Pulmonary Complications of HIV Infection Study (PACS)

Objectives

The objective of PACS was to evaluate the types, incidence, course, and outcome of pulmonary disorders in newly diagnosed cases of Acquired Immune Deficiency Syndrome (AIDS), newly diagnosed cases of AIDS-related complex (ARC) and newly diagnosed asymptomatic human immunodeficiency virus (HIV) infection. Knowledge of the incidence and natural history of pulmonary complications associated with HIV infection was important for establishing diagnostic strategies in the development of new treatment regimens and new approaches for clinical research.

Background

Pulmonary infections as a group are the most commonly recognized life threatening disorders in patients with AIDS. Although Pneumocystis carinii was the predominant pulmonary pathogen found in these patients, other organisms were clearly of importance as well, not with early years of the HIV epidemic only in patients with AIDS and ARC but in individuals with asymptomatic HIV infection. In the mid-1980s, physicians who examined many AIDS patients had the impression that a shift was occurring in the types and incidence of pulmonary complications associated with HIV infection. For example, there appeared to be an increased incidence of serious infections caused by pyogenic bacteria and pulmonary and extrapulmonary infection with M. tuberculosis had been noted with increased frequency. Furthermore, lymphoid interstitial pneumonitis (LIP), which is diagnostic of AIDS in children under 13 years old who are HIV antibody positive, was diagnosed with increased frequency in adults. Nonspecific interstitial pneumonitis also appeared to be on the rise. Legionella pneumonia, in contrast to its increased incidence during 1981-83, was seldom encountered by the mid-1980’s.. However, apart from the increased incidence of tuberculosis, a reportable disease, these other shifts in the incidence of pulmonary complications had not been verified.

Subjects

Subjects were recruited from persons who were receiving hospital services, were involved in other cohort studies, homosexual community groups, HIV testing sites, private physicians' practices, methadone treatment programs, support groups; and from unsolicited volunteers. The study participants included HIV-infected homosexual or bisexual men, male and female injection drug users, and female sexual partners of HIV-infected men. Seronegative injection drug users and homosexual or bisexual men were enrolled as controls. The study enrolled 1,353 participants from six clinical centers from different geographic areas in the United States. It was initiated in 1987. Each participant was followed for 3 to 4 years (depending on date of entry) or until death, and data describing the course and outcome of pulmonary processes were collected over the full duration of the study. In addition to the observational aspects of the study, a randomized clinical trial component was also included with the purpose of ascertaining whether intensive follow-up with subsequent treatment improves patient outcomes. The study cohort included two groups of HIV seropositive participants and an HIV seronegative control group. Group A participants were HIV seropositive, had circulating CD4 lymphocyte (T helper cells) counts >400/ul of blood, and had no HIV-related morbidity at baseline. Participants in Group B, who had more severe immunosuppression than did Group A participants, had CD4 lymphocyte counts <400/ul and/or manifestations of HIV infection that were not AIDS-defining (thrush, hairy leukoplakia, fever > 38°C persisting > 2 weeks, involuntary weight loss > 10% of usual weight, or diarrhea persisting > 1 month). The seronegative control group (Group C), comprised of homosexual/bisexual men and injection drug users. It was frequency-matched by age and race with Groups A and B. Group A and Group B members were randomized to either the “intensive” or “routine” follow-up group. The intensive follow-up group underwent screening (chest radiography and pulmonary function tests), blood studies, physical examination, and history at 3-month intervals; the routine follow-up group underwent screening at 12 month intervals and blood studies, physical examination, and history at 6-month intervals. Group C members followed the same schedule as the routine follow-up group. During the period of 1992- 1997, the study was extended to identify patterns of complications among demographic subgroups that had not been extensively studied previously, such as women and African Americans, and to defining differences between HIV transmission groups.

Design

Pulmonary disease is a common in HIV-infected patients and impacts progression of the HIV, respiratory function and survival. PACS demonstrated the high incidence of tuberculosis associated with HIV-infection and delineated risk factors for TB. It established that bacterial pneumonia is more frequent in HIV-positive persons than in seronegative controls, and that the risk is highest among those with CD4 lymphocyte counts below 200 per cubic millimeter and among injection-drug users. In addition, PACS showed that both P. carinii pneumonia and bacterial pneumonia are associated with a significantly worse subsequent HIV disease course and that both Pneumocystis carinii pneumonia and bacterial pneumonia result in expiratory airflow reductions that persist after the acute infection resolves. The clinical implications of this are still being explored. PACS also showed that HIV-infected patients admitted to intensive care units and on mechanical ventilation for PCP and other pulmonary disorders had a high mortality rate, but that mechanical ventilation for non-pulmonary disorders, and admission to the ICU for non-pulmonary diagnoses was associated with a more favorable outcome.

Publications

1. Markowitz N, Hansen NI, Hopewell PC, Glassroth J, Kvale PA, Mangura BT, Wilcosky TC, Wallace JM, Rosen MJ, Reichman LB. Incidence of tuberculosis in the United States among HIV-infected persons. The Pulmonary Complications of HIV Infection Study Group. Ann Intern Med. 1997 Jan 15;126(2):123-32.
2. Hirschtick RE, Glassroth J, Jordan MC, Wilcosky TC, Wallace JM, Kvale PA, Markowitz N, Rosen MJ, Mangura BT, Hopewell PC. Bacterial pneumonia in persons infected with the human immunodeficiency virus. Pulmonary Complications of HIV Infection Study Group. N Engl J Med. 1995 Sep 28;333(13):845-51.
3. Rosen MJ, Clayton K, Schneider RF, Fulkerson W, Rao AV, Stansell J, Kvale PA, Glassroth J, Reichman LB, Wallace JM, Hopewell PC. Intensive care of patients with HIV infection: utilization, critical illnesses, and outcomes. Pulmonary Complications of HIV Infection Study Group. Am J Respir Crit Care Med. 1997 Jan;155(1):67-71.
4. Osmond DH, Chin DP, Glassroth J, Kvale PA, Wallace JM, Rosen MJ, Reichman LB, Poole WK, Hopewell PC. Impact of bacterial pneumonia and Pneumocystis carinii pneumonia on human immunodeficiency virus disease progression. Pulmonary Complications of HIV Study Group. Clin Infect Dis. 1999 Sep;29(3):536-43.
5. Morris AM, Huang L, Bacchetti P, Turner J, Hopewell PC, Wallace JM, Kvale PA, Rosen MJ, Glassroth J, Reichman LB, Stansell JD. Permanent declines in pulmonary function following pneumonia in human immunodeficiency virus-infected persons. The Pulmonary Complications of HIV Infection Study Group. Am J Respir Crit Care Med. 2000 Aug;162(2 Pt 1):612-6.

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