Original Report Histopathology of Cryptococcosis and Other Fungal Infections in Patients with Acquired Immunodeficiency Syndrome Kazutoshi Shibuya, MD;* Walter E Coulson, MD;+ Jerome S. Wollman, MD;* Megumi Wakayama, MD;* Tsunehiro Ando, MD;* Toshiaki Oharaseki, MD;* Kei Takahashi, MD; and Shiro Naoe, MD* ARSTRACT Conclusions: The absence of T cells and decreasing function of antigen-presenting activity in histiocytes were confirmed by Objective: To gain insight into the histopathologic characteris- immunohistologic examination. These findings suggest that the tics of fungal infection in acquired immunodeficiency syndrome lungs in AIDS patients provide little resistance to blood stream (AIDS). dissemination by cryptococci. Methods: A review was conducted of the histopathology for 162 patients with evident fungal infection. Key Words: acquired immunodeficiency syndrome, candidiasis, Cryptococcosis, CD4+ cells, histopathology Results: The microscopic appearance of esophageal candi- diasis that was common in patients with single organ involve- Int J Infect Dis 2001; 5:78-85. ment revealed necrotic debris containing proliferating hyphae at the site of mucosal erosions without fungal invasion of under- In the past, various factors have resulted in an increase lying tissue. The incidence of oral and esophageal candidiasis in the number of immunocompromised patients. None of was followed by that of pulmonary aspergillosis and Candida these, however, has had the impact of the dramatic world- infection. Eighteen patients had generalized cryptococcosis, wide epidemic of acquired immunodeficiency syndrome representing the commonest generalized fungal disease. The (AIDS). The pathologic and clinical features of AIDS, fol- essential histologic features of the disease consisted of yeast lowing infection by the human immunodeficiency virus cell proliferation with a histiocytic response, but only minor lym- (HIV), is associated with a progressive decrease of cell- phocytic and neutrophilic components. This was different from mediated immunity, owing to defective functioning of the manifestations of both Candida and Aspergillus infections. CD4+ cells.‘,* For this reason, certain mycoses have risen The two histologic patterns recognized in the pulmonary crypto- coccal lesions could be graded with respect to the degree and dramatically in frequency, particularly systemic crypto- type of inflammatory reaction. The milder one consisted of small coccosis and oral or esophageal candidiasis. The inci- scattered foci of intra-alveolar cryptococcal proliferation with a dence of opportunistic fungal infections, including any histiocytic response. Another pattern involved massive crypto- species of fungus, provoking both localized and general- coccal infection, which might be simply more extensive than ized disease in AIDS patients, has been variously reported that in the former. Capillary involvement of alveolar septa was to be between 58% and 81X, of whom 10 to 20% of an important common finding in all 18 patients. patients have died as a direct consequence of the fungal infection.?,‘{ It is known that cryptococcal infection in AIDS patients often induces fatal disease.3,s.”The present article describes the histologic features of cryptococco- *Department of Pathology, Toho University Ohashi Hospital, Tokyo, Japan. +Department of Pathology and Laboratory Medicine, University sis and other fungal infections in patients with AIDS, of California at Los Angeles Medical Center, Los Angeles, California. focusing on the differences in inflammatory responses *Department of Pathology, VA Wadsworth Medical Center, Los Angeles, to the various fungal pathogens and details of pulmonary California. cryptococcal lesions, as determined at autopsy. Presented in part at the XII Congress of the International Society for Human and Animal Mycology, Adelaide, South Australia, March 13- 18, 1994. MATERIALS AND METHODS Supported by Toho University 60th Anniversary Research Foundation, Toho University Project Research Foundation t4-27, and Research The autopsy files of the UCLA Medical Center and the Foundation of Traffic and Preventive Medicine. West Los Angeles Veterans Affairs Medical Center were searched for patients with AIDS who had either localized Address correspondence to Dr. Kazutoshi Shibuya, Department of Pathology, Toho University Ohashi Hospital, 2-17-6 Ohashi Meguro-Ku, or generalized infection by any species of fungus. Here, Tokyo 153-8515, Japan. E-mail: [email protected]. the term generalized fungal disease is restricted to 78 Histopathology of Cryptococcosis in AIDS / Shibuya et al 79 patients in whom more than two organs were involved containing many encapsulated yeasts, in cortical and sub- by the fungal infection, excluding mucosal lesions. cortical areas, that were also present in the adjacent sub- The histopathologic examination to determine organ arachnoidal space. There was a histiocytic response that involvement by fungal pathogen and to determine details varied from case to case, but necrosis and neutrophilic of tissue responses was carried out on routine hematoxylin infiltrates were not encountered. and eosin (H&E) preparations, along with selective stain- Localized lung disease was associated with two fun- ing with the periodic acidschiff reactions (PAS) and gal species, Aspergillus and Candida. The essential fea- Grocott methods. ture of the pulmonary lesions with both fungi was To compare the histology of pulmonary cryptococ- purulent bronchopneumonia in which bronchioles and cal infections, sections of pulmonary lesions obtained alveoli were filled with necrotic debris, neutrophils, and from two groups of non-AIDS patients with and without proliferating fungi. Alveolar septa often showed coagula- immunosuppressed condition were employed. The for- tive necrosis and disruption, but lymphocytes and fibro- mer consisted of five patients, ranging in age from 36 to sis were not present. Bacteria were occasionally observed 78 years (mean, 62.4 y). Four of them had carcinoma and within necrotic debris. With Aspergillus infection, the one had been diagnosed with Evans syndrome. The lat- mucosa was focally necrotic and eroded with readily vis- ter comprised seven patients without any immunosup- ible hyphae. pressed condition, ranging in age from 21 to 73 years (mean, 43.7 y), who had a wedge biopsy or lobectomy for Generalized Disease their incidental abnormal shadows on chest roentgeno- Eighteen cases (11.1%) of generalized cryptococcosis grams. In addition, a standard peroxidase-antiperoxidase were found to present the commonest generalized fun- technique was used for the antibodies to CD45R0, ~26, gal infection among 162 autopsies. Much less commonly human leukocyte antigen (HLA)-DR, and interleukin encountered were generalized histoplasmosis (1.9’%), coc- (IL)-lj3, and the antigen-antibody complexes were visu- cidioidomycosis (1.2%) and candidiasis (1.2%). Granulo- alized with diaminobenzidine. Sections of pulmonary matous lesions were demonstrated in the lungs of cryptococcal lesions from both immunocompetent and patients with generalized histoplasmosis and coccid- AIDS patients were employed. The former, showing the ioidomycosis, but were poorly formed in coccidioido- typical features of peripheral pulmonary granulomas- mycosis (Figure 1). In addition, most of the affected were chosen from the group of non-immunosuppressed patients with generalized cryptococcosis had widespread patients as controls. lesions. The lung was the commonest organ involved (94.4%). Lymph nodes, spleen, and the CNS were also fre- RESULTS quently involved (Table l).Yeast cell proliferation, a his- tiocyte response and minor lymphocytic infiltration but There were 162 autopsies on AIDS patients who had died an absence of neutrophils and eosinophils were common during the period from 1983 to 1992 in the UCLA findings. However, a minor neutrophilic infiltrate was Medical Center, and from 1982 to 1991 in the West Los infrequently observed in lung, liver, and kidney The classic Angeles VA Medical Center. Localized Disease The prevalence of localized infection associated with oral candidiasis was 7.4%; esophageal candidiasis, 6.2%; pul- monary aspergillosis, 4.3%; candidal pneumonia, 3.1%; cryptococcal meningoencephalitis, 2.5%; and renal can- didiasis (pyelonephritis), 0.6%, among the study group. The lesions of esophageal candidiasis were characterized by necrotic debris at the site of erosions with underlying infiltrates of chronic and a few acute inflammatory cells. Hyphae proliferated in the necrotic debris, but did not invade tissue in any patient. Whereas most central nervous system (CNS) cryp- tococcal infections were found as a part of generalized disease, four patients had the infection localized to the CNS at the time of autopsy. One of them had a history of antifungal chemotherapy for generalized disease, but the remaining three patients had not been treated for any Figure 1. Pulmonary lesion of generalized cocadioidomycosis, show- ing spherules (arrow) and loosely aggregated macrophages (PAS reac- fungal infection. Lesions consisted of multiple small cysts tion, original magnification X400). 80 International Journal of Infectious Diseases / Volume 5, Number 2,200l Table 1. Number of Organs Involved in Cases of Generalized Cryptococcosis Number of Cases Organs Involved n= 78(%j Lung 17 (94.4) Lymph node 14 (77.8) Spleen 13 (72.2) CNS 13 (72.2) Liver 8 (66.7) Kidney 8 (66.7) Bone marrow 6 (33.3) Adrenal gland 5 (27.8) Pituitary gland 3 (16.7) Heart 3 (16.7)