Surveillance of Cryptococcosis in Alabama, 1992–1994

Surveillance of Cryptococcosis in Alabama, 1992–1994 CAROLYNN J. THOMAS, MSPH, RN, JEANNETTE Y. LEE, PHD, LAURA A. CONN, MPH, MARY E. BRADLEY, RN, ROGER W. GILLESPIE, MSN, RN, S. REEVES DILL, MD, ROBERT W. PINNER, MD, AND PETER G. PAPPAS, MD

PURPOSE: Although cryptococcosis is a significant opportunistic infection among patients with human immunodeficiency virus (HIV), there is conflicting information on rates of cryptococcosis among HIVpositive and HIV-negative patients. Precise state-wide epidemiologic data for cryptococcosis are not available in Alabama. METHODS: We conducted an active laboratory and hospital medical record-based surveillance for cryptococcosis in Alabama from October 1, 1992 to September 30, 1994. A case of cryptococcosis was defined as a patient’s initial episode of cryptococcal disease and based on either a positive culture for C. neoformans from any normally sterile site, a positive latex agglutination serologic test for cryptococcal antigen in CSF or serum, or histopathologic findings consistent with C. neoformans. RESULTS: Over the two year period, 153 cases were identified. The diagnosis was based on positive culture (37%), positive antigen (24%), positive autopsy culture (2%), and histopathologic findings (4%). Further, 33% of the total cases were diagnosed from combined positive culture, antigen, or histopathology. Of the total 153 cases, 55% were in HIV-positive patients and 44% were in HIV-negative individuals and one case (1%) had an unknown HIV status. The overall annual incidence rate of cryptococcosis was 1.89 cases per 100,000 population. The incidence was 1638.7 per 100,000 in the HIV-positive population and 0.84 per 100,000 in the HIV-negative population. CONCLUSION: The first Alabama statewide active surveillance system for cryptococcosis confirms previous observations that rates of cryptococcosis are consistently higher in HIV-infected individuals than in their HIV-negative counterparts. In Alabama, cryptococcosis occurs more commonly in urban residents and in men. Cryptococcosis in HIV-positive persons is more likely to occur in the 20 to 44 year age group, whereas cryptococcosis in HIV-negative persons is more likely to occur in those greater than 45 years old. Ann Epidemiol 1998;8:212–216.  1998 Elsevier Science Inc. KEY WORDS: Cryptococcosis, Incidence, Meningitis, Fungus, Cryptococcus neoformans, Epidemiology, Surveillance, Acquired Immunodeficiency Syndrome.

INTRODUCTION Cryptococcus neoformans is a yeast-like fungus with worldwide distribution that may cause disease in both animals and man (1, 2). Originally described by Busse in 1894, the organism has been isolated from soil samples and pigeon excreta (3). Cryptococcosis in man is a relatively rare disorder, but since 1970, the reported rates of cryptococcosis have increased, largely due to increasing numbers of immunocompromised patients, including transplant recipients, patients receiving cytotoxic chemotherapy, and other pa-

From the University of Alabama at Birmingham, Birmingham, AL (C.J.T., J.Y.L., M.E.B., R.W.G., P.G.P); University of South Alabama, Mobile, AL (S.R.D.); National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA (L.A.C., R.W.P.); and TRW Government Information Services Division, Atlanta, GA (L.A.C.). Address reprint requests to: Carolynn J. Thomas, M.S.P.H., R.N., Mycoses Study Group, UAB Division of Infectious Diseases, 335 BDB–1808 7th Avenue South, Birmingham, AL 35294-0012. Received September 29, 1997; revised November 21, 1997; accepted November 25, 1997.  1998 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010

tients on long term immunosuppressive therapy (4–9). Prior to the acquired immunodeficiency syndrome (AIDS) epidemic, up to 50% of all patients with cryptococcosis had no readily identifiable underlying immune defect (1). Cryptococcal disease is currently recognized as one of the most common life-threatening opportunistic fungal infections in immunocompromised patients, particularly among those with AIDS, and it is the commonest central nervous system fungal pathogen among all patients (1, 2, 10–13). Given the development of more effective antiretroviral therapy and prophylactic treatment regimens designed to prevent the development of common life-threatening opportunistic infections (OIs) such as Pneumocystis carinii pneumonia, it has been predicted that the increasing rate of cryptococcal disease in patients with AIDS may parallel improved survival in that population (12). Furthermore, several retrospective and prospective studies have observed that cryptococcal meningitis was often the initial AIDS-defining OI among patients with advanced human immunodeficiency virus (HIV) disease, and in a large proportion of these cases, 1047-2797/98/$19.00 PII S1047-2797(97)00234-2

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Thomas et al. SURVEILLANCE OF CRYPTOCOCCOSIS IN ALABAMA, 1992–1994

Selected Abbreviations and Acronyms AIDS 5 acquired immunodeficiency syndrome OI 5 opportunistic infection HIV 5 human immuno-defiiciency virus ASDPH 5 Alabama State Department of Public Health

presentation with cryptococcosis corresponded with the patient’s initial diagnosis of HIV infection (11, 14–16). Studies from the pre-AIDS era suggested that cryptococcosis occurred two to three times more often in men than women (1,17–21). As the HIV-infected population has increased, so have the rates of cryptococcosis, particularly in African-American men, injection drug users and residents of the southeastern United States (1, 22, 23). Epidemiologic data for cryptococcosis and other fungal diseases are limited due to the lack of systematic reporting of systemic mycoses (13). The establishment and maintenance of high quality surveillance for cryptococcosis is critical to understanding this disease. University of Alabama at Birmingham and Centers for Disease Control (CDC) investigators collaborated on an active surveillance of fungal diseases in Alabama from 1992 to 1994 (24–26). Conducting surveillance for cryptococcosis in Alabama was of particular interest. A large proportion of patients in multicenter clinical trials evaluating the treatment of cryptococcosis have been from Alabama (10, 12, 16), and clinicians in Alabama have long suspected that high rates of cryptococcosis prevail there. However, this incidence had not been previously measured. In this paper, the results of a two-year cryptococcosis surveillance study in Alabama are reported.

METHODS In October 1992, we established a two-year, laboratory and medical record-based, active cryptococcal surveillance system in the state of Alabama. The statewide incidence of cryptococcosis was based on surveillance data from the 20 counties with the largest populations and with regional medical centers, at which virtually all of the cryptococcosis cases in the state would be treated. In each surveillance county, all hospital laboratories or commercial laboratories utilized by hospitals, and all medical record departments were contacted and asked to report all cases of cryptococcal disease to the surveillance monitors. In addition, all infectious disease physicians received a letter and follow-up telephone call to orient them to the surveillance system and solicit them to report any newly diagnosed cases. The Alabama State Department of Public Health (ASDPH), which provides a central fungal testing laboratory available to all Alabama hospitals and clinics, was also asked to report cases to surveillance monitors. Monitors abstracted additional de-

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mographic and risk factor data from medical records or from direct physician reports. Medical records were accessed, at each hospital medical record department within active surveillance counties, utilizing the International Classification of Diseases coding system (ICD-9) of the World Health Organization for cryptococcosis diagnoses. Duplication of cases reported from the state laboratory and from other primary sources was avoided by comparing all demographic and source data. Any available data on subsequent infections in cases were recorded on the case report forms; however, follow-up of cases was not pursued. A case was defined as an Alabama resident’s initial episode of cryptococcal disease based on either a positive culture for C. neoformans from any normally sterile site, a positive latex agglutination serologic test for cryptococcal antigen from serum or spinal fluid, or histopathology consistent with C. neoformans. Positive sputum cultures alone were excluded because of the difficulty in distinquishing nondisease-related colonization from infection. In estimating the incidence rates, it was assumed that the population was stable over the two years of active surveillance. All incidence rates are reported per 100,000 population. Population data were obtained from the U.S. Department of Commerce, Alabama State Data Center (ASDC) 1990 Census of Population and Housing, STF3 (27). The total Alabama population in 1990 was 4,040,587: 36% were white males; 38% were white females; 11% were AfricanAmerican males; 14% were African-American females; and , 1% were of other racial origins. The ASDPH HIV/AIDS Surveillance Branch provided data on the number of Alabama residents who were living with AIDS by gender, race, age, and county of residence for the two surveillance years. These data were used as population denominators for HIV-positive cases. The total Alabama population who were living with AIDS during the two year surveillance period were 1395 and 1168, respectively. The population distribution based on gender and ethnicity in persons living with AIDS was identical for each year: 42% were white males; 4% were white females; 42% were African-American males; 11% were African-American females; and 1% were of other racial origins. A stepwise logistic regression analysis model was used to evaluate the association of race, gender, and HIV status on the proportion of the population diagnosed with cryptococcosis. To evaluate any difference between urban and rural residence on cryptococcal disease, the following counties were classified as urban: Jefferson (population 651,525), Montgomery (population 209,085), and Mobile (population 378,643). About one-third of the total state population and 53% of the Alabamians living with AIDS reside in these three counties. Further, these counties also comprise the predominant urban population of the entire state, each having greater than 80% of their population designated as urban by the U.S. Department of Commerce (27). All other counties in the

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TABLE 1. Incidence of cryptococcosis per 100,000 per year in Alabama and 95% confidence intervals, 1992–1994

White males African-American males White females African-American females

Total

HIV1

HIV2

2.04 (1.30, 2.78) 6.09 (3.86, 8.32) 0.75 (0.32, 1.18) 0.82 (0.06, 1.58)

1262.86 (1244.53, 1281.19) 2264.33 (2221.86, 2307.40) 1869.16 (1847.50, 1890.82) 361.01 (345.13, 376.89)

1.11 (0.57, 1.65) 0.85 (0.01, 1.69) 0.62 (0.23, 1.01) 0.64 (0, 1.31)

State were designated as rural. A stepwise logistic regression analysis was used to evaluate the role of urban/rural residence and HIV status on the incidence of cryptococcosis.

RESULTS From October 1992 through September 1994, 153 cases of cryptococcosis were identified. The overall annual incidence of cryptococcosis in the State of Alabama was estimated to be 1.89 per 100,000 population (95% CI 1.60–2.18 per 100,000 population). An underlying disease was reported in 138 of the 153 cases (90%). Eighty-four (55%) cases were HIV-positive. The underlying diseases reported in the remaining 54 cases include diabetes (20%), cancer (20%), lung disease (19%), organ (kidney and heart) transplant (6%), and miscellaneous disorders (including both rheumatoid arthritis and sarcoidosis) in 15%. Among the HIV-positive cases, 5% reported having another underlying condition such as diabetes (2%), lung disease (2%), and cancer (1%). No underlying disease was reported in 15 (23%) of the HIV-negative cases. The incidence in Alabama of cryptococcosis in the HIVnegative population was 0.84 (95% CI 0.62–1.1 per 100,000 population) while the incidence of cryptococcosis in persons living with AIDS was 1638.7 per 100,000 population. A large variation was observed in the HIV-positive cases based on gender and race, potentially due to the small number of HIV-positive cases in the state of Alabama. The logistic regression analysis showed that cryptococcosis was significantly associated with HIV positivity (p , 0.001) and male gender (p 5 0.004). In the HIV-positive population, the incidence rates were 1746.3 and 1133.6 per 100,000 population for men and women, respectively. Among HIV-negative persons, the incidence rates were 1.08 and 0.62 per 100,000 population for men and women respectively (Table 1). The incidence of cryptococcosis was highest among persons 20 to 44 years old. The proportion of cases attributable to HIV infection was 90% in 20 to 44 year olds, but only 5% in those older than 65 years (Figure 1). On the 153 cases, the diagnosis of cryptococcosis was

FIGURE 1. Age distribution of cryptococcosis cases by HIV status.

made based on: culture (37%), antigen (24%), autopsy culture (2%), and histopathologic findings (4%). Fifty cases (33%) were diagnosed by more than one method: culture and antigen (29%), culture and histopathologic findings (1%), antigen and histopathologic findings (3%), and culture, antigen, and histopathologic findings (, 1%). While culture was the predominant diagnostic methodology in both the HIV-positive and HIV-negative groups, diagnosis based on latex agglutination antigen positivity occurred more frequently in the HIV-positive group (33%) compared to the HIV-negative group (13%) (p 5 0.004). Overall, 57% of cases had central nervous system disease: in 66% of HIV-positive cases compared to 46% of HIVnegative cases (p , 0.014). Fungemia was present in 31/ 153 (20%) of the total cases. Among HIV-positive patients, fungemia was present in 26 of 84 (31%) as compared to 5 of 68 (7%) HIV-negative patients (p , 0.001). Almost 70% of cases involved only one infection site; however, 36 of 153 (23%) of cases involved multiple organ sites. Among the 36 total cases with multiple sites of infection, 27 of 36 (75%) were HIV-positive and 9 (25%) were HIV-negative. When comparing urban and rural residence in the HIVpositive population, urban residents were at higher risk for cryptococcosis in comparison to rural residents (p , 0.001). However, in comparing urban and rural residence in the HIV-negative population, no significant difference was appreciated (Table 2). The overall number of cases did not vary by year, 75 of 153 (49%) and 78 of 153 (51%), respectively (p 5 0.60). Furthermore, the distribution of cases by season was unre-

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TABLE 2. Urban and rural distributions of cryptococcosis by HIV status in Alabama, 1992–1994 Counties Urban Jefferson Montgomery Mobile Total urban

Rural Total rural

All

Total population

N

HIV1 population

HIV1 cases

HIV2 population

HIV2 cases

651,525 209,085 378,643 1,239,253 Incidence/ 100,000 population

32 7 30 69 2.78

763 267 467 1497

24 6 22 52 1736.0

650,762 208,818 378,176 1,237,756

8 1 8 17 0.69

2,801,334 Incidence/ 100,000 population 4,040,587 Incidence/ 100,000 population

84 1.5

1066

32 1501.0

2,800,268

51 0.91

153 1.89

2563

84 1638.7

4,038,024

68 0.84

markable (p 5 0.29): Winter (December through February), 31%; Spring (March through May), 24%; Summer (June through August), 23%, and Fall (September through November), 22%.

DISCUSSION Our first Alabama statewide active surveillance program for cryptococcosis revealed several important findings. In our study, 55% of cases were HIV-positive, confirming that cryptococcosis is primarily a disease among severely immunosuppressed individuals, especially those with advanced HIV disease. Further, our data indicate that cryptococcosis also occurs in non-HIV infected persons who are either immunocompromised, have less severe underlying diseases, such as diabetes (20%), or have no apparent risk-factors (10%). According to the CDC 1990 Diabetes Fact Sheets, the prevalence of diabetes in Alabama (5%) is nearly twice as high as estimated for the United States. In our study, the frequency of DM in the HIV-negative cryptococcosis population is four times higher than the overall state-wide population estimates for diabetes mellitus. Furthermore, of all HIV-negative diabetic cryptococcosis cases, nine had had diabetes mellitus without another immunocompromising condition, suggesting a 2.6 higher risk. In addition, cryptococcosis was shown to be significantly associated with HIVstatus (p , 0.001) and gender (p 5 0.004). Moreover, a majority of the cases resided in urban areas, confirming previous observations that cryptococcosis is largely a ‘‘cosmopolitan’’ disease. Previous attempts to estimate the incidence or prevalence of cryptococcosis have been limited despite its importance as an opportunistic infection in HIV-infected and

other immunocompromised patients (4, 28–34). A recent CDC study evaluating hospital discharge data estimated that the annual incidence of cryptococcosis in the United States increased at least five-fold between 1980 and 1989, to approximately 2 per 100,000 population (24). This rate is comparable to the rate observed in our study of 1.89 per 100,000 population. Another study of the prevalence of cryptococcosis in New York City illustrates the coincidence of cryptococcal disease with the AIDS epidemic (28). Hajjeh and colleagues conducted a surveillance study of cryptococcosis in metropolitan San Francisco, Atlanta, and Houston in which rates of cryptococcosis averaged 5.26 per 100,000 population (35). In our study, over half of the cases of cryptococcal disease occurred in HIV-infected individuals even though these individuals make up only 0.06% of the Alabama population. In summary, we have described the incidence of cryptococcosis from 1992 to 1994 in an Alabama statewide surveillance project. Infection with human immunodeficiency virus continues to be the most important risk factor for development of cryptococcosis, while other underlying conditions are much less common risk factors. A small proportion of patients have no demonstrable evidence of immune dysfunction. Additional population-based studies should be conducted which better address potential risk factors for exposure to C. neoformans and the development of clinical disease. In this way we can more accurately define populations at high risk for cryptococcosis so that better interventional strategies can be developed and utilized. We would like to acknowledge the assistance of the following institutions and individuals who made this surveillance possible: Kathryn Rivers, Alabama State Data Center; Richard Holmes, Dana Strickland, Alabama State Department of Public Health, HIV/AIDS Surveillance Branch; and

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especially Jeffrey Roseman, M.D., Ph.D., University of Alabama at Birmingham, School of Public Health and William E. Dismukes, M.D., Professor and Vice-Chairman, University of Alabama at Birmingham, Department of Medicine. Additionally, we would like to thank DeShandra Odom for her diligent monitoring and follow-up of cases in the latter half of the project. This work was supported in part by funds from the Centers for Disease Control and Prevention (CDC) and the NIAID Mycoses Study Group, Contract N01-AI-65296, and the University of Alabama at Birmingham. The data from this project was presented, in part, at the 33rd Annual Meeting of Infectious Diseases Society of America, San Francisco, CA, September 16–18, 1995.

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