Who Should Receive Corticosteroids as Adjunctive Treatment for Pneumocystis carinii Pneumonia?
1991; Elsevier BV; Volume: 99; Issue: 5 Linguagem: Inglês
10.1378/chest.99.5.1058
ISSN1931-3543
Autores Tópico(s)HIV/AIDS drug development and treatment
ResumoPneumocystis carinii pneumonia remains the most common cause of serious morbidity and mortality in patients with the acquired immunodeficiency syndrome (AIDS). For patients who present with room air PaO2 35 mm Hg, the risk of a fatal outcome is in the range of 20 to 40 percent with conventional therapies. 1Wachter RM Luce JM Turner J Volberding P Hopewell PC Intensive care of patients with the acquired immunodeficiency syndrome: outcome and changing patterns of utilization.Am Rev Respir Dis. 1986; 134: 891-896Crossref PubMed Scopus (142) Google Scholar, 2Brenner M Ognibene FP Lack EE Simmons JT Suffredini AF Lane HC et al.Prognostic factors and life expectancy of patients with acquired immunodeficiency syndrome and Pneumocystis carinii pneumonia.Am Rev Respir Dis. 1987; 136: 1199-1206Crossref PubMed Scopus (130) Google Scholar, 3el-Sadir W Simberkoff MS Survival and prognostic factors in severe Pneumocystis carinii pneumonia requiring mechanical ventilation.Am Rev Respir Dis. 1988; 137: 1264-1267Crossref Scopus (76) Google Scholar, 4Rogers PL Lane HC Henderson DK Parrillo J Masur H. Admission of AIDS patients to a medical intensive care unit: causes and outcome.Crit Care Med. 1989; 17: 113-117Crossref PubMed Scopus (48) Google Scholar Experimental therapies such as eflornithine or trimetrexate have not substantially improved outcome for patients with severe episodes. Thus, results of three controlled studies indicating that early adjunctive therapy with corticosteroids improves outcome and reduces mortality should be embraced with considerable enthusiasm.5Montaner JSG Lawson LM Levitt N Belsberg A Schechter TM Ruedy J. Corticosteroids prevent early deterioration in patients with moderately severe Pneumocystis carinii pneumonia and the acquired immunodeficiency syndrome (AIDS).Ann Intern Med. 1990; 113: 14-20Crossref PubMed Scopus (204) Google Scholar, 6Bozzette SA Sattler FR Chui J Wu AW Gluckstein D Kemper C et al.A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome.N Engl J Med. 1990; 323: 1451-1457Crossref PubMed Scopus (408) Google Scholar, 7Gagnon S Boota AM Fischl MA Baier H Kirksey OW La Voie L. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a double-blind, placebo controlled trial.N Engl J Med. 1990; 323: 1444-1450Crossref PubMed Scopus (307) Google Scholar The first study was a double-blind trial that involved 38 patients with baseline oxygen saturations of 85 to 90 percent at rest or a 5 percent decline in saturation with exercise.5Montaner JSG Lawson LM Levitt N Belsberg A Schechter TM Ruedy J. Corticosteroids prevent early deterioration in patients with moderately severe Pneumocystis carinii pneumonia and the acquired immunodeficiency syndrome (AIDS).Ann Intern Med. 1990; 113: 14-20Crossref PubMed Scopus (204) Google Scholar Of those patients randomized to receive 60 mg of prednisone daily for three weeks, only 6 percent had a 10 percent or greater decline in oxygen saturation, compared with 42 percent in the group who received placebo. There was no difference in survival between the groups. However, in the second study, which evaluated 40 mg of prednisone twice daily for five days followed by tapering doses over the three-week course of anti-Pneumocystis therapy, there were major clinical benefits.6Bozzette SA Sattler FR Chui J Wu AW Gluckstein D Kemper C et al.A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome.N Engl J Med. 1990; 323: 1451-1457Crossref PubMed Scopus (408) Google Scholar Of 220 patients with proven and 31 with presumed Pneumocystis pneumonia, oxygenation failure (defined by PaO2/FIO2 350. The study was flawed by the lack of a blinded design. However, the nature of the end points makes it unlikely that bias could have affected the favorable outcome that occurred. This problem was overcome in a third study, which, like the first trial, was of a double-blind design.7Gagnon S Boota AM Fischl MA Baier H Kirksey OW La Voie L. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a double-blind, placebo controlled trial.N Engl J Med. 1990; 323: 1444-1450Crossref PubMed Scopus (307) Google Scholar Patients with initial respiratory rates >30/min, P(A-a)O2 >30 mm Hg, or PaO2 35 percent were randomized to 40 mg of methylprednisolone intravenously every 6 h for seven to ten days or placebo. The study was discontinued after an interim analysis by a safety monitoring board discovered that only 2 of 11 patients who had received placebo had survived, compared with 9 of 12 corticosteroid recipients. The only downside effects of the corticosteroids in the three studies was an increased incidence of mucocutaneous herpes infection in patients receiving corticosteroids in the second trial.6Bozzette SA Sattler FR Chui J Wu AW Gluckstein D Kemper C et al.A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome.N Engl J Med. 1990; 323: 1451-1457Crossref PubMed Scopus (408) Google Scholar These three studies (and a fourth unreported trial, summarized in 8National Institutes of Health-University of California Panel for Corticosteroids as Adjunctive Therapy for Pneumocystis Pneumonia.Consensus statement on the use of corticosteroids as adjunctive therapy for Pneumocystis pneumonia in the acquired immunodeficiency syndrome.N Engl J Med. 1990; 323: 1500-1504Crossref Scopus (331) Google Scholar) provide compelling evidence that corticosteroids improve outcome and survival when prescribed early in the hospital course for patients with moderate-to-severe episodes of Pneumocystis pneumonia, namely, those with initial room air PaO2 35 mm Hg. In the three studies, adjunctive therapy with corticosteroids was administered within 72 h of initiating treatment with specific anti-Pneumocystis treatments. A panel of experts representing the US Public Health Service and the State of California University-wide Task Force has, therefore, recommended that early treatment with corticosteroids be prescribed for these patients.8National Institutes of Health-University of California Panel for Corticosteroids as Adjunctive Therapy for Pneumocystis Pneumonia.Consensus statement on the use of corticosteroids as adjunctive therapy for Pneumocystis pneumonia in the acquired immunodeficiency syndrome.N Engl J Med. 1990; 323: 1500-1504Crossref Scopus (331) Google Scholar Several issues remain unresolved, however, and caution should be exercised before prescribing corticosteroids for certain populations of patients. In particular, it is unclear whether corticosteroids are beneficial for patients in whom conventional treatments for Pneumocystis pneumonia overtly fail and respiratory failure develops. In a prospective trial in which 41 patients were randomized to receive 60 mg of methylprednisolone intravenously or placebo every 6 h when their PaO2 declined to 350) in the second study,6Bozzette SA Sattler FR Chui J Wu AW Gluckstein D Kemper C et al.A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome.N Engl J Med. 1990; 323: 1451-1457Crossref PubMed Scopus (408) Google Scholar the risk of respiratory failure or death in this group was inherently small. Thus, evaluation of enormous numbers of patients with mild episodes may have been necessary to demonstrate a small but significant benefit for adjunctive corticosteroids. However, there may be major risks in prescribing corticosteroids for all patients with Pneumocystis pneumonia, especially if establishing a definitive diagnosis of Pneumocystis pneumonia is not possible. Patients with miliary tuberculosis or disseminated fungal infections who test positive for human immunodeficiency virus (HIV) may present with clinical manifestations and diffuse interstitial infiltrates indistinguishable from Pneumocystis pneumonia. Moreover, they might initially improve during empiric anti-Pneumocystis pneumonia treatment, which would give the false impression that their pulmonary infection was due to Pneumocystis pneumonia and that diagnostic procedures are not necessary. The problem is likely to be most deleterious with infection due to Mycobacterium tuberculosis, since the organism appears to be more virulent in HIV-positive immuno-deficient patients than fungal opportunists are. In particular, tuberculosis often occurs with only modest-to-moderate CD4 lymphocyte depletion (median of 354 CD4 lymphocytes per cubic millimeter in one study10Chaisson RE, Theur CP Schechter GF HIV infection in patients with tuberculosis, Presented at the Fourth International Conference on AIDS 1988 Stockholm June 12-16Google Scholar and mean of 170/cu mm in another investigation11Modilevsky T Sattler FR Barnes PF Mycobacterial disease in patients with human immunodeficiency virus infection.Arch Intern Med. 1989; 149: 2201-2205Crossref PubMed Scopus (159) Google Scholar), whereas systemic mycoses and other opportunistic lung infections generally occur with severe CD4 immunodeficiency (<100/cu mm). The immunosuppressive effects of corticosteroids could be catastrophic, therefore, in patients with tuberculosis but might have little effect on host immunity in patients who are already severely compromised and infected with other opportunistic pathogens. Thus, considerable caution should be given to prescribing corticosteroids for patients who are at increased risk for tuberculosis. If patients are unwilling or too ill to undergo sputum induction or bronchoscopy for Pneumocystis pneumonia, consideration should be given to initiating treatment with antituberculosis drugs if corticosteroids are to be prescribed empirically for patients at risk for tuberculosis (namely, those with evidence of past exposure to tuberculosis, those of certain ethnicity, and intravenous drug users). In addition, there are anecdotal data indicating that corticosteroids may cause acute exacerbations of pulmonary and cutaneous Kaposi's sarcoma.12Gill P Loureiro C Berstein-Singer M Rarick M Sattler F Levine A. Clinical effect of glucocorticoids on Kaposi's sarcoma related to the acquired immunodeficiency syndrome (AIDS).Ann Intern Med. 1989; 110: 937-940Crossref PubMed Scopus (116) Google Scholar, 13Schulhafer EP Grossman ME Fagin G Bell KE Steroid-induced Kaposi's sarcoma in a patient with pre-AIDS.Am J Med. 1987; 82: 213-217Abstract Full Text PDF PubMed Scopus (52) Google Scholar, 14Real FX Krown SE Koziner B. Steroid-related development of Kaposi's sarcoma in a homosexual man with Burkitt's lymphoma.Am J Med. 1986; 80: 119-122Abstract Full Text PDF PubMed Scopus (32) Google Scholar, 15Koop HO Holodniy M List A. Fulminant Kaposi's sarcoma complicating long term corticosteroid therapy.Am J Med. 1987; 83: 787-789Abstract Full Text PDF PubMed Scopus (22) Google Scholar There is also in vitro evidence that corticosteroids stimulate a Kaposi's sarcoma-dependent growth factor.16Nakamura S Salahuddin SZ Biberfeld P Ensoli B Markham PD Wong-Staal F et al.Kaposi's sarcoma cells: long-term culture with growth factor from retrovirus-infected CD4 + T cells.Science. 1988; 242: 426-430Crossref PubMed Scopus (268) Google Scholar, 17Salahuddin SZ Nakamura S Biberfeld P Kaplan MH Markham PD Larson L et al.Angiogenic properties of Kaposi's sarcoma-derived cells after long-term culture in vitro.Science. 1988; 242: 430-433Crossref PubMed Scopus (284) Google Scholar In many cases, pulmonary Kaposi's sarcoma is associated with typical nodular or “alveolar” consolidation superimposed on interstitial infiltrates, hilar adenopathy, or pleural effusions that are different from Pneumocystis pneumonia.18Meduri GU Stover DE Lee M Myskowski PL Carabelli IF Zaman MB Pulmonary Kaposi's sarcoma in the acquired immunodeficiency syndrome: clinical, radiographic and pathologic manifestations.Am J Med. 1986; 81: 11-18Abstract Full Text PDF PubMed Scopus (141) Google Scholar, 19Gill PS Akil B Colletti P Rarick M Loureiro C Bernstein-Singer M et al.Pulmonary Kaposi's sarcoma: clinical findings and results of therapy.Am J Med. 1989; 87: 57-61Abstract Full Text PDF PubMed Scopus (103) Google Scholar However, a sizable proportion of patients with pulmonary Kaposi's sarcoma have only interstitial infiltrates19Gill PS Akil B Colletti P Rarick M Loureiro C Bernstein-Singer M et al.Pulmonary Kaposi's sarcoma: clinical findings and results of therapy.Am J Med. 1989; 87: 57-61Abstract Full Text PDF PubMed Scopus (103) Google Scholar similar to Pneumocystis pneumonia, and the diagnosis of Kaposi's sarcoma must be established at bronchoscopy on the basis of the appearance of cherry red or purple endobronchial lesions. Thus, corticosteroids should be prescribed cautiously in patients with cutaneous Kaposi's sarcoma, and consideration should be given to withholding their use in patients with typical radiographic features or documented evidence of pulmonary Kaposi's sarcoma. In conclusion, corticosteroids may not be beneficial for all groups of patients at risk for Pneumocystis pneumonia, since this treatment could delay diagnosis of other opportunistic complications or worsen certain infections, such as tuberculosis, or tumors like Kaposi's sarcoma. Therefore, every effort should be made to definitively confirm that patients to be treated with corticosteroids have Pneumocystis pneumonia and not another pulmonary complication. Finally, there are currently inconclusive data to justify use of adjunctive corticosteroids as salvage therapy for patients in whom conventional treatments specific for Pneumocystis pneumonia have failed or for patients with mild episodes who have a low risk for a fatal outcome. With the current wave of enthusiasm for corticosteroids, it may be difficult to conduct well-controlled studies to address the role of this treatment for the latter patient group. However, it is likely that history will repeat itself and that investigators will ultimately challenge the value of corticosteroids for certain subsets of patients with Pneumocystis pneumonia. Those who are more inquisitive will attempt to define the mechanism whereby these and other anti-inflammatory agents might reduce lung injury in response to Pneumocystis pneumonia.
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