grade fever, inguinal adenopathy, and a pruritic skin rash. Evaluation elsewhere led to a diagnosis of amebiasis and giardiasis. Despite treatment with diiodohydroxyquin and quinacrine hydrochloride, his diarrhea continued. Pneumocystis carinii pneumonia developed in July 1981, requiring prolonged mechanical ventilation. He responded to intravenous trimethoprimsulfamethoxazole therapy. Biopsy of an inguinal lymph node showed hyperplasia and did not take up acid-fast stain. Persistent diarrhea and weight loss led to further evaluation in January 1982. Stool examination was positive for occult blood but negative for leukocytes, ova, and parasites. Stool cultures grew predominantly Candida species. Barium enema, upper GI and small bowel series, and
GASTROENTEROLOGY Vol. 85, No.5
1188 GILLIN ET AL.
Table 1. Malabsorption Studies Test
Patient
Control
72-h stool fecal fat (g/24 h) ['4Cjtriglyceride breath test" D-xylose (mg% in urine at 5 h) Serum carotene (JLg%) Serum 25-hydroxyvitamin D (ng/ml)
58.5 4 0.9 12 11
<7 >60 >5 50-300 10-55
° 14C02, % dose, in expired air 4 h after 6.4 JLCi (0.1 JLCi/kg body wt) of 14C-Iabeled glycerol tripalmitinin per os at time zero
colonoscopy were normal. He was discharged on a prophylactic regimen of trimethoprim-sulfamethoxazole and ketoconazole. The patient was admitted to Memorial Hospital in April 1982, complaining of diarrhea, fever, and a 30-lb weight loss. He denied arthralgias. There was no history of illicit drug use or previous exposure to tuberculosis. Examination revealed a thin, chronically ill-appearing man with a temperature of 39°C. The lungs were clear. A 2/6 systolic murmur was heard at the left sternal border. Abdominal examination showed hepatomegaly without evidence of ascites. Rectal exam revealed two perianal ulcerations. Firm lymph nodes were palpated in the inguinal and axillary areas. A maculopapular rash was seen on the trunk and the lower extremities. There were no joint abnormalities. Neurologic examination demonstrated memory loss, episodic disorientation, and cognitive deficits. Laboratory data included a hemoglobin of 7.3 mg/dl; a white blood cell count of 2100 cells/mm 3 (80% polymorphonuclear leukocytes, 6% lymphocytes, 8% monocytes, 4% eosinophils, and 2% basophils); and a platelet count of 152,000 cells/mm 3 • The erythrocyte sedimentation rate was 70 mm/h (normal 0-9 mm/h). Additional blood tests showed serum glutamic oxaloacetic transaminase (SGOT) 26 u/L (normal 0-25 U/L); alkaline phosphatase 171 U/L (normal 30-115 U/L); protein 5.9 g/dl (normal 6.3-8.1 g/dl); albumin 2.8 g/dl (normal 4.0-5.2 g/dl). Blood and urine cultures were negative. Stool cultures grew predominantly Candida species. The chest radiograph was normal. Absorption tests, as shown in Table 1, were markedly abnormal. Studies of immunity, shown in Table 2, were consistent with acquired immunodeficiency syndrome (AIDS). The patient underwent esophagogastroduodenoscopy, which showed minute superficial ulcerations throughout the duodenum. Biopsy of the distal duodenum showed numerous PAS-positive diastase-resistant macrophages throughout the mucosa (Figure 1). Acid-fast stain revealed bacilli within these macrophages and free in the lamina propria (Figure 2). This was confirmed ultrastructurally by the electron microscopic demonstration of intact rodshaped bacilli with waxy cell walls within the macrophages (Figure 3). This appearance was felt to be consistent with mycobacterial species. Initial cultures of the small intestinal biopsy grew a few colonies of enterococci, viridans streptococci, and Candida albicans. There was no growth of mycobacterial species. Biopsies of the liver and colon also stained positive
for acid-fast bacilli, but again initial culture results showed no mycobacterial growth. A bone marrow aspirate and biopsy revealed numerous granulomata but no acidfast organisms. A lumbar puncture, electroencephalogram, and computerized transaxial tomography of the brain were negative. The patient was begun on isoniazid, rifampin, and ethambutol because of the presumptive diagnosis of disseminated mycobacteriosis. Trimethoprim-sulfamethoxazole and ketoconazole were continued. On the ninth hospital day, he developed a herpetic facial eruption and was treated with intravenous 2' -fluoro-5-iodo-{3-o-arabinofuranosylcytosine (FIAC). Because of severe malabsorption and malnutrition, total parenteral nutrition was started. On the 17th hospital day, he became hypotensive with bilateral pulmonary infiltrates and renal insufficiency. Upon transfer to the intensive care unit, he was placed on mechanical ventilation, peritoneal dialysis, and pressor agents. Ethambutol was discontinued, and clofazimine, moxalactam, amikacin, and amphotericin B were added. Generalized seizures were treated with diphenylhydantoin. On the next day, the patient died. Postmortem examination revealed disseminated acidfast infection involving small intestine, lymph nodes, liver, spleen, heart, kidneys, and lungs. Periodic acidSchiff-positive macro phages were present in lymph nodes and the small bowel mucosa. The lungs contained pseudohyphae consistent with Candida and intranuclear inclusions within alveolar cells consistent with cytomegalovirus. Of interest was the presence of a multifocal demyelinating leukoencephalopathy of undetermined etiology that was felt to be responsible for the neurologic symptomatology.
Table 2. Immunologic Profile Test Skin test PPD SKSD Mumps Dermatophyton 0 Absolute lymphocyte count per mm 3 T cell (%J B cell (%J Lymphocyte to proliferati ve response o Phytohemagglutinin con A Pokeweed mitogen Serum immunoglobulins (mg%J IgG IgA IgM IgE
Patient nonreactive nonreactive nonreactive nonreactive 126
Control
{ 98% respond to at least one 900-4400
37 34
55-75 15-25
1376 384 104
>17,000 >8900 >3500
1383 436 95 35
800-1800 90-450 60-250 10-256
PPD = purified protein derivative. SKSD =, streptokinase/streptodornase. con A = concanavalin A. Net counts per minute of tritiated thymidine incorporated after 3 days' incubation for phytohemagglutinin and con A; after 5 days' incubation for pokeweed mitogen. 0
November 1983
AIDS MIMICKING WHIPPLE'S DISEASE
1189
Figure 1. Dense infiltration of the small intestinal lamina propria by macro phages (H&E, x40). These macro phages also exhibited PAS-positive diastase-resistant staining.
After completion of the autopsy, cultures from blood grew Mycobacterium nvium-intracellulare.
Discussion The clinical presentation of this case initially suggested the diagnosis of Whipple's disease. Supporting this diagnosis were chronic malabsorption and progressive weight loss, low-grade fever, and the light microscopic features of the small intestine after
Figure 2. Small intestinal macrophages with numerous acid-fast rods packing the cytoplasm (ZiehlNeelsen, x 100).
H&E and PAS staining. The patient also demonstrated immune abnormalities consistent with acquired immunodeficiency syndrome (AIDS). Characteristic immunologic findings in AIDS include lymphopenia, reduction in the number of helper T cells with normal or increased proportion of suppressor lymphocytes, impaired lymphocyte proliferation to mitogens, and skin test anergy (18-20). Immunologic abnormalities recently reported in Whipple's disease include phytohemagglutinin unresponsiveness (21), decreased macrophage processing (22), and altered
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GASTROENTEROLOGY Vol. 85 , No. 5
Figure 3. Electron micrograph of the intestinal macrophage demonstrating rod-shaped organisms wi th thick electron lucent cell walls. The organisms, seen in longitudinal and cross section, appear to be intact without varying degrees of digestion ( X 6000) .
T-cell macrophage interactions (23). Three cases studied after therapy have shown decreased numbers of peripheral blood lymphocytes (24). A review by Dobbins of studies reported since 1971 reveals no demonstrable defect in humoral immunity but consistent T-cell abnormalities before and after therapy (17). Whipple's disease and AIDS, therefore, appear to share an immune defect characterized predominantly by a depression in T-cell function. Despite these similarities, an important difference between this case and Whipple 's disease is the presence of M. avium-intracellulare within the macrophages packing the lamina propria of the small intestine. The absence of the typical Whipple's bacillus was confirmed by electron microscopy (Figure 3). In contrast to Whipple's disease, the intracellular M. avium-intracellulare appear to exist intact without various degrees of dissolution. The PAS reaction of macrophages in our patient, although not as intense as seen in classical cases of Whipple's disease , is probably due to the densely packed mycobacteria rather than to degenerating components of bacilli, as in Whipple's disease. This finding suggests that defective macrophage processing of these pathogens may lead to the same accumulation of
mactophages and secondary malabsorption as is classically seen in Whipple's disease. Defective Tcell activation of macro phages has likewise been proposed as a mechanism in the pathogenesis of Whipple's disease (25). In foals, Corynebacterium equi, an organism distinct from Whipple 's bacillus on electron microscopy, also causes intense infiltration of the intestine and mesenteric lymph nodes with PAS-positive macrophages (26). It is, therefore, conceivable that a number of different organisms may induce similar morphologic and functional changes in the small intestine. Although Whipple's bacillus could have been absent from our specimens because of continuous therapy with trimethoprim-sulfamethoxazole, the persistent malabsorption suggests that a. macrophage response to ongoing M. avium-intracellulare infection was responsible for the findings in this case . The recent recognition of association between AIDS and disseminated M . avium-intracellulare infection has been a subject of intense investigation (27,28). We are not aware of previous cases in which M. avium-intracellulare has been cultured from the small intestine or of reports implicating mycobacte-
November 1983
rial species in the pathogenesis of Whipple's disease. Kuhajda and associates (29) reported a submucosal variant of Whipple's disease in a patient treated for Mycobacterium tuberculosis. However, autopsy specimens of the small bowel showed no mycobacteria but did reveal bacillary bodies compatible with Whipple's bacillus. In summary, we report a patient with AIDS and chronic malabsorption associated with light microscopic findings similar to those observed in Whipple's disease. Only after acid-fast staining and electron microscopy was M. avium-intracellulare identified within macro phages of the small intestinallamina propria. The similar immunologic abnormalities in this patient and in some cases of Whipple's disease suggest a role for immunodeficiency in the development of the mucosal macrophage infiltration. Although Whipple's bacillus is a distinctive organism associated with classic Whipple's disease, we propose that other intracellular pathogens in appropriate hosts may incite histologic changes that result in malabsorption with a clinical picture similar to Whipple's disease.
References 1. Whipple GI. A hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal and mesenteric lymphatic tissues. Bull Johns Hopkins Hosp 1907;18:382-5. 2. Chears WC, Ashworth CT. Electron microscopic study of the intestinal mucosa in Whipple's disease. Gastroenterology 1961;41:129-37. 3. Yardley JH, Hendrix TR. Combined electron and light microscopy in Whipple's disease. Bull Johns Hopkins Hosp 1961;109:80-96. 4. Dobbins WO, Kawanishi H. Bacillary characteristics in Whipple's disease: an electron microscopic study. Gastroenterology 1981;80:1468-75. 5. Clancy RL, Tompkins WAF, Muckle TJ, Richardson H, Rawls WE. Isolation and characterization of an etiologic agent in Whipple's disease. Br Med J 1975;3:568-70. 6. Kirkpatrick PM, Kent SP, Mihas A, Pritchett P. Whipple's disease: a case report with immunologic studies. Gastroenterology 1978;74:297-301. 7. Tytgat GN, Hoogendijk JL, Agenant D, Schellekeus PT. Etiopathogenetic studies in a patient with Whipple's disease. Digestion 1977;15:309-21. 8. Dybkaer R. The diagnosis, pathogenesis, and treatment of Whipple's disease illustrated by 2 cases. Dan Med Bull 1965;12:138-44. 9. Greenberger NJ, Delor J, Fisher J, et al. Whipple's disease. Characterization of anaerobic corynebacteria and demonstration of bacilli in vascular endothelium. Am J Dig Dis 1971;16:1127-36. 10. Kent TH, Layton JM, Clifton JA, Schedl HP. Whipple's dis-
AIDS MIMICKING WHIPPLE'S DISEASE
1191
ease. Light and electron microscopic studies combined with clinical studies suggesting an infective nature. Lab Invest 1963;12:1163-78. 11. Kjerheim A, Midtvedt T, Skrede S, Gjone E. Bacteria in Whipple's disease. Acta Pathol Microbiol Scand 1966; 66:135-42. 12. Knox DL, Bayless TM, Yardley JH, Charache P. Whipple's disease presenting with ocular inflammation and minimal intestinal symptoms. Johns Hopkins Med J 1968;123:175-82. 13. Charache P, Bayless TM, Shelley WM. Atypical bacteria in Whipple's disease. Trans Assoc Am Physicians 1966;79:399408. 14. Keren DF, Weisburger WR, Yardley JH, Salyer WR, Arthur RR, Charache P. Whipple's disease: demonstration by immunofluorescence of similar bacterial antigens in macrophages from 3 cases. Johns Hopkins Med J 1976;139:51-9. 15. Kent SP, Kirkpatrick PM. Whipple's disease. Immunologic and histochemical studies of 8 cases. Arch Pathol Lab Med 1980;104:544-7. 16. Du Boulay CEH. An immunohistochemical study of Whipple's disease using the immunoperoxidase technique. Hum PathoI1982;13:925-9. 17. Dobbins WOo Is there an immune defect in Whipple's disease? Dig Dis Sci 1981;26:247-52. 18. Gottlieb MS, Schroff R, Schanker HM, et al. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. N Engl J Med 1981;305:1425-31. 19. Siegal FP, Lopez C, Hammer GS, et al. Severe acquired immunodeficiency in male homosexuals manifested by chronic perianal ulcerative herpes simplex lesions. N Engl J Med 19J1;305:1439-44. 20. Stahl RE, Friedman-Kien A, Dubin R, Maraor M, Zolla-Pazner S. Immunologic abnormalities in homosexual men. Am J Med 1982;73:171-8. 21. Maxwell JD, Fergueson A, McKay AM, Imrie RL, Watson WC. Lymphocytes in Whipple's disease. Lancet 1968;i:887-9. 22. Maizel H, Ruffin JM, Dobbins WOo Whipple's disease: a review of 19 patients from one hospital and a review of the literature since 1950. Medicine 1970;49:175-205. 23. Groll A, Valberg LS, Simon JB, Eidinger D, WHson B, Forsdyte DR. Immunologic defect in Whipple's disease. Gastroenterology 1972;63:943-50. 24. Keren DF, Weinrieb MJ, Bertovitch MJ, Brady PG. Whipple's disease: no consistent mitogenic or cytotoxic defect in lymphocyte function from 3 cases. Gastroenterology 1979; 77:991-6. 25. Dobbins WOo Current concepts of Whipple's disease. J Clin Gastroenterol 1982;4:205-8. 26. Cimprich RE, Rooney JR. Corynebacterium equi enteritis in foals. Vet Pathol 1977;14:95-102. 27. Fainstein V, Boliran R, Mavligit G, Rios A, Luna M. Disseminated infection due to Mycobacterium avium-intracellulare in a homosexual man with Kaposi's sarcoma. J Infect Dis 1982;145:586. 28. Greene JB, Sidhu GS, Lewin S, et al. Mycobacterium aviumintracellulare: a cause of disseminated life-threatening infection in homosexuals and drug abusers. Ann Intern Med 1982;97:539-46. 29. Kuhajda FP, Belitsos NJ, Keren DF, Hutchins GM. A submucosal variant of Whipple's disease. Gastroenterology 1982; 82:46-50.
Disseminated Mycobacterium aviumintracellulare Infection in Acquired Immunodeficiency Syndrome Mimicking Whipple's Disease J.
SCOTT GILLIN, CARLOS URMACHER, REARDON WEST, and MOSHE SHIKE
Departments of Medicine and Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
We report a patient with acquired immunodeficiency syndrome whose clinical presentation and histologic features resembled Whipple's disease. The unique feature of this case was the absence of Whipple's bacillus and the presence of Mycobacterium avium-intracellulare within macrophages infiltrating the smaIl intestinal lamina propria. In 1907, Whipple described a case initially believed to represent mesenteric tuberculosis but which at autopsy revealed large deposits of fat within the intestinal submucosa and mesenteric lymph nodes. An associated finding was the presence of 2-JLm-Iong rod-shaped structures "resembling the tubercle bacillus" contained within peculiar, foamy, mononuclear cells located within submucosa and lymph nodes (1). Not until the 1960s was the presence of rod-shaped structures in affected tissues confirmed and identified as bacterial in nature (2,3). With electron microscopy, these bacilli have been demonstrated to be small (0.25 JLm x 1.5-2.5 JLm), to be gram-positive, to possess a unique outer membrane external to their cell wall, to undergo binary fission , to exist in variable states of intracellular digestion, and to disappear after antibiotic therapy (4). It is believed that degenerating masses of these organisms represent the periodic acid-Schiff (PAS) positivity of the macrophages of Whipple's disease (2,3). Attempts to identify Whipple's bacilli have isolat-
Received December 3.1982 . Accepted May 17 , 1983. Address requests for reprints to: Moshe Shike, M.D., Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021. This work was supported by grants 1 P 30 CA-29502 and CA20449 from the National Institutes of Health. © 1983 by the American Gastro enterological Association 0016-5085/83/$3. 00
ed viridans streptococci, group D streptococci, Lforms of streptococci, anaerobic Corynebacteria, Listeria, Hemophilis, KlebsieIla, SalmoneIla, and Shigella (5-13). More recently, immunohistochemical examination of bacterial antigens has implicated streptococcal species in the pathogenesis of the disease (14-16). To date, however, the identity of Whipple's bacillus remains unclear. Recently, it has been found that patients with Whipple's disease may have a defect in cellular immunity (17). The following case is unique in that despite clinical, immunologic, and light microscopic features similar to Whipple's disease, the inciting organism is not Whipple's bacillus but Mycobacterium avium-intraceIIulare, a frequent opportunistic infection in acquired immunodeficiency syndrome.
Case Report A 39-yr-old white, homosexual male was admitted to Memorial Hospital for evaluation of chronic diarrhea. The patient, who averaged 80 different homosexual partners per year, was well until June 1981, when 10-15 watery, nonbloody bowel movements per day developed. He noted an associated low-grade fever, inguinal adenopathy, and a pruritic skin rash. Evaluation elsewhere led to a diagnosis of amebiasis and giardiasis. Despite treatment with diiodohydroxyquin and quinacrine hydrochloride, his diarrhea continued. Pneumocystis carinii pneumonia developed in July 1981, requiring prolonged mechanical ventilation. He responded to intravenous trimethoprimsulfamethoxazole therapy. Biopsy of an inguinal lymph node showed hyperplasia and did not take up acid-fast stain. Persistent diarrhea and weight loss led to further evaluation in January 1982. Stool examination was positive for occult blood but negative for leukocytes, ova, and parasites. Stool cultures grew predominantly Candida species. Barium enema, upper GI and small bowel series, and
GASTROENTEROLOGY Vol. 85, No.5
1188 GILLIN ET AL.
Table 1. Malabsorption Studies Test
Patient
Control
72-h stool fecal fat (g/24 h) ['4Cjtriglyceride breath test" D-xylose (mg% in urine at 5 h) Serum carotene (JLg%) Serum 25-hydroxyvitamin D (ng/ml)
58.5 4 0.9 12 11
<7 >60 >5 50-300 10-55
° 14C02, % dose, in expired air 4 h after 6.4 JLCi (0.1 JLCi/kg body wt) of 14C-Iabeled glycerol tripalmitinin per os at time zero
colonoscopy were normal. He was discharged on a prophylactic regimen of trimethoprim-sulfamethoxazole and ketoconazole. The patient was admitted to Memorial Hospital in April 1982, complaining of diarrhea, fever, and a 30-lb weight loss. He denied arthralgias. There was no history of illicit drug use or previous exposure to tuberculosis. Examination revealed a thin, chronically ill-appearing man with a temperature of 39°C. The lungs were clear. A 2/6 systolic murmur was heard at the left sternal border. Abdominal examination showed hepatomegaly without evidence of ascites. Rectal exam revealed two perianal ulcerations. Firm lymph nodes were palpated in the inguinal and axillary areas. A maculopapular rash was seen on the trunk and the lower extremities. There were no joint abnormalities. Neurologic examination demonstrated memory loss, episodic disorientation, and cognitive deficits. Laboratory data included a hemoglobin of 7.3 mg/dl; a white blood cell count of 2100 cells/mm 3 (80% polymorphonuclear leukocytes, 6% lymphocytes, 8% monocytes, 4% eosinophils, and 2% basophils); and a platelet count of 152,000 cells/mm 3 • The erythrocyte sedimentation rate was 70 mm/h (normal 0-9 mm/h). Additional blood tests showed serum glutamic oxaloacetic transaminase (SGOT) 26 u/L (normal 0-25 U/L); alkaline phosphatase 171 U/L (normal 30-115 U/L); protein 5.9 g/dl (normal 6.3-8.1 g/dl); albumin 2.8 g/dl (normal 4.0-5.2 g/dl). Blood and urine cultures were negative. Stool cultures grew predominantly Candida species. The chest radiograph was normal. Absorption tests, as shown in Table 1, were markedly abnormal. Studies of immunity, shown in Table 2, were consistent with acquired immunodeficiency syndrome (AIDS). The patient underwent esophagogastroduodenoscopy, which showed minute superficial ulcerations throughout the duodenum. Biopsy of the distal duodenum showed numerous PAS-positive diastase-resistant macrophages throughout the mucosa (Figure 1). Acid-fast stain revealed bacilli within these macrophages and free in the lamina propria (Figure 2). This was confirmed ultrastructurally by the electron microscopic demonstration of intact rodshaped bacilli with waxy cell walls within the macrophages (Figure 3). This appearance was felt to be consistent with mycobacterial species. Initial cultures of the small intestinal biopsy grew a few colonies of enterococci, viridans streptococci, and Candida albicans. There was no growth of mycobacterial species. Biopsies of the liver and colon also stained positive
for acid-fast bacilli, but again initial culture results showed no mycobacterial growth. A bone marrow aspirate and biopsy revealed numerous granulomata but no acidfast organisms. A lumbar puncture, electroencephalogram, and computerized transaxial tomography of the brain were negative. The patient was begun on isoniazid, rifampin, and ethambutol because of the presumptive diagnosis of disseminated mycobacteriosis. Trimethoprim-sulfamethoxazole and ketoconazole were continued. On the ninth hospital day, he developed a herpetic facial eruption and was treated with intravenous 2' -fluoro-5-iodo-{3-o-arabinofuranosylcytosine (FIAC). Because of severe malabsorption and malnutrition, total parenteral nutrition was started. On the 17th hospital day, he became hypotensive with bilateral pulmonary infiltrates and renal insufficiency. Upon transfer to the intensive care unit, he was placed on mechanical ventilation, peritoneal dialysis, and pressor agents. Ethambutol was discontinued, and clofazimine, moxalactam, amikacin, and amphotericin B were added. Generalized seizures were treated with diphenylhydantoin. On the next day, the patient died. Postmortem examination revealed disseminated acidfast infection involving small intestine, lymph nodes, liver, spleen, heart, kidneys, and lungs. Periodic acidSchiff-positive macro phages were present in lymph nodes and the small bowel mucosa. The lungs contained pseudohyphae consistent with Candida and intranuclear inclusions within alveolar cells consistent with cytomegalovirus. Of interest was the presence of a multifocal demyelinating leukoencephalopathy of undetermined etiology that was felt to be responsible for the neurologic symptomatology.
Table 2. Immunologic Profile Test Skin test PPD SKSD Mumps Dermatophyton 0 Absolute lymphocyte count per mm 3 T cell (%J B cell (%J Lymphocyte to proliferati ve response o Phytohemagglutinin con A Pokeweed mitogen Serum immunoglobulins (mg%J IgG IgA IgM IgE
Patient nonreactive nonreactive nonreactive nonreactive 126
Control
{ 98% respond to at least one 900-4400
37 34
55-75 15-25
1376 384 104
>17,000 >8900 >3500
1383 436 95 35
800-1800 90-450 60-250 10-256
PPD = purified protein derivative. SKSD =, streptokinase/streptodornase. con A = concanavalin A. Net counts per minute of tritiated thymidine incorporated after 3 days' incubation for phytohemagglutinin and con A; after 5 days' incubation for pokeweed mitogen. 0
November 1983
AIDS MIMICKING WHIPPLE'S DISEASE
1189
Figure 1. Dense infiltration of the small intestinal lamina propria by macro phages (H&E, x40). These macro phages also exhibited PAS-positive diastase-resistant staining.
After completion of the autopsy, cultures from blood grew Mycobacterium nvium-intracellulare.
Discussion The clinical presentation of this case initially suggested the diagnosis of Whipple's disease. Supporting this diagnosis were chronic malabsorption and progressive weight loss, low-grade fever, and the light microscopic features of the small intestine after
Figure 2. Small intestinal macrophages with numerous acid-fast rods packing the cytoplasm (ZiehlNeelsen, x 100).
H&E and PAS staining. The patient also demonstrated immune abnormalities consistent with acquired immunodeficiency syndrome (AIDS). Characteristic immunologic findings in AIDS include lymphopenia, reduction in the number of helper T cells with normal or increased proportion of suppressor lymphocytes, impaired lymphocyte proliferation to mitogens, and skin test anergy (18-20). Immunologic abnormalities recently reported in Whipple's disease include phytohemagglutinin unresponsiveness (21), decreased macrophage processing (22), and altered
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GASTROENTEROLOGY Vol. 85 , No. 5
Figure 3. Electron micrograph of the intestinal macrophage demonstrating rod-shaped organisms wi th thick electron lucent cell walls. The organisms, seen in longitudinal and cross section, appear to be intact without varying degrees of digestion ( X 6000) .
T-cell macrophage interactions (23). Three cases studied after therapy have shown decreased numbers of peripheral blood lymphocytes (24). A review by Dobbins of studies reported since 1971 reveals no demonstrable defect in humoral immunity but consistent T-cell abnormalities before and after therapy (17). Whipple's disease and AIDS, therefore, appear to share an immune defect characterized predominantly by a depression in T-cell function. Despite these similarities, an important difference between this case and Whipple 's disease is the presence of M. avium-intracellulare within the macrophages packing the lamina propria of the small intestine. The absence of the typical Whipple's bacillus was confirmed by electron microscopy (Figure 3). In contrast to Whipple's disease, the intracellular M. avium-intracellulare appear to exist intact without various degrees of dissolution. The PAS reaction of macrophages in our patient, although not as intense as seen in classical cases of Whipple's disease , is probably due to the densely packed mycobacteria rather than to degenerating components of bacilli, as in Whipple's disease. This finding suggests that defective macrophage processing of these pathogens may lead to the same accumulation of
mactophages and secondary malabsorption as is classically seen in Whipple's disease. Defective Tcell activation of macro phages has likewise been proposed as a mechanism in the pathogenesis of Whipple's disease (25). In foals, Corynebacterium equi, an organism distinct from Whipple 's bacillus on electron microscopy, also causes intense infiltration of the intestine and mesenteric lymph nodes with PAS-positive macrophages (26). It is, therefore, conceivable that a number of different organisms may induce similar morphologic and functional changes in the small intestine. Although Whipple's bacillus could have been absent from our specimens because of continuous therapy with trimethoprim-sulfamethoxazole, the persistent malabsorption suggests that a. macrophage response to ongoing M. avium-intracellulare infection was responsible for the findings in this case . The recent recognition of association between AIDS and disseminated M . avium-intracellulare infection has been a subject of intense investigation (27,28). We are not aware of previous cases in which M. avium-intracellulare has been cultured from the small intestine or of reports implicating mycobacte-
November 1983
rial species in the pathogenesis of Whipple's disease. Kuhajda and associates (29) reported a submucosal variant of Whipple's disease in a patient treated for Mycobacterium tuberculosis. However, autopsy specimens of the small bowel showed no mycobacteria but did reveal bacillary bodies compatible with Whipple's bacillus. In summary, we report a patient with AIDS and chronic malabsorption associated with light microscopic findings similar to those observed in Whipple's disease. Only after acid-fast staining and electron microscopy was M. avium-intracellulare identified within macro phages of the small intestinallamina propria. The similar immunologic abnormalities in this patient and in some cases of Whipple's disease suggest a role for immunodeficiency in the development of the mucosal macrophage infiltration. Although Whipple's bacillus is a distinctive organism associated with classic Whipple's disease, we propose that other intracellular pathogens in appropriate hosts may incite histologic changes that result in malabsorption with a clinical picture similar to Whipple's disease.
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