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 derangement 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-surveillance 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, we developed a classification system that provides a framework for managing patients 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 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 lymphadenopathy 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 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 carini pneumonia), other disorders associated with AIDS include the parasitic infectious toxoplasmosis (which typically attacks the intestinal tract, causing chronic diarrhea).

Stage 6 opportunistic diseases also include the fungal infectious cryptococeosis (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 are two treatments, including a medicine (ganciclovir) that can halt the progression of cytomegalovirus- 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.