Case-Finding and Surveillance
The initial discoveries heralding a new disorder of unknown origin were made by physicians treating patients in Los Angeles. Dr. Michael Gottlieb and his colleagues alerted the CDC that between October 1980 and May 1981 five young, previously healthy homosexual men had been treated in local hospitals for biopsy-confirmed Pneumocystis carinii pneumonia (PCP). Two of the patients had already died. An investigation by an EIS officer confirmed the diagnosis of PCP, a protozoan-produced condition that occurs almost exclusively in persons with severely suppressed or defective immune systems. On June 5, 1981, a short paper describing the patients was published by the CDC in its Morbidity and Mortality Weekly Report (MMWR ).[7]
Gottlieb's communication to the CDC was closely followed by another from both New York City and San Francisco, which reported that in the thirty months prior to July 1981, Kaposi's sarcoma (KS) had been diagnosed in twenty-six male homosexuals between twenty-six and fifty-one years of age.[8] A rare cancer in the United States, KS had historically occurred in this country primarily in elderly males and immuno-suppressed transplant recipients. Its manifestation in a relatively large number of young men was considered highly unusual, as was the appearance of PCP in individuals without a clinically apparent cause for immunodeficiency disease.
An editorial note in the MMWR issue that had published Gottlieb's paper hypothesized that "the fact that these patients were all homosexuals suggests an association between some aspect of a homosexual life-
style or disease acquired through sexual contact and Pneumocystis pneumonia in this population."[9] The conjecture that some aspect of homosexuality predisposed the patients to immune dysfunction and infections was made on the basis of five cases from a single community—a broad generalization indeed to formulate from so small a sample.
The basis for that sweeping hypothesis lay in a rough mixture of analysis and opinion. The CDC had just completed a cooperative study with a number of gay community health clinics. It was a multiyear, multisite study of risk factors for hepatitis B, a disease that can be sexually transmitted and whose prevalence is very high among homosexual men.[10] In analyzing the interrelation of life-style and hepatitis B, the researchers found that blood markers for the disease were significantly associated with, among other factors, the number of male sexual partners and with sexual practices that involved anal contact. On average, the subjects tended to have a high mean number of partners. Nonetheless, because these were younger men (with a mean age of twenty-nine years), all of whom were attending clinics that specialized in sexually transmitted diseases, they were not necessarily representative of homosexual men.
The CDC-associated study took place against a background of other investigations that suggested an increase in the incidence as well as the types of sexually transmitted diseases (STDs) in homosexual men.[11] Analysts linked this epidemic of STDs among gay men to gay liberation and the attendant life-style of bars, discos, and bathhouses and of anonymous sexual partners.[12] These charges reinforced a set of assumptions, often expressed in medical texts (discussed in greater detail below) by venereologists, that gay men, because of their "pathetic promiscuity" and supposed hedonism, are more vulnerable to sexually related diseases than are heterosexual men and women.[13]
The combination of the CDC's recent work on risk factors for hepatitis B transmission, which had increased its awareness of gay sexuality, and its knowledge of the epidemicity of STDs among subgroups within the gay community, probably accounts, in part, for the hypothesis suggested in the MMWR . A greater awareness of homosexual life-style and disease patterns alone cannot explain the CDC's proposal of a hypothesis on the strength of so few actual cases and without seeking evidence that other segments of the U.S. population might be at risk. One might fairly infer that the CDC was prematurely ready to find the etiology of this mysterious disorder in an exotic subculture. This inference is strengthened by the ensuing scientific work undertaken by epidemiologists within and outside the CDC to find in gay culture—particularly in
its perceived "extreme" and "nonnormative" aspects (that is, "promiscuity" and "recreational" drugs)—the crucial clue to the cause of the new syndrome.
Part of the reason for the CDC's speedy adoption of the "life-style" hypothesis was, most likely, that in certain previous outbreaks of diseases of uncertain origin (in particular, Legionnaires' disease in 1976), CDC officials had been criticized for having committed themselves too strongly to a microbial hypothesis without having paid sufficient attention to alternative causative theories.[14] This probably influenced their desire to throw a wide causative net in the case of HIV infection.[15]
A special task force on KS and opportunistic infections was established at the CDC in mid-1981 and charged with the surveillance of all new cases. According to Dr. James W. Curran, head of the task force, the purpose of surveillance was to confirm that the observed disorder was new, that it was occurring in the specific populations and geographic areas reported, and that all cases were verified.[16]
Prior to surveillance, the CDC had to define what constituted a case. It initially described a case as "a person who (1) has either biopsy-proven KS or biopsy-proven, life-threatening opportunistic infection, (2) is under age 60, and (3) has no history of either immunosuppressive underlying illness or immunosuppressive therapy."[17] By September 1982, when the CDC first used the term "AIDS" in the MMWR , it refined this description to define an AIDS case as one with "a disease at least moderately predictive of a defect in cell-mediated immunity, occurring in a person with no known cause for diminished resistance to that disease." Included among the diseases were KS, PCP, and a specific list of "other opportunistic infections," a list that the CDC has amended over the years.[18] The surveillance definition, whose prime purpose is to assist national reporting of the disorder, has, with as much precision as possible, been limited to the more severe manifestations of the disease.[19]
To establish a count of, and to verify, all cases, the task force and EIS officers conducted a letter and telephone survey of physicians in eighteen U.S. metropolitan areas. In addition, by August 1981 all state health departments had formally been asked to notify the CDC of all suspected cases.[20]
To determine if Kaposi's sarcoma had occurred before 1980 in individuals less than sixty years of age, the task force contacted epidemiologists at state or local tumor registries. Because the CDC was the sole supplier of pentamidine, a drug used in the treatment of PCP, its own files could reveal whether the infection had been seen in adults
without underlying illness. Both investigations suggested that the disease was new, the first documented community-acquired epidemic of immunosuppression.[21]
What caused this disorder? With limited clinical data at hand, the CDC did a "quick and dirty" survey of 420 males attending STD clinics in San Francisco, New York, and Atlanta with the intention of finding cases with KS or PCP. The thirty-five cases culled from the sample (biased, or unrepresentative, in that such patients may be more active sexually than the general population) were interviewed on many subjects in the hope that a lead might be discovered.
The researchers found two patterns of behavior that "fell out": sex and drugs. The cases, all homosexuals, had had many sexual partners in the past year (the median number of partners was eighty-seven) and had frequently used marijuana, cocaine, and amyl or butyl nitrite—inhalant sexual stimulants.[22] Were sex and drugs independent of each other, however? The rate of nitrite use, for example, was closely associated with the number of sexual partners, suggesting that nitrite inhalation might be associated with other hypothetical causal variables, including STDs or the medications used to treat them, or types of sexual behavior, or attendance at gay bathhouses.[23] It was also possible that nitrite use was not an etiological factor, but appeared to be one because it was associated with a causal, or "confounding," variable like sexual behavior.
"There are a lot of theories . . . at the start," James W. Curran is quoted as saying:
You get heterosexual doctors examining gays, and they jump on the first possible hypothesis, that it must be due to the sexual behavior of homosexuals. Because gays are involved, there is also the assumption that they are doing drugs. There were suggestions that it had something to do with amebiasis, a type of dysentery that poses a particular threat to gay men because the guilty protozoa can be spread through anal contact. There wasn't any evidence for this either.[24]
Despite the dearth of clinical evidence, amyl nitrite (AN) became one of the first hypothetical causal variables to be investigated. The "quick and dirty" survey had found that 86.4 percent of homosexual or bisexual men had used nitrite in the previous five years, compared to 14.9 percent of male heterosexuals.[25] As a clue, amyl nitrite seemed worth pursuing, particularly as it appeared to be a component of the "gay life-style" thesis that was posited in the MMWR and was riveting the epidemiological researchers. Studies in which nitrite inhalant was a variable will be evaluated below.
Published scientific papers in 1981 were mainly case and surveillance reports—attempts to define the new syndromes and the patients, that is, to formulate what constituted a "case." By describing the population at risk in terms of person, place, and time, and by learning from physicians the clinical details of the disorder, epidemiologists could grope for etiological clues they might use to design formal studies.
One of the first clinical clues the CDC pursued was the possibility that the new syndrome was caused by the cytomegalovirus (CMV), a microbe suspected of being both sexually transmitted and a cause of KS. In September 1981 the British medical journal, The Lancet , published a clinical study of Kaposi's sarcoma in eight homosexual men hospitalized in New York City; the investigation found that of four patients tested, all were positive for CMV.[26] Three months later Michael Gottlieb and his colleagues reported in the New England Journal of Medicine that four previously healthy men with PCP were both infected with cytomegalovirus and were suffering from a marked decrease in white blood cells, particularly of a kind known as "T4 helper cells."[27] Although acknowledging that CMV infection might result from T4-cell deficiency and the reactivation of a dormant infection, Gottlieb and his colleagues preferred to hold CMV highly suspect. Their position was based on previous studies that had shown that exclusively homosexual men had a higher rate of CMV infection than heterosexual men attending the same STD clinic (94 percent versus 54 percent), that the virus could shed in the semen for prolonged periods of time, and that some evidence existed that CMV produced immunosuppression. Consequently, the authors reasoned that CMV might be responsible for immune-system defects, leaving its victims susceptible to opportunistic infections such as PCP and to cancers such as Kaposi's sarcoma.
CMV was also cited by the CDC as one of three possible etiological agents in its year-end summary on the epidemic.[28] Other putative causes, perhaps more closely related to the "life-style" hypothesis, were amyl nitrite and opiate addiction (a recent investigation of eleven immuno-compromised men with PCP treated in New York City had found that seven of the patients, including five heterosexuals, were drug "abusers"[29] ). Did any of these agents bear a relationship to any other? How did CMV fit into the "life-style" hypothesis? An editorial in the New England Journal of Medicine addressed these issues in December 1981.
Ignoring the heterosexual cases of PCP and other opportunistic infections, the editorialist noted that "the question of cause is obviously central. What clue does the link with homosexuality provide?",[30] positing
that the answer was a high incidence of sexually transmitted diseases, including viral infections such as CMV and hepatitis B, which might cause immunosuppression and KS. But because neither homosexuality nor CMV is new, the author suggested that a new factor may have modified the host-agent relationship: recreational drugs, particularly amyl nitrite. Based on this reasoning, he postulated a possible multifactorial disease model,[31] proposing that the joint effects of persistent, sexually transmitted viral infection (presumably from CMV) and a recreational drug like amyl nitrite precipitated immunosuppression in genetically predisposed males. From this followed a clinical course that included minor illnesses, then KS or other neoplasms, and serious opportunistic infections. In essence, the model was an elaboration of the hypothesis originally proposed in the editorial note appended to the first MMWR on the new disease.