GASTROENTEROLOGY 1992;102:1054-1058

Peritoneal Coccidioidomycosis Associated With Human Immunodeficiency Virus Infection PRIYA A. JAMIDAR, DONALD and STEPHEN A. KLOTZ

R. CAMPBELL,

JAMES L. FISHBACK,

Departments of Medicine and Pathology, Department of Veterans Affairs Medical Center, Kansas City, Missouri; and University of Kansas School of Medicine, Kansas City, Kansas

Peritoneal coccidioidomycosis is extremely rare. This report describes a patient infected with the human immunodeficiency virus who presented with unexplained ascites and was found to have peritoneal coccidioidomycosis. The ascites had a low serum-ascites albumin gradient, and laparoscopy showed peritoneal implants that grew Coccidioides immitis. This case is unique in several ways: this is the first case in which a patient’s acquired immunodeficiency syndrome-defining illness was peritoneal coccidioidomycosis, and the serum-ascites albumin gradient determination as well as laparoscopy provided information critical to the diagnosis. This patient’s dramatic response to systemic antifungal therapy, as evidenced by resolution of ascites and constitutional symptoms, underscores the importance of timely diagnosis and prompt therapy. In summary, this report reviews the previous cases of coccidioidal peritonitis and reports the first case in which localized peritoneal coccidioidomycosis was the acquired immunodeficiency syndrome-defining illness in a human immunodeficiency virus-infected patient.

C

occidioidomycosis is a disease caused by the fungus Coccidioides immitis, which is endemic to the southwestern United States, Mexico, and parts of South America. Coccidioidomycosis has a variety of clinical presentations ranging from asymptomatic to fulminant disseminated disease involving multiple organs.’ In some endemic areas, 30% of patients with acquired immunodeficiency syndrome (AIDS) have either pulmonary or widely disseminated coccidioidal infection.2 We report a patient infected with the human immunodeficiency virus (HIV) who presented with ascites and a low serum-ascites albumin gradient. He was found to have coccidioidal peritoneal implants on laparoscopy. This is the first reported case of peritoneal coccidioidal deposits causing a low-gradient ascites, and it is the first case

in which peritoneal AIDS-defining illness.

coccidioidomycosis

was the

Case Report History A 42-year-old white man presented with a &week history of increasing abdominal girth, anorexia, diarrhea, and general lethargy. He denied having fever, chills, night sweats, or weight loss. Eighteen months before presentation, he was evaluated for jaundice and was found to have acute hepatitis A and to be positive for HIV-1 antibody by enzyme immunoassay. This discovery was confirmed by Western blot. He denied homosexual activities but related a long history of IV drug abuse and moderately heavy alcohol consumption. He was employed as a truck driver and was in southern California on numerous occasions. Approximately 7 months before presentation, the patient was evaluated for unexplained fever. Perihilar adenopathy was detected on chest radiography and computed tomography. Bronchoscopy revealed several endobronchial nodules, and histologic examination showed nonspecific chronic inflammatory changes. Stains for acid-fast bacilli (AFB) and fungi were negative. Bone marrow biopsy revealed myeloid and megakaryocytic hyperplasia, and AFB, fungal stains, and cultures were negative. A diagnosis of AIDS-related complex was made. Six months before this presentation, his absolute CD4 count decreased to ~200 cells/mm3, and therapy with zidovudine, 600 mg/ day, and aerosolized pentamidine was initiated. Hospital

Course

Physical examination revealed a comfortable-appearing white man with stable vital signs, a temperature of 98.2”F, and seborrheic dermatitis over the face and scalp. Results of cardiopulmonary examination were entirely normal. There was no adenopathy, scleral icterus, jugular venous distention, or peripheral edema. His abdominal examination was remarkable for gross ascites as evidenced by shifting dullness, a fluid wave, and bulging flanks. The 0 1992 by the American Gastroenterological 0016-5085/92/$3.00

Association

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liver and spleen were not palpable, and no abdominal masses or tenderness were observed. Laboratory studies revealed normal serum electrolyte concentrations, with blood urea nitrogen and creatinine levels of 9 and 0.9 mg/dL, respectively. Alkaline phosphatase concentration was 88 IU/L, total and direct bilirubin were 13.7 pmol/L (0.8 mg/dL) and 8.6 pmol/L (0.5 mg/ dL), respectively, and aspartate aminotransferase and alanine aminotransferase levels were 3 and 25 IU/L, respectively. Prothrombin time was 11 seconds, hemoglobin concentration was 105 g/L (10.5 g/dL) (with a mean corpuscular volume of 106.1), and platelet count was 402 X log/L (402 X 103/co mm). No aerobic or anaerobic organisms were isolated from the blood. Results of other serum studies are presented in Table 1. Abdominal paracentesis was performed, and fluid analysis revealed the values shown in Table 1. The calculated serum-ascites albumin gradient was 0.4 mg/dL. Cultures and stains of fluid obtained at therapeutic and diagnostic paracenteses for fungi and bacteria (including AFB) were negative. Radiographs of the chest were normal, and computed tomography of the abdomen revealed gross ascites, no filling defects of the liver, no hepatosplenomegaly, and no intraabdominal masses. There was no response to intradermal injection of purified protein derivative or histoplasmin control. The serum-ascites albumin gradient was consistent with a nonportal hypertensive origin for the patient’s ascites. Because the patient developed low-grade fevers and chills during the hospitalization, laparoscopy was performed to further evaluate the unexplained ascites and the low serum-ascites albumin gradient and to specifically exclude peritoneal tuberculosis. Laparoscopy showed numerous large white plaques (Figure lA), multiple miliary-type deposits on the parietal peritoneum (Figure lB), and several adhesions. Biopsy specimens were obtained from the

Table 1. Simultaneous

Ascites and Blood Chemistries

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Figure 1. (A) Laparoscopic view showing a white, heaped-up: plaquelike coccidioidal deposit (arrows). (B) Laparoscopic view showing multiple miliary-type coccidioidal deposits (arrow) on the peritoneum.

deposits, and histological examination of H&E-stained tissue revealed multiple granulomas. Acid-fast stains did not reveal bacilli, but silver staining revealed a pleomorphic population of small to large silver-positive organisms. The larger structures had thick cell walls consistent with

and

Cell Counts Laboratory parameters

Ascites

Blood

Total protein

Albb&ww [g/L

(g/W

Lactic dehydrogenase V/L) Red blood cell count [cells/L (celJs/mm3)] White blood cell count [cells/L (cells/mm3)] Differential

Carcinoembryonic antigen

58 (5.8)

86 (8.6)

28 (2.8)

32 (3.2)

74 7.90 x lo8 (790) 1.15x 109 (1150)

a9

lOL, llM, 5E, 6OP, 12s

0

2.74X lOI2 (2.74 X 106) 2.8 x log (2800) 61L, 2oM, 5E, 3B, 2P

NA

L, % lymphocytes; M, % monocytes; E, % eosinophils; B, % basophils; N, % polymorphonuclear leukocytes; S, % band forms. NA, not applicable.

Figure 2. High-power (original magnification X400) photomicrograph of a giant cell containing periodic acid-Schiff-positive spherules (arrows) consistent with C. immitis.

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JAMIDARET AL.

spherules of C. immitis. Within the spherules were smaller oval to rounded structures consistent with endospores of C. immitis. Periodic acid-Schiff stains confirmed these findings (Figure 2). C. immitis was subsequently cultured from the peritoneal biopsy specimens. Serum for fungal serology was obtained, and the complement fixation titer to C. immitis was 1:128.There was no evidence of extraperitoneal involvement, but the patient was unwilling to undergo bone marrow studies. Therapy with amphotericin B was initiated; the patient’s fevers resolved, and his appetite, energy level, and mood improved. Before initiating antifungal therapy, his ascites had steadily increased, and several large-volume paracenteses were required to relieve his abdominal discomfort. Wi& antifungal therapy there was no further accumulation, and, at the time of discharge, after z weeks of antifungal therapy, the amount of ascites had markedly diminished. Six months after discharge, he remains afebrile and has no clinically detectable ascites. Discussion At least 50,000 new C. immitis infections occur in endemic regions of the United States annually. These infections generally occur in immunocompetent patients, are self-limited, and may be subclinical or may present with lower respiratory tract symptoms. Coccidioidal infections rarely cause a protracted respiratory illness, and even less frequent are extrathoracic infections of the supraclavicular lymph nodes, skin, bones, meninges, and other sites. Widespread dissemination is unusual, but when it does occur it is most common in immunocompromised hosts and may be life-threatening.3 The altered cell-mediated immunity associated with HIV infection predisposes HIV-infected patients to numerous unusual infections. Laboratory studies4 and recent reports of coccidioidomycosis in AIDS5-7 support the impression that normal cell-mediated immunity is required to control coccidioidal infections. The clinical manifestations of coccidioidal infection in 77 HIV-infected patients were recently reported, and in that study* 66% of patients had pulmonary involvement as evidenced by lesions on chest radiographs, although no patient had peritoneal disease. In a recent review9 of high-protein (exudative) ascites in patients with AIDS, the investigators reviewed all laparoscopies performed at their institution over a h-year period and performed a computer search of discharge diagnoses over a g-year period. Only eight noncirrhotic patients with AIDS and high-protein ascites were identified, and none had coccidioidal peritonitis. Despite the prevalence of coccidioidomycosis in the southwestern United States and the increasing incidence of HIV infection, coccidioidal peritonitis is rare. Excluding autopsy series, 15 cases of coccidioidal peritonitis have been reported,‘&15 and only one of

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these occurred in a patient with AIDS, That patient’s medical history included alcohol-induced cirrhosis, portal hypertension, and secondary hypersplenism. His AIDS-defining illness was C. immitis infection of the lungs and meninges for which he received antifungal therapy. Two years after his initial presentation, he developed ascites, and C. immitis was cultured from his peritoneal fluid and urine. Although the etiology of the ascites is unclear, the fact that he died within 2 months with hepatic encephalopathy suggests that he had end-stage liver disease. Additionally, the presence of C. immitis in both the peritoneal fluid and urine is suggestive of generalized dissemination.” The majority of the 14 other cases of coccidioidal peritonitis occurred in the pre-AIDS era with only three cases being reported after 1980. Coccidioidomycosis of the peritoneum, mesentery, and retroperitoneal lymph nodes was diagnosed in a 21year-old man with a pleural effusion and ascites whose case was reported in 1986.” In 1983 two additional cases of peritoneal coccidioidomycosis were reported by Chen.” In both instances, the diagnosis was made at the time of surgery, and neither of the patients received systemic antifungal therapy. None of these four cases reported after 1980 involved laparoscopy or serum-ascites albumin gradient determination. Laparoscopy has been used to diagnose peritoneal coccidioidomycosis on two occasions, once in 193913 and later in 1974.14 The diagnosis of coccidioidal peritonitis was made by culturing the peritoneal fluid in 2 of the other 15 reported cases; the remaining 11 cases required a surgical procedure to establish the diagnosis. Laparoscopy can be very useful in establishing the diagnosis of tuberculous peritonitis? and, in this case, was performed to exclude this diagnosis. In the current case, diffuse peritoneal disease was detected through laparoscopy, and C. immitis was cultured from biopsy specimens from those lesions. Laparoscopy allowed the definitive diagnosis to be established, whereas other studies, including culture of large volumes of peritoneal fluid, were nondiagnostic. Despite its high diagnostic yield, laparoscopy is underused and its use should be considered in any patient with unexplained “low-gradient” ascites. Although all cultures and stains were negative, the serum-ascites albumin gradient (0.4 mg/dL) was highly suggestive of a nonportal hypertensive origin for the ascites. The serum-ascites albumin concentration gradient method of classification is based on the concept of oncotic-hydrostatic balance,17 and the superiority of this classification over the “exudatetransudate” method has been well established.” Patients with portal hypertension and cardiogenic ascites show large differences (>l.l mg/dL) between

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serum and ascitic albumin concentrations, whereas the causes of low-gradient ascites include peritoneal carcinomatosis, pancreatic ascites, nephrotic syndrome, benign chylous ascites, and peritoneal infection and inflammation. Ascitic amylase and lactate dehydrogenase levels and cell counts can be used to distinguish pancreatic, malignant, and inflammatory and infectious etiologies. Although the serumascites gradient is not calculable in any of the 15 previously reported cases of coccidioidal peritonitis, the ascitic fluid was characterized as an exudate in eight of the eight cases in which the total protein of the ascites was reported. The exudative character of the ascites and the low serum albumin gradient of the case being reported were both suggestive of significant peritoneal disease. Although laparoscopy allowed the diagnosis of peritoneal coccidioidomycosis to be easily established, confirming the diagnosis of coccidioidal peritonitis can be difficult. Isolating the organism from the involved site is most desirable, but the organism can be difficult to culture. Serological tests can also be useful in establishing the diagnosis in addition to following the activity of the disease.3 Positive precipitin titers (immunoglobulin M antibodies) are found soon after primary infection and remain elevated for days to a few weeks. Results of the complement-fixation test (immunoglobulin G antibodies) become positive later in the course of the disease (as late as 3 months), and levels remain elevated for 6-9 months. However, in patients with immunological disorders, complement-fixation antibody titers may be low. Although a combination of both serological tests is reported to yield positive results in approximately 90% of HIV-infected patients infected with C. immitis,l’ there was no antibody response in the only other case of coccidioidal peritonitis in an HIV-infected patient.” Skin testing with coccidioidin antigen is helpful for epidemiological studies, but it is of limited value for the initial diagnosis and may be negative with dissemination. In addition to culture, serological testing, and skin testing, biopsies and examination of wet preparations can be useful in evaluating patients suspected of having coccidioidal infections. Of the 15 previously reported cases of coccidioidal peritonitis, 5 had localized disease, and 10 had extraperitoneal disease. Antifungal therapy was used in 1 of the 5 with localized disease and 7 of the 10 with coccidioidal peritonitis and extraperitoneal disease. Follow-up information is available on 14 of those patients. Eleven did well, and 3 died with disseminated disease. Of those who died with disseminated disease, all had peritoneal and pulmonary disease, 1 received systemic amphotericin B, and 2 were not treated. Intravenous amphotericin B remains the

most commonly used initial treatment for disseminated coccidioidal disease. The patient in the current study had a dramatic response to amphoteritin B therapy with complete resolution of ascites. In summary, this is the first reported case of peritoneal coccidioidomycosis being the AIDS-defining illness in an HIV-infected patient. In addition, it is the first time the serum-ascites albumin gradient has been reported in coccidioidal peritonitis, and it is only the third case in which laparoscopy was used to establish that diagnosis. Based on our experience with this case and our review of the 15 other cases in the literature, we recommend that all patients with new-onset ascites undergo serum-ascites albumin gradient determinations, and that those with lowgradient ascites be considered for early laparoscopic evaluation. The dramatic response of this patient to systemic antifungal therapy underscores the importance of considering this therapy for any patient with coccidioidal peritonitis. References 1.

AmpeI NM, Ryan KJ, Carry PJ, Weiden MA, Schifman RB.

Fungemia due to Coccidioides immitis: an analysis of 16 episodes in 15 patients and a review of the literature. Medicine 1986;65:312-321. 2. Bronnimann DA, Adam RD, Galgiani JN, Habib MP, Petersen EA, Porter B, Bloom JW. Coccidioidomycosis in the acquired immunodeficiency syndrome. Ann Intern Med 1987;106:372379. 3. Galgiani JN, Ampel NM. Coccidioidomycosis in human immunodeficiency virus-infected patients. J Infect Dis 1990; 162:1165-1169. 4. Beaman L, Pappagianis D, Benjamini E. Mechanisms of resistance to infection with Coccidioides immitis in mice. Infect Immun 1979;23:681-685. 5. Abrams DI, Robia M, Blumenfeld W, Simonson J, Cohen MB, Hadley WK. Disseminated coccidiomycosis in AIDS (letter). N Engl J Med 1984;310:986-987, 6. Kovacs A, Forthal DN, Kovacs JA, Overturf GD. Disseminated coccidiomycosis in a patient with acquired immune deficiency syndrome. West J Med 1984;140:447-449. 7. Roberts CJ. Coccidioidomycosis in acquired immune deficiency syndrome. Depressed humoral as well as cellular immunity. AmJMed 1984;76:734-736. 8. Fish DG, Ampel NM, Galgiani JN, Dols CL, Kelly PC, Johnson CH, Pappagianis D, Edwards JE, Wasserman RB, Clark RJ, Antoniskis D, Larsen RA, Englender SJ, Petersen EA. Coccidioidomycosis during human immunodeficiency virus infection: a review of 77 patients. Medicine 1990;69:384-391. 9. Wilcox CM, Forsmark CE, Darragh T, Benedict Yen TS, Cello JP. High protein ascites in the acquired immunodeficiency syndrome. Gastroenterology 1991;100:745-748. 10. Bryne WR, Dietrich RA. Disseminated coccidioidomycosis with peritonitis in a patient with acquired immunodeficiency syndrome. Prolonged survival associated with skin test reactivity to coccidioidin. Arch Intern Med 1989:149:947-948. 11. Weisman IM, Moreno AJ, Parker AL, Sippo WC, Liles WJ. Gastrointestinal dissemination of coccidioidomycosis. Amer J Gastroenterol 1986;81:589-593. 12. Chen KTK. Coccidioidal peritonitis. Am J Clin Path01 1983;80:514-516.

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13. Ruddock JC, Hope RB. Coccidioidal peritonitis: diagnosis by peritoneoscopy. JAMA 1939;113:2054-2055. 14. Saw EC, Shields SJ, Comer TP, Huntington RW Jr. Granulomatous peritonitis due to Coccidioides immitis. Arch Surg 1974;108:369-371, Arch Surg 1959; 15. Crum RB. Peritoneal coccidioidomycosis. 78:91-95. 16. Geake TMS, Spitaels JM, Moshal MG, Simjee AE. Peritoneoscopy in the diagnosis of tuberculous peritonitis. Gastrointest Endosc 1981;27:66-68. 17. Pare P, Talbot J, Hoefs JC. Serum-ascites albumin concentration gradient: A physiologic approach to the differential diagnosis of ascites. Gastroenterology 1983;85:240-244. 18. Rector WG, Reynolds TB. Superiority of serum-ascites albu-

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min difference over the ascites total protein concentration in separation of transudative and exudative ascites. Amer J Med 1984;77:83-85. 19. Weiden M, Galgiani JN, Pappagianis D. Comparison of immunodiffusion techniques with standard complement fixation assay for quantitation of coccidioidal antibodies. J Clin Microbiol 1983;18:529-534.

Received Address enterology 2300, 926 5250.

April 9, 1991. Accepted July 2, 1991. requests for reprints to: Priya A. Jamidar, M.D., GastroDivision, Indiana University Medical Center, Suite West Michigan Street, Indianapolis, Indiana 46202-