Today AIDS has become a major cause of morbidity and mortality in the U.S. Indeed, it has become the leading cause of death in the country among people with hemophilia and users of
illegal intravenous (IV) drugs. Moreover, nation-wide morbidity and mortality rates will increase in the next few years as some of the one to 1.5 million Americans who are already infected with the human immunodeficiency virus (HIV) develop AIDS. Most of those affected in the near future will be either homosexual men or IV drug abusers, and a significant proportion of them will be blacks and Hispanics. Yet, given the fact that the virus is transmitted through sexual contact, through the traces of blood in needles and other drug paraphernalia and from mother to newborn infant, one can envision many possible chains of infection, which leave no segment of the U.S. population completely unaffected by the threat of AIDS.
The discovery of the epidemic, the enumeration of the varied manifestations of HIV infection and the analysis of the circumstances that made it possible for such an infection to spread have been missions assigned to epidemiology: the study of the occurrence and distribution of disease as well as its control in a given population. Epidemiologists monitor mortality and morbidity rates associated with HIV infection and AIDS; they also make predictions of likely changes in HIV infection rates in the course of time.
Most important, by carrying out studies to define the ways HIV is transmitted from person to person, epidemiologists can identify the population groups that are at greatest risk of acquiring AIDS and thereby develop strategies for the prevention and control of the disease — strategies that are independent of the development of an effective vaccine or therapy. Indeed, determining the risk factors for AIDS enabled the U.S. Public Health Service and other groups to issue recommendations for the prevention of AIDS as early as 1983, a full year before HIV was firmly identified and two years before laboratory tests to detect the presence of the virus became widely available.
To carry out all these tasks epidemiologists depend on surveillance: the gathering of high-quality, consistent and interpretable data on a disease or an infection. Surveillance data are routinely compiled from reports filed with state and local health departments that are then forwarded to the U.S. Centers for Disease Control (CDC).
Because the disease appeared to be transmitted through the exchange of blood or by sexual contact, most investigators were convinced by late 1982 that the cause of AIDS was an infectious agent (most likely a virus) and not the result of exposure to toxic substance^ or other environmental or genetic factors. The infection hypothesis was finally confirmed when HIV was isolated by Luc Montagnier and his colleagues at the Pasteur Institute in Paris and by Robert C. Gallo and his colleagues at the National Cancer Institute.
Soon after the discovery of the AIDS agent a laboratory test was developed to detect antibodies to HIV in the blood. A positive result in a test of a person's 'blood sample was a, reliable sign that the person was infected with the virus. Such a serological test made it possible to detect HIV infection in people who showed no clinical symptoms, and to confirm clinical diagnoses of AIDS and other HIV-related conditions. It also made it possible to measure directly the prevalence of HIV infection (the number of infected people in a given population at a given time) and its incidence (the number of new infections occurring within a defined period in a specific population). Most important, perhaps, was the fact that the national supply of donated blood could now be screened, so that additional cases of AIDS due to blood transfusions and contaminated blood products could be avoided.
RISK OF HIV INFECTION
The possibility that one can become infected with HIV if contaminated blood penetrates the skin or mucous membranes also represents a small but definite occupational risk for health-care workers. In a national collaborative study done by the CDC, four of 870 health-care workers who had accidentally punctured their skin with needles contaminated with the blood of HIV-infected people developed HIV infection, but none of the 104 workers whose mucous membranes or skin had been exposed to blood became infected. In another study of health-care workers at the National Institute of Health, no HIV infections occurred among 103 workers with needle-stick injuries, nor were there any HIV infections among 691 workers who had a total of more than 2000 reported skin and mucous-membrane exposures to blood or body fluids of AIDS patients. The studies are consistent with other data indicating that the occupational risk of acquiring HIV infection in health-care settings is low and is most often associated with percutaneous inoculation of blood from an infected patient.
HIV is also transmitted from an infected mother to her newborn child, but. the extent of transmission that takes place respectively during pregnancy, at birth or soon afterward is as yet unknown. Detection of HIV in fetal tissues supports the hypothesis that infection occurs in utero, and case reports of women who became infected with HIV immediately after giving birth, and subsequently infected their infants, suggest that the virus may be transmitted through breast-feeding.
Studies of such perinatal transmission are greatly complicated by the lack of a reliable diagnostic test to determine HIV infection in newborns.. As is the case with other infections, infants born
to HlV-infected mothers have maternaJly derived HIV antibodies circulating in their blood — regardless of whether or not they have been infected. The maternal HIV antibodies may persist for as long as 12 months and cannot be distinguished from antibodies that may be present in an infant infected with HIV. Other tests are under development for identifying HIV infection in these newborns. Currently all infants born to infected mothers must be followed closely for at least 12 months to see whether there is any clinical or laboratory evidence of HIV infection or AIDS.
To evaluate the' risk of HIV transmission through other casual contacts, several prospective studies (which are carried out over several years) have been done of the families of infected adults and children. In spite of tens of thousands of.days of household contact with infected individuals, not one of more than 400 family members has been infected with HIV — except for sexual partners of the infected person and children born to infected mothers. In these studies the documented risk of household transmission was zero, and therefore the. actual risk must be extremely low, even in crowded households. The risk of transmission in other social settings, such as schools and offices, is presumably even lower than in household settings.
Epidemiological studies in the U.S. and other countries throughout the world show no patterns of HIV infection consistent with transmission by insect vectors. If HIV were transmitted by insect vectors, additional cases of infection would be seen in people who share environments with infected individuals. Such evidence is lacking, in spite of extensive surveillance efforts.
Although HIV can survive for from several hours to several days in insects artificially fed blood with high concentrations of the virus, there is no evidence that HIV" actually grows in insects. Such a biological event is important in most viral diseases transmitted by insects.
To be sure, the existence of other unrecognized modes of HIV transmission can never be entirely excluded, but if they do exist, they appear to be extremely rare.
HIV INFECTION: THE CLINICAL PICTURE
As physicians we are often asked to describe the typical course of AIDS: the severe immune deficiency that enables normally benign organisms to flourish destructively in patients. Our answer is that people are asking the wrong question. Now that AIDS is known to be caused by a virus — the human immunodeficiency virus, or HIV — the focus should be on the full course of the viral infection, not solely on AIDS. HIV causes a predictable, progressive derange-
ment of immune function, and AIDS is just one, late manifestation of that process.
An emphasis on HIV is important because it facilitates both treatment and prevention. Prompt diagnosis of HIV infection enables the patient to receive optimal medical care from the earliest moments of the disease. Such care can often prevent complications from developing or getting unnecessarily out of hand. For instance, the lethal opportunistic infection "Pneumocystis carinii" pneumonia (PCP), which has been a hallmark of AIDS, can now actually be prevented with medication given early in the course of HIV disease. (Opportunistic infections are ones that occur because the immune system has broken down.) In addition, the medicine Retrovir (also known as AZT), which has been shown to prolong life in patients with late-stage disease, holds promise as a therapy for patients in earlier stages of infection. Early diagnosis also eliminates the unwitting transmission of HIV and gives people the opportunity to consider changing their behavior before they pass the virus to others.
Although the continuing emphasis on AIDS alone is seriously misguided, it is somewhat understandable. When AIDS was first identified in 1981, it was a mysterious syndrome: a cluster of rare diseases that had suddenly become alarmingly common in homosexual men. In order to identify similar cases of AIDS, and thereby help to uncover the cause and means of transmission, the U.S. Center for Disease Control (CDC) adopted a strict epidemiological-surveil-lance definition. People were said to have AIDS if they contracted Kaposi's sarcoma (a rare cancer) or if they developed any of a few rare opportunistic infections, most notably PCP.
Because we and our colleagues at the Walter Reed Army Medical Center believe HIV-infected patients must be treated on the basis of the fullest possible understanding of their disease, in 1984 we developed a classification system that provides a framework for managing patierrts and understanding the progression of the disease. The system groups patients according to their stage of infection.
The Walter Reed classification system begins with stage zero: exposure to the virus through any of the known transmission routes. Noting exposure facilitates early diagnosis: people who are known to have been exposed to HIV can be evaluated for evidence of infection, such as the presence of antibodies to HIV in the blood. Even before infection is detected they can be told that they may be infected with HIV and so should take steps to avoid spreading the possible infection to others; HIV usually causes no symptoms at first and can take root from six weeks to a year before it is detected by the standard (antibody) HIV test.
Once the presence of HIV has been documented by any reliable test, patients are said to be in Walter Reed stage 1, provided they do not meet the criteria for a higher stage.
Although most people have no symptoms when HIV infection is first diagnosed, some patients develop a disorder resembling mononucleosis. Its symptoms include fatigue, fever and swollen glands, which may or may not be accompanied by a rash. In addition self-limited disorders of the central nervous system have been noted. These range from headaches to encephalitis (inflammation of brain tissue). The cause of these symptoms is not entirely clear. In any event, they disappear, usually within a few weeks.
For the majority of patients the first sign that something is amiss in the immune system is the development of chronically swollen lymph nodes. With the appearance of this chronic lym-phadenopathy a patient moves into stage 2.
Stage 2 typically lasts for from three to five years, and patients still feel well even when it ends. The beginning of stage 3 is defined by a persistent drop in the T4-cell count to less than 400, which is a harbinger of a decline in immune functioning. Patients remain in this stage, however, until direct evidence of an impairment in cell-mediated immunity is discovered — usually about 18 months later — at which point they enter stage 4. That evidence is the failure to respond to three out of four skin tests that measure what is called delayed hypersensitivity: the individual's ability to mount a cellular immune response against specific proteins injected under the skin.
Progression to stage 5 is usually determined on the basis of the development of anergy (a total absence of delayed hypersensitivity). Some time later the first overt symptom of a breakdown in cell-mediated immunity arises: the development of thrush, a fungal infection of the mucous membranes of the tongue or the oral cavity. Thrush is identified by the presence of white spots and ulcers covering the infected area.
In addition to thrush, stage 5 patients often develop unusually severe or persistent viral or fungal infections of the skin and mucous membranes. One example is chronic infection with the Herpes simplex virus, which often produces painful and persistent sores in the skin surrounding the anus, the genital area or the mouth.
Many people develop chronic or disseminated opportunistic infections at sites beyond the skin and mucous membranes within a "year or two after entering stage 5. The emergence of these infections reflects an extremely severe decline in immune function and constitutes progression to stage 6, or what is also called opportunistic-infection-defined AIDS. Most patients enter stage 6
with a T4-cell count of 100 or less and most, unfortunately, die within two years.
Any pathogen that can be eradicated only with the help of vigorous cell-mediated immunity can cause serious disease.
In addition to PCP (Pneumocystis carinii pneumonia), other disorders associated with AIDS include the parasitic infectious toxoplasmosis (which often infects the brain and can lead to seizures and coma) and chronic cryptosporidiosis (which typically attacks the intestinal tract, causing chronic diarrhea). Stage-6 opportunistic diseases also include the fungal infectious cryptoco-ceosis (which frequently causes meningitis but may also damage the liver, bone, skin and other tissues), and histoplasmosis (which can cause self-limited pneumonia in individuals with an intact immune system but causes a disseminated infection of the liver, bone marrow and other tissues in HIV-infected patients and is a frequent cause of chronic fevers).
A common viral infection is cytomegalovirus, a cause of pneumonia, encephalitis, blindness and inflammation of the gastrointestinal tract. As is the case with histoplasmosis and tuberculosis, the cytomegalovirus infection seen in HIV patients is usually a reactivation of a childhood infection that was well controlled until HIV seriously hobbled the patient's immune system. Such bacteria as "Legionella" and "Salmonella" can also be a severe problem for someone in stage 6.
Standard or experimental therapies exist for all these disorders. Among the most exciting developments in recent years is the discovery of several medications that control or even prevent PCP. Pentamidine, Septra/Bactrium and Dapsone are all effective in clearing up the infection; the first two — and a drug called Fansidar — serve as preventives as well.
Also exciting are new treatments for cytomegalovirus. Just two years ago investigators had little hope of discovering an effective therapy for the virus. Today there a.re two treatments, including a medicine (ganciclovir) that can halt the progression of cytomega-lovirus-induced blindness. Research workers are making progress against other HIV-related diseases as well. A drug called acyclovir is under study for the prevention of Herpes simplex infection, and new treatments have been developed for cryptococcal meningitis, disseminated histoplasmosis and mycobacterial diseases.
