HIV AND AIDS Edited by S. Diane Goodwin and Courtney V. Fletcher

ADJUVANT CORTICOSTEROID THERAPY FOR PNEUMOCYSTIS CARINII PNEUMONIA IN AIDS PATIENTS Catherine J. Sistek, Cindy J. Wordell, and Stephen P. Hauptman

OBJECTIVE: To review published abstracts, case reports, and joumal articles and evaluate data examining the use of systemic corticosteroids as adjuvant treatment for Pneumocystis carinii pneumonia (PCP) in patients with AIDS.

Computerized online databases, peer-reviewed joumals from January 1986 through September 1991, and personal communication with a National Institutes of Health correspondent.

controlled trial and recommended by the expert panel is prednisone 40 mg bid (days 1-5), then 40 mg/d (days 6-10), then 20 mg/d (days 1-21).

Ann Pharmacother 1992;26:1127-33.

DATA SOURCES:

The authors identified 13 reports pertinent to this review. By author consensus, five studies were selected for analysis based on sample size, controlled study design, and clinical outcome measures. Recommendations of an expert panel from the National Institutes of Health and the University of California also are discussed. STIIDY SELECTION:

DATA EXTRALIION: Data are presented based on the methodologic strength of the studies reviewed. Studies are assessed on sample size, inclusion criteria, comparative cohort populations, specific patient outcome measures, and statistical analysis.

Results of the study analysis support the use of systemic corticosteroids as early adjunctive therapy for AIDS patients with moderate-to-severe PCP who have an initial arterial oxygen partial pressure of 35 mm Hg on room air. Improved outcomes included decreased mortality, respiratory failure, and deterioration of oxygenation. Data evaluated have shown that adjuvant corticosteroid therapy is most effective when initiated within 72 hours of beginning specific antipneumocystis therapy. A small, but sometimes significant, increased rate of infection in steroid-treated patients was noted. DATA SYNTHESIS:

Based on the literature reviewed, early systemic adjuvant corticosteroid therapy can benefit patients with moderateto-severe AIDS-related PCP. The steroid regimen used in the largest

CONCLUSIONS:

CATHERINE J. SISTEK, Phann.D., at the time of writing. was an Administrative Pharmacy Resident; she is now a Clinical Manager, Department of Pharmacy: CINDY J. WORDELL, Phann.D., is the Assistant Director of Pharmacy, Drug Information Division. Department of Pharmacy: and STEPHEN P. HAUPTMAN, D.O.• is a Professor of Medicine, Department of Medicine, Infectious Disease Division, Thomas Jefferson University Hospital, Philadelphia, PA 19107. Reprints: Catherine J. Sistek, Phann.D., Department of Pharmacy, Thomas Jefferson University Hospital, 11th and Walnut Sts., Philadelphia, PA 19107. S. DIANE GOODWIN, Phann.D., is an Assistant Professor, Division ofPhannacy Practice, School of Pharmacy, University of Colorado Health Sciences Center, Box C238,4200 E. Ninth Ave., Denver, CO 80262; and COURTNEY V. FLETCHER, Phann.D., is an Associate Professor, Department of Pharmacy Practice, College of Pharmacy, University of Minnesota, 7-115 HSUP. 308 Harvard St. S.E., Minneapolis, MN 55455.

This article is approved for continuing education credit.

continues to increase in the US with over 218 300 cases reported as of March 31, 1992. 1 The growing number of AIDS cases is expected to be paralleled by increasing episodes of Pneumocystis carinii pneumonia (PCP),2 the most common life-threatening opportunistic infection associated with the diagnosis of AIDS in HIV-infected patients. It is estimated that up to 80 percent of patients with AIDS will acquire PCP sometime during the course of their disease.' More than 40 000 cases of PCP were estimated to have occurred in 1990, and over 60000 episodes were expected by 1992.4.5 Despite a recent report of improved short-term survival in patients with AIDS-related PCP, the infection remains a significant source of morbidity and mortality.v' Respiratory failure occurs in 5-30 percent of patients with AIDS-related PCP and most will die in the hospital." A near-Hf) percent mortality rate for these patients is not uncommon despite aggressive antipneumocystis prophylaxis, early diagnosis, and rapid initiation of antimicrobial therapy.v"

THE INCIDENCE OF AIDS

Pathophysiology P. carinii is a ubiquitous organism. Most investigators classify the organism as a protozoan based on its response to antiprotozoan drugs (pentamidine and trimethoprim/sulfamethoxazole [TMP/SMXD. However, some argue that it should be labeled a fungus based on specific structural characteristics and staining properties.l':" PCP occurs in the setting of impaired immune function. It has been suggested that asymptomatic primary infection with P. carinii occurs in childhood and pneumocystis pneumonia actually represents the reactivation of latent infection in immunocompromised patients.s" Although the specific immune defects associated with the development of PCP are poorly understood, most cases involve severe defects in 'I'-lymphocyte function." Populations at risk include, but are not limited to, premature, malnourished infants; children with multiple primary immunodeficiencies; cancer patients; and transplant recipients receiving immunosuppressive drug therapy. AIDS is the most common underlying disease as-

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sociated with the development of pneumocystis pneumonia; lllV-infected patients with a CD4+ T-cell count of less than 200/mm3 are particularly susceptible.v" Animal models have been helpful in identifying the pathophysiology of pneumocystis pneumonia. Animals with previous exposure to P. carinii spontaneously develop this illness when given systemic corticosteroids for approximately 60 days. When corticosteroids are withdrawn, the animals mount a dynamic inflammatory response in an attempt to clear pneumocystis organisms from the lung. The disease pathophysiology in animals is identical to that which occurs in humans. P. carinii attaches to type I pneumocytes (primarily responsible for surfactant production) on the surface of alveolar epithelial cells in the lung. The organism multiplies and fills alveolar lumens with a foamy exudate. The typical host inflammatory response is characterized by hypertrophy and hyperplasia of type II pneumocytes (primarily involved with gas exchange)." Eventually the type I pneumocytes are damaged. The diffuse alveolar injury, including increased permeability of alveolar capillary membranes and loss of surfactant, leads to significant impairment of respiratory mechanics.' Therefore, pneumocystis-induced pulmonary damage results from both the .organism itself and the inflammatory response that is elicited.' A heavy influx of alveolar macrophages floods the lungs and invades the interstitium." In almost all cases of PCP, mononuclear cell infiltration and influx of alveolar macrophages are accompanied by granulocyte and lymphocyte accumulation in the lungs. Reports have shown that an increased number of neutrophils in the bronchoalveolar lavage fluid of patients with AIDS-related PCP was associated with a complicated or fatal course.v-" Bronchoalveolar neutrophilia is also a common pathologic finding in adult respiratory distress syndrome (ARDS).ls It has been suggested that the initial lung injury results from complement-induced aggregation of neutrophils that release oxygen free radicals and cause capillary leakage and damage to lung tissue." Pathologic findings in AIDS-related PCP are similar to those found in ARDS and include mononuclear cell infiltration, hyperplasia of type II pneumocytes, interstitial thickening and fibrosis, and filling of alveolar spaces with a foamy exudate. I6,17 Progression of the pulmonary inflammatory process eventually results in alveolar damage and significant lung injury. Patients with AIDS and pneumocystis pneumonia exhibit progressive dyspnea, hypoxia, and marked alterations in gas exchange that can be attributed to both damage from the pneumocystis organism itself and a vigorous host inflammatory response. Specific clinical and laboratory information has been helpful in predicting outcomes for AIDS patients with PCP and respiratory dysfunction. One study reported that patients were more likely to survive an episode of PCP if they had a shorter duration of symptoms prior to and better arterial oxygenation upon admission to the hospital. Respiratory deterioration shortly after bronchoscopy, rapid improvement in arterial blood gas values upon intubation, and a decrease in serum lactic dehydrogenase (LDH) concentrations after intubation also were found to correlate with improved survival," Severity of initial chest X-ray and interstitial edema or fibrosis on lung biopsy are indicative of lung injury." These parameters, along with survival, are representative of those measured and analyzed in trials that 1128



evaluate clinical outcomes for patients with AIDS-related PCP and respiratory dysfunction. Standard drug therapy for PCP is TMP/SMX or intravenous pentamidine. Both drugs have been shown to be comparable in efficacy for treatment of this disease." Interestingly, initiation of antipneumocystis therapy has been associated with progressive deterioration in clinical status over the first few days of treatment. This characteristic initial deterioration in AIDS patients with PCP is thought to be caused by drug-induced damage to pneumocystis organisms resulting in exacerbation of the inflammatory response in the lung." The reaction occurs independently of which drug is used for treatment, and a significant number of patients progress to respiratory failure and death. The precise mechanism by which the oxygen desaturation occurs in AIDS patients with PCP is not known. However, severe pneumocystis pneumonia is associated with extensive damage to lung tissue."

Corticosteroids in AIDS-Associated Pneumocystis carinii Pneumonia Corticosteroids are potent antiinflammatory drugs that are beneficial in a variety of inflammatory and infectious processes, including rheumatoid arthritis, bacterial and tuberculous meningitis, and typhoid fever,":" Corticosteroids also have been shown to be beneficial when used as adjunctive therapy in moderate to severe AIDS-related PCP.8,24-29 The inflammatory response associated with PCP provides a pharmacologic basis for the benefits observed when potent antiinflammatory drugs are administered. Corticosteroids may suppress the pneumocystis-induced inflammatory response by decreasing neutrophil aggregation, blocking increases in membrane capillary permeability, or inhibiting the infiltration of macrophages and mononuclear cells into the lung interstitium." Adjunctive corticosteroid therapy is based on the principle that a vigorous host inflammatory response plays an important role in the lung damage and respiratory decompensation that occur in pneumocystis pneumonia. It is believed that reduced lung injury may lead to improved clinical outcome. Theoretically, there are several disadvantages to administering potent immunosuppressive agents to patients who are already immunocompromised. The potential for further immunosuppression, manifested by increased severity or recurrence of PCP and development of new or resistant opportunistic infections or malignancy, is a legitimate concern in AIDS patients receiving systemic corticosteroids. However, controlled trials and retrospective analysis have not substantiated this theory.8,2S·29,31 There is little evidence that further immunosuppression or increased rates of infection occur in HIV-infected patients. This is in contrast to the use of systemic corticosteroids to induce a laboratory model of PCP in animals." It should also be noted that a short course of systemic corticosteroid therapy does not typically produce the same type or degree of immunosuppression that occurs with long-term corticosteroid adminis-

tration." Reports of PCP development in immunosuppressed patients after corticosteroids were withdrawn first suggested that potent antiinflammatory drugs might be beneficial to treat pneumocystis pneumonia33,34 Almost two decades later, the first case reports of patients with lllV-related PCP who

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Adjuvant Corticosteroid Therapy

benefited from corticosteroid therapy were published.P-" More recent support for the use of corticosteroids in severe AIDS-related pneumocystis pneumonia stems from case reports and uncontrolled studies, which have demonstrated a beneficial effect when steroids are given concurrently with standard antipneumocystis drugS.16,24,25,37,38 The promising

results of these anecdotal reports have led investigators to perform more substantial, controlled studies (Table 126-Z9). A prospective, double-blind trial by Montaner et al. evaluated the effects of adjunctive corticosteroid therapy in 37 AIDS patients with moderately severe, documented PCP infection. All patients had an oxygen saturation by

Table 1. Summary of Studies Evaluating Adjunctive Corticosteroid Therapy for PCP in AIDS Patients VARIABLE

REF. 29

REF. 26

REF. 28

REF. 27

Type ofstudy Patients evaluated (n) Patient follow-up (d) Entry criteria oxygenation measure

C,N,R 251 84

DB,PC,R 41 51

DB,PC,R 23 120--420

DB.PC,R 37 30

hypoxemia ratio 30 breaths/min P(A-a)Oz >30 mm Hg on room air PaOz 60 mm Hg on

pulse oximetry 0z saturation on room air at rest of~85% «90%) or 5% point decrease in Oz saturation with exercise

duration of antipneumocystis therapy before initiation of corticosteroids (h) confmned P. carinii Antipneumocystis therapy drug(s) dose

Adjuvant corticosteroid therapy for Pneumocystis carinii pneumonia in AIDS patients.

To review published abstracts, case reports, and journal articles and evaluate data examining the use of systemic corticosteroids as adjuvant treatmen...
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