Acquired Immune Deficiency Syndrome in the United States: The First 1,000 Cases

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1 THE JOURNAL OF INFECTIOUS DISEASES * VOL. 148, NO. 2 * AUGUST 1983 Acquired Immune Deficiency Syndrome in the United States: The First 1,000 Cases Harold W. Jaffe, Dennis J. Bregman, and Richard M. Selik From the Acquired Immune Deficiency Syndrome Activity, Center for Infectious Diseases, Centers for Disease Control, Atlanta, Georgia Between June 1981 and February 1983, the Centers for Disease Control (Atlanta) received reports of 1,000 patients living in the United States who met a surveillance definition for the acquired immune deficiency syndrome (AIDS). Seventy-three percent of these patients were diagnosed after January 1, The 1,000 patients included 284 with Kaposi's sarcoma (KS), 497 with Pneumocystis carinii pneumonia (PCP), 83 with KS and PCP, and 136 with opportunistic infections other than PCP. The overall mortality has been 39.2%o. Cases have been reported from 32 states and the District of Columbia; New York, California, New Jersey, and Florida account for 82.7% of the reports. All but 61 of the patients could be classified into one or more of the following groups: homosexual or bisexual men, intravenous drug abusers, Haitian natives, or patients with hemophilia. Epidemiologic trends in AIDS cases are consistent with the gradual extension of an infectious agent into new populations. In the spring of 1981, the Centers for Disease Control (CDC), Atlanta, received reports of the unexpected occurrence of Pneumocystis carinii pneumonia (PCP) and Kaposi's sarcoma (KS) among young homosexual men in California and New York City [1, 2]. These illnesses were associated with an acquired cellular immunodeficiency of a type not previously described [3-5]. This immune disorder and the accompanying illnesses became known as the acquired immune deficiency syndrome (AIDS). AIDS has been subsequently reported from other parts of the United States and among heterosexual men and women [6, 7]. In addition to PCP, patients with AIDS were found to be susceptible to a variety of other life-threatening opportunistic infections [5, 7]. The CDC began national surveillance for these diseases in June By February 1983, 1,000 case reports had been received. This report summarizes the epidemiologic features of the first 1,000 cases of AIDS reported from the United States. Received for publication May 3, We thank Paul Pinsky, Ann Rumph, and Jean Smith for assistance with data analysis and David Auerbach, Mary Chamberland, Selma Dritz, James Monroe, Pauline Thomas, and the many other physicians and health department representatives who have assisted in the surveillance of acquired immune deficiency syndrome. Please address requests for reprints to Dr Harold W. Jaffe, Acquired Immune Deficiency Syndrome Activity, Center for Infectious Diseases, Centers for Disease Control, Atlanta, Georgia Cases and Methods Case definition. For surveillance purposes, AIDS is defined as the occurrence of biopsyproven KS and/or biopsy- or culture-proven infection at least moderately predictive of cellular immune deficiency (table 1). Patients who either had received immunosuppressive therapy before the onset of illness or had preexisting illnesses associated with immunosuppression, such as congenital immunodeficiency or lymphoreticular malignancy, are excluded. Also excluded are persons with KS who are over 60 years of age. Although AIDS-like illness has been described in infants [8], the present report is limited to patients who are at least 10 years old. Immunologic testing is not required for inclusion of persons meeting the case definition. Surveillance. AIDS surveillance has been both retrospective and current. Active retrospective surveillance methods have been previously described [7]. In brief, they included (1) review of selected cancer tumor registries, (2) contact with selected physicians in 18 major metropolitan areas, and (3) review of requests received by the CDC's Parasitic Diseases Drug Service for pentamidine isethionate. Current surveillance is predominantly passive in nature, through receipt of reports from individual physicians and local or state health departments. These reports are sup- plemented by the active review of new requests for pentamidine isethionate. 339

2 20 - but 340 Jaffe, Bregman, and Selik Table 1. Infections considered at least moderately predictive of underlying cellular immune deficiency. A. Protozoal and helminthic infections 1. Cryptosporidiosis, intestinal, causing diarrhea for over one month (on histology or stool microscopy) 2. Pneumocystis carinii pneumonia (on histology or on microscopy of a "touch" preparation or bronchial washings) 3. Strongyloidosis, causing pneumonia, CNS infection, or disseminated infection (on histology) 4. Toxoplasmosis, causing pneumonia or CNS infection (on histology or microscopy of a "touch" preparation) B. Fungal infections 1. Aspergillosis, causing CNS or disseminated infection (on culture or histology) 2. Candidiasis, causing esophagitis (on histology, microscopy of a "wet" preparation from the esophagus, or endoscopic findings of white plaques on an erythematous mucosal base) 3. Cryptococcosis, causing pulmonary, CNS, or disseminated infection (on culture, antigen detection, histology, or India ink preparation of CSF) C. Bacterial infection 1. "Atypical" mycobacteriosis (species other than tu-berculosis or lepra), causing disseminated infection (on culture) D. Viral infection 1. Cytomegalovirus, causing pulmonary, gastrointestinal tract, or CNS infection (on histology) 2. Herpes simplex virus, causing chronic mucocutaneous infection with ulcers persisting more than one month or pulmonary, gastrointestinal tract, or disseminated infection (on culture, histology, or cytology) 3. Progressive multifocal leukoencephalopathy (presumed to be caused by papovavirus) (on histology) NOTE. Within each category, the diseases are listed in alphabetical order. "Disseminated infection" refers to involvement of lungs and multiple lymph nodes. The requirediagnostic methods with positive results are shown in parentheses. Statistical techniques. The incidence of AIDS was examined using a least-squares linear regression [9] of the natural log of the exponential function Y = aebx (a > o), where Y = number of cases and x = calendar quarter since the first quarter of The estimated value of the slope (b) was taken to represent the case reporting rate. The ratio of the case reporting rate for PCP to the rate for KS cases was interpreted as the relative reporting rate. Other statistical methods included the Z test for differences between proportions [9], the odds ratio for a single 2 x 2 table with a Taylor series confidence limit [10], and the X2 test of independence for 2 x 2 tables [9]. The acceptable type I error rate was taken to be Results whose test statistic revealed a higher error rate were treated as CASES Cases with Kaposi's sarcoma, not Pneumocystis carini pneumonia Cases with Pneumocystis carinii pneumonia, 20- but not Kaposi's sarcoma 10 0o Cases with both Kaposi's sarcoma -- and Pneumocystis carinii pneumonia Cases with neither Kaposis sarcoma 20 nor Pneumocystis carinii pneumonia, but some other opportunistic 10- infection T Quarter of Diagnosis Figure 1. The first 1,000 reported cases of AIDS in the United States, by quarter of diagnosis, for each of four mutually exclusive disease groups. insignificant. Confidence intervals following a statistic represent a two-tailed interval with 2.50oo in each tail. Results AIDS appears to be a new illness of rapidly increasing incidence (figure 1). Retrospective surveillance established that 77 patients meeting our case definition had been diagnosed before the first cases were reported in the spring of The earliest KS cases were diagnosed in the first quarter of 1978, while the first PCP case was diagnosed in the second quarter of Seventy-three percent of the first 1,000 cases have been diagnosed since January 1, The rates of increase for patients reported to have KS only and PCP only are approximated by exponential curves with PCP cases reported at a 20% faster rate than KS

3 First 1,000 Cases of AIDS 341 Table 2. group. Distribution and mortality of AIDS by disease No. of No. of Disease group cases deaths Mortality (%)* KS but not PCP PCP but not KS KS and PCP Othert Total 1, * Percentage of patients reported to have died, as of January 31, 1983, regardless of when AIDS was diagnosed. t Neither KS nor PCP, but some other opportunistic infection. cases. The apparent small decrease in patients with both KS and PCP and with opportunistic infections other than PCP during the last quarter of 1982 is probably a result of the lag time between diagnosis and receipt of a case report. Mortality from AIDS has been high (table 2). The overall crude mortality of 39.2% is an underestimate of the true mortality because it does not consider that most cases have been diagnosed recently and have not been followed long enough to reasonably assess outcome. Of the 269 AIDS patients diagnosed before January 1, 1982, 196 (73%) are reported to have died. Cases have been reported from 32 states and the District of Columbia (figure 2). The states of New York, California, New Jersey, and Florida accounted for 827 of the 1,000 cases. Within these states, the great majority of cases were reported from major metropolitan areas: New York City, San Francisco, Los Angeles, Newark, and Miami. Comparing the geographic distribution of the first 250 reported cases to the last 250 cases (table 3), one finds that the proportion of cases reported from New York State has significantly decreased (P < 0.05), while there has been a corresponding increase in reported cases from New Jersey and other states. All but 61 of the 1,000 cases could be classified into one or more of the following risk groups: homosexual or bisexual men, iv drug abusers, Haitians living in the United States, or patients with hemophilia. As shown in a schematic Venn diagram (figure 3), these risk groups were not mutually exclusive. The largest overlap betweeni risk groups was for homosexual or bisexual men and iv drug abusers. Of the 882 patients who belonged to one of these groups, 81 (9.2%) belonged to both. Only rarely did Haitians or hemophiliacs intersect with other risk groups. To simplify data analysis, the 1,000 cases were reclassified into a hierarchy of mutually exclusive risk groups. Arbitrarily, homosexual or bisexual men were placed first in the hierarchy whether or not they had other risk factors. The second group consisted of iv drug abusers without a history of male homosexuality (either heterosexual or of unknown sexual orientation). The third group consisted of persons of Haitian origin without a history of male homosexuality or iv drug abuse. The fourth group included persons with hemophilia in none of the previously mentioned groups, and the Chicago 18 Boston 12 New York City 465 San Francisco Newark Los Angeles Number of Cases S Houston D SO.&MG Miami None Figure 2. Distribution of AIDS by state of residence at onset of illness (asterisks refer to standard metropolitan statistical areas).

4 342 Jaffe, Bregman, and Selik Table 3. Distribution of AIDS by state of residence for each consecutively reported set of 250 cases. Total State of First 250 Second 250 Third 250 Fourth 250 first 1,000 residence reported cases (%) reported cases (%) reported cases (%) reported cases (%) reported cases (%) California Florida New Jersey New York Other fifth group consisted of persons in none of the other four groups. Within this hierarchial classification, homosexual or bisexual men accounted for 727 of the 1,000 cases. Compared with the iv drug abusers, Haitians, and persons with hemophilia, homosexual or bisexual patients were 22.9 (11.1 to 47.2) times more likely to have KS (table 4). Only 3.8% of the patients belonging to these three heterosexual risk groups had KS, with or without PCP. The distribution of cases by state of residence varied among the risk groups (table 5). Almost three-quarters of the homosexual or bisexual male patients were from either New York or California, while about 90% of the cases among iv drug abusers were from either New York or New Jersey. The Haitian patients tended to live in either Florida or New York; the patients with hemophilia did not live in the states which accounted for most of the cases from other risk groups. Demographic characteristics of cases by mutually exclusive risk groups are shown in table 6. Although patients ranged in age from 10 to 73 years, 47.9% were years old. The Haitian patients and patients who abused iv drugs tended to be slightly younger than the homosexual or bisexual men. Of the 59 female patients, 49.2% were iv drug abusers. Compared with the homosexual or bisexual male patients, the iv-drug-abusing patients were 6.9 (4.7 to 10.3) times more likely to be either black or Hispanic. The distribution of cases by mutually exclusive risk groups has changed over time (table 7). Between the first and second sets of 250 reported cases, the proportion of homosexual or bisexual men decreased significantly (P < 0.001), while there was a corresponding increase in the proportion of iv drug abusers, Haitians, and hemophiliac patients. From the first to the last set of 250 cases, the proportion belonging to no identified risk group has doubled. The 61 patients who seem not to belong to any of the recognized risk groups (tables 4-6) are under investigation to determine whether new population groups are at risk for AIDS. Unfor- tunately, information regarding risk factors is inadequate for some of these patients because they have died or cannot be interviewed at the time they are reported. Another portion of the 61 patients probably represents the expected "background" occurrence of KS-that is, disease not associated HEMOPHILIACS: 8 INTRAVENOUS DRUG 1 ABUSERS: 236 NONE OF THE OTHER GROUPS: HAITIANS: 54 Figure 3. Overlap of groups at increased risk for AIDS. HOMOSEXUAL OR BISEXUAL MEN: 727

5 First 1,000 Cases of AIDS 343 Table 4. Distribution of AIDS by disease group for each risk group. Distribution by disease group (%) Risk group* No. of cases KS but not PCP PCP but not KS KS and PCP Othert Homosexual or bisexual men Intravenous drug abusers Haitians Hemophiliacs Others Total 1, t Neither KS nor PCP, but some other opportunistic infection. with AIDS. Several new risk groups may, however, be emerging from the study of these 61 patients. For example, five of the 61 patients are women with PCP who deny iv drug abuse themselves but who have been steady sexual partners of male iv drug abusers. One of these men had AIDS himself. Five other patients with no apparent risk factors were reported to have received a transfusion of blood components within three years of the onset of their illness. The donors of the blood components received by these patients are now under investigation. Discussion Because of the predominantly passive nature of the CDC's present AIDS surveillance systems, the results presented in this report must be interpreted cautiously. Some AIDS cases may not be diagnosed, and others may be diagnosed but not reported. These biases may vary over time and from place to place. Active AIDS surveillance in selected New York City hospitals and among patients with hemophilia is underway; programs are being implemented by the CDC in collaboration with the New York City Health Department and the National Hemophilia Foundation. Although the present surveillance has limita- tions, it has established that AIDS is a rapidly emerging, highly serious health problem in the United States. Mortality has been very high. Earlier diagnosis and treatment of KS and the opportunistic infections may improve survival. However, spontaneous return of normal immune function has not been reported in AIDS patients who met the CDC case definition. Until a therapy to reverse the immune dysfunction of AIDS becomes available, mortality is likely to remain high. The occurrence of AIDS among the diverse population groups described in this report suggests an infectious etiology. Reports of AIDS among the sexual partners of homosexual and heterosexual AIDS patients are consistent with transmission of a putative "AIDS agent" by sexual or other intimate person-to-person contact [11, 12]. Transmission of such an agent through blood or blood products is consistent with the occurrence of AIDS in iv drug abusers, patients with hemophilia, and transfusion recipients. The overlap between the homosexual or bisexual male risk group and the iv drug abuser group might explain spread of an "AIDS agent" from one group to the other. Geographically, this overlap occurs particularly in New York City and northern New Jersey. Relatively little overlap between the Haitian Table 5. Distribution of AIDS by state of residence for each risk group. Distribution by state of residence (%) Risk group* No. of cases California Florida New Jersey New York Others Homosexual or bisexual men Intravenous drug abusers Haitians Hemophiliacs Others Total 1,

6 344 Jaffe, Bregman, and Selik Table 6. Demographic characteristics of AIDS by risk group. Distribution Distribution by race/ethnicity (%) by sex (%) No. of Median age in White, Black, Risk group* cases years (range) Male Female non-hispanic non-hispanic Hispanic Other Unknown Homosexual or bisexual men (19-73) Intravenous drug abusers (20-53) Haitians (19-54) Hemophiliacs 7 49 (10-59) Others (15-64) Total 1, (10-73) group and other risk groups has been documented. Illnesses indicative of AIDS have occurred in Haitians living in Haiti, and some Haitians diagnosed in the United States became ill before leaving Haiti [13] (AIDS Activity, CDC, unpublished observations). Whether other Haitians living in the United States acquired their disease here or in Haiti is unknown. Although a single-infectious-agent hypothesis would seem to explain much of the AIDS epidemic, certain epidemiologic observations remain puzzling. For example, what explains the excess of KS cases among homosexual or bisexual men compared with other AIDS risk groups? Perhaps the route of transmission (sexual vs nonsexual) of an "AIDS agent" into a susceptible host plays a role in determining clinical outcome. Or perhaps a cofactor present in the homosexual male population, such as repeated exposure to cytomegalovirus or use of inhalant sexual stimulants, predisposes homosexual AIDS patients to develop KS. The epidemiologic trends presented here suggest that AIDS, a disease first recognized among homosexual men in California and New York City, is now becoming an increasing problem in other population groups and in other parts of the United States. Although these passive surveillance data must be interpreted cautiously, the trends are consistent with the gradual extension of an infectious agent into new populations. Although we believe that the diseases included in the CDC surveillance definition are at least moderately predictive of acquired cellular immune deficiency, the spectrum of AIDS may not be limited to KS and opportunistic infections. Other unusual malignancies, including both a lymphoma classified as either Burkitt's lymphoma or diffuse undifferentiated non-hodgkin's lymphoma [14, 15] and lymphoma limited to the brain [16], have been reported among young homosexual men, with or without previously described manifestations of AIDS. Autoimmune thrombocytopenia associated with impaired cellular immunity has been described among both homosexual men and patients with hemophilia [17, 18]. Physicians from several major metropolitan areas in the United States have reported the occurrence of chronic, generalized, unexplained lymphadenopathy in homosexual men [19]. Many of these patients have laboratory evidence of cellular immunodeficiency, Table 7. Distribution of AIDS by mutually exclusive risk groups for each consecutively reported set of 250 cases. Total first First 250 Second 250 Third 250 Fourth 250 1,000 reported Risk group* reported cases (%) reported cases (0%7) reported cases (0/o) reported cases (0) cases (%) Homosexual and bisexual men Intravenous drug abusers Haitians Hemophiliacs Others

7 First 1,000 Cases of AIDS 345 and a few have developed life-threatening manifestations of AIDS [20] (AIDS Activity, unpublished observations). Finally, abnormalities of cell-mediated immunity have been noted in both asymptomatic homosexual men and patients with hemophilia [21-25]. The meaning of this "asymptomatic immunosuppression" is not clear. It may represent a mild manifestation in the AIDS spectrum or may be an unrelated phenomenon. Continuing surveillance will be needed to determine whether AIDS will continue to increase in incidence and appear in new population groups. The full range of illness associated with AIDS may not yet be known. References 1. Centers for Disease Control. Pneumocystis pneumonia- Los Angeles. MMWR 1981;30: Centers for Disease Control. Kaposi's sarcoma and Pneumocystis pneumonia among homosexual men-new York City and California. MMWR 1981;30: Gottlieb MS, Schroff R, Schanker HM, Weisman JD, Fan PT, Wolf RA, Saxon A. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a newly acquired cellular immunodeficiency. N Engl J Med 1981;305: Masur H, Michelis MA, Greene JB, Onorato I, Vande Stouwe RA, Holzman RS, Wormser G, Brettman L, Lange M, Murray HW, Cunningham-Rundles S. An outbreak of community-acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction. N Engl J Med 1981;305: Siegal FP, Lopez C, Hammer GS, Brown AE, Kornfeld SJ, Gold J, Hassett J, Hirschman SZ, Cunningham- Rundles C, Adelsberg BR, Parham DM, Siegal M, Cunningham-Rundles S, Armstrong D. Severe acquired immunodeficiency in male homosexuals, manifested by chronic perianal ulcerative herpes simplex lesions. N Engl J Med 1981;305: Centers for Disease Control. Follow-up on Kaposi's Sarcoma and Pneumocystis pneumonia. MMWR 1981;30: Centers for Disease Control Task Force on Kaposi's sarcoma and Opportunistic Infections. Epidemiologic aspects of the current outbreak of Kaposi's sarcoma and opportunistic infections. N Engl J Med 1982;306: Centers for Disease Control. Unexplained immunodeficiency and opportunistic infections in infants - New York, New Jersey, California. MMWR 1982;31: Snedecor GW, Cochran WG. Statistical methods. 6th ed. Ames, Iowa: Iowa State University Press, Kleinbaum DG, Kupper L, Morgenstern H. Epidemiologic research: principles and quantitative methods. London: Lifetime Learning Publications, Centers for Disease Control. A cluster of Kaposi's sarcoma and Pneumocystis carinii pneumonia among homosexual male residents of Los Angeles and Orange Counties, California. MMWR 1982;31: Centers for Disease Control. Immunodeficiency among female sexual partners of males with acquired immune deficiency syndrome (AIDS)-New York. MMWR 1983;31: Pitchenik AE, Fischl MA, Dickinson GM, Becker DM, Fournier AM, O'Connell MT, Colton RM, Spira TJ. Opportunistic infections and Kaposi's sarcoma among Haitians: evidence of a new acquired immunodeficiency state. Ann Intern Med 1983;98: Doll DC, List AF. Burkitt's lymphoma in a homosexual [letter]. Lancet 1982;1: Ziegler JL, Drew WL, Miner RC, Mintz L, Rosenbaum E, Gershow J, Lennette ET, Greenspan J, Shillitoe E, Beckstead J, Casavant C, Yamamoto K. Outbreak of Burkitt's-like lymphoma in homosexual men. Lancet 1982;2: Snider WD, Simpson DM, Aronyk KE, Nielsen SL. Primary lymphoma of the nervous system associated with acquired immune-deficiency syndrome [letter]. N Engl J Med 1983;308: Morris L, Distenfeld A, Amorosi E, Karpatkin S. Autoimmune thrombocytopenic purpura in homosexual men [part 1]. Ann Intern Med 1982;96: Ratnoff OD, Menitove JE, Aster RH, Lederman MM. Coincident classic hemophilia and "idiopathic" thrombocytopenic purpura in patients under treatment with concentrates of antihemophilic factor (factor VIII). 1983;308: Centers for Disease Control. Persistent generalized lymphadenopathy among homosexual males. MMWR 1982; 31: Mathur U, Enlow RW, Spigland I, William DC, Winches- ter RJ, Mildvan D. Generalized lymphadenopathy: a prodrome of Kaposi's sarcoma in male homosexuals? [abstract no. 853]. In: Program and abstracts of the 22nd Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, Wallace JI, Coral FS, Rimm IJ, Lane H, Levine H, Reinherz EL, Schlossman SF, Sonnabend J. T-cell ratios in homosexuals [letter]. Lancet 1982;1: Stahl RE, Friedman-Kien A, Dubin R, Marmor M, Zolla- Pazner S. Immunologic abnormalities in homosexual men: relationship to Kaposi's sarcoma. Am J Med 1982; 73: Kornfeld H, Vande Stouwe RA, Lange M, Reddy MM, Grieco MH. T-lymphocyte subpopulations in homosexual men. N Engl J Med 1982;307: Lederman MM, Ratnoff OD, Scillian JJ, Jones PK, Schacter B. Impaired cell-mediated immunity in patients with classic hemophilia. N Engl J Med 1982;308: Menitove JE, Aster RH, Casper JT, Lauer SJ, Gottschall JL, Williams JE, Gill JC, Wheeler DV, Piaskowski V, Kirchner P, Montgomery RR. T-lymphocyte subpopulation in patients with classic hemophilia treated with cryoprecipitates and lyophilized concentrates. N Engl J Med 1983;308:83-6