Pneumocystis carinii Pneumonia Without Acquired Immunodeficiency Syndrome: Who Should Receive Prophylaxis?
1996; Elsevier BV; Volume: 71; Issue: 1 Linguagem: Inglês
10.4065/71.1.102
ISSN1942-5546
Autores Tópico(s)Pneumonia and Respiratory Infections
ResumoPathogens that cannot be cultivated rapidly and reliably cause myriad difficulties for patients and physicians. Treponema pailidum, Borrelia burgdorferi, and Mycobacterium tuberculosis are familiar examples; the diagnosis and natural history of syphilis and Lyme disease, as well as a means of monitoring response to therapy, remain puzzling and even mysterious. Meanwhile, an entire cottage industry of masks, respirators, air sterilizers, and related equipment has developed around the numerous uncertainties that surround the diagnosis of tuberculosis. One more important pathogen to add to this list is Pneumocystis carinii. As demonstrated in the article by Yale and Limper in the current issue of the Mayo Clinic Proceedings (pages 5 to 13), P. carinii pneumonia (PCP) occurred in 116 patients without acquired immunodeficiency syndrome (AIDS) encountered at the Mayo Clinic from 1985 to 1991 and was noted in patients with an unpredictable array of underlying diseases. This difficulty in diagnosis has important clinical consequences. Studies done by Hughes and associates1Hughes WT Kuhn S Chaudhary S Feldman S Verzosa M Aur RJ et al.Successful chemoprophylaxis for Pneumo-cystis carinii pneumonitis.N Engl J Med. 1977; 297: 1419-1426Crossref PubMed Scopus (483) Google Scholar and others in the 1970s identified the groups at high risk for development of PCP: children with acute lymphocytic leukemia and patients with Hodgkin's disease, rhabdomyosarcoma, or severe combined immunodeficiency syndrome, all of whom had attack rates that exceeded 20% before routine use of prophylaxis.1Hughes WT Kuhn S Chaudhary S Feldman S Verzosa M Aur RJ et al.Successful chemoprophylaxis for Pneumo-cystis carinii pneumonitis.N Engl J Med. 1977; 297: 1419-1426Crossref PubMed Scopus (483) Google Scholar, 2Hughes WT Rivera GK Schell MJ Thornton D Lott L Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis.N Engl J Med. 1987; 316: 1627-1632Crossref PubMed Scopus (323) Google Scholar, 3Sepkowitz KA Brown AE Armstrong D Pneumocystis carinii pneumonia without acquired immonodeficiency syndrome: more patients, same risk [editorial].Arch Intern Med. 1995; 155: 1125-1128Crossref PubMed Scopus (155) Google Scholar Similarly, attack rates for organ transplant recipients were determined in the 1980s and ranged from 5 to 40%, depending on the organ being transplanted.3Sepkowitz KA Brown AE Armstrong D Pneumocystis carinii pneumonia without acquired immonodeficiency syndrome: more patients, same risk [editorial].Arch Intern Med. 1995; 155: 1125-1128Crossref PubMed Scopus (155) Google Scholar PCP, however, continues to occur in groups outside those with high attack rates because of the use of chemotherapeutic agents or corticosteroid therapy. In the series presented by Yale and Limper, PCP developed in 37 patients (32%) with inflammatory or miscellaneous diseases—conditions for which most physicians would not offer PCP prophylaxis. The list of underlying conditions is likely to grow as chemotherapy is given for additional conditions. Methotrexate and cycloserine, for example, may be given for diseases ranging from ulcerative colitis and glomcruloncphritis to rheumatoid arthritis and asthma. Risk Assessment.—Determining who among the thousands of patients receiving these therapies is actually at risk for PCP is crucial. At Memorial Sloan-Kettering Cancer Center, PCP developed in 1.3% of patients with primary or metastalic central nervous system tumors who received corticosteroid therapy,4Sepkowitz KA Brown AE Telzak EE Gottlieb S Armstrong D Pneumocystis carinii pneumonia among patients without AIDS at a cancer hospital.JAMA. 1992; 267: 832-837Crossref PubMed Scopus (259) Google Scholar the first group of patients with solid tumors described as having an appreciable risk. Subsequently, institution of routine prophylaxis has led to a decrease in cases. The aforementioned inflammatory diseases, however, are likely to have attack rates far less than 1.3%; thus, the need exists for rational recommendations for prophylaxis among these patients. The questions underlying any recommendation for prophylaxis are the same: How many patients must be given prophylaxis needlessly to prevent a single case, and what are the consequences of the disease if not prevented? Use of corticosteroids is the common association in the current series and all other reports of PCP in patients with human immunodeficiency virus (HIV) infection, as shown again by Yale and Limper. In their series, 91% of the patients had received corticosteroids, identical to the proportion of patients who had received corticosteroids in an earlier report from Mayo5Peters SG Prakash UBS Pneumocystis carinii pneumonia: review of 53 cases.Am J Med. 1987; 82: 73-78Abstract Full Text PDF PubMed Scopus (82) Google Scholar and similar to rates in other series.4Sepkowitz KA Brown AE Telzak EE Gottlieb S Armstrong D Pneumocystis carinii pneumonia among patients without AIDS at a cancer hospital.JAMA. 1992; 267: 832-837Crossref PubMed Scopus (259) Google Scholar, 6Arend SM, Kroon FP, van't Wout JW. Pneumocystis carinii pneumonia in 78 immunocompromised patients without AIDS: clinical presentation, immunosuppressive state, and factors associated with outcome. Arch Intern Med [in press]Google Scholar In the current report, the dose and duration—from 20 to 56 mg of prednisone for 9 to 16 weeks (depending on the underlying disease)—approximated the regimen used in patients at Memorial Sloan-Kettering Cancer Center, where 113 patients received corticosteroids at a median maximal dose of 80 mg of prednisone for a median duration of 3 months.9Linnemann Jr, CC Cannon CG Staneck JL McNeely BL Prolonged hospital epidemic of salmonellosis: use of trimethoprim-sulfamethoxazole for control.Infect Control. 1985; 6: 221-225PubMed Google Scholar Unfortunately, no series has examined corticosteroid use in a prospective or in a case-control fashion. Thus, additional information is unavailable about why PCP develops in one patient with cancer but not in another who is receiving an identical dose of a corticosteroid for a similar condition. Determining any additional risks is crucial in the control of PCP because it would allow focused prophylactic therapy to be administered to those patients who need it but withheld from the many hundreds who, despite corticosteroid therapy, are seemingly not at risk. Only a scant portion of the literature addresses the central question of how much corticosteroid is too much. In an interesting review of opportunistic infections that occurred in 23 patients with endogenous Cushing's syndrome,7Graham BS Tucker Jr, WS Opportunistic infections in endogenous Cushing's syndrome.Ann Intern Med. 1984; 101: 334-338Crossref PubMed Scopus (154) Google Scholar the investigators found that morning plasma cortisol levels were highest among patients in whom PCP developed in comparison with other opportunistic infections such as cryptococcosis or aspergillosis; this finding suggests that relatively more immunosuppression is necessary for PCP to occur. In a meta-analysis of 71 clinical trials that involved more than 4,000 patients, the risk of occurrence of any type of infection was significantly increased in patients who received corticosteroids versus those who did not (12.7% versus 8.0%).8Stuck AE Minder CE Frey FJ Risk of infectious complications in patients taking glucocorticosteroids.Rev Infect Dis. 1989; 11: 954-963Crossref PubMed Scopus (664) Google Scholar The authors, however, did not specifically analyze the subset of patients with opportunistic infections. Widespread Prophylaxis?—The next obvious question is, because prophylaxis with trimelhoprim-sulfamethoxazole is almost 100% effective, why not simply provide this prophylaxis for all patients with neoplastic diseases, organ transplants, or inflammatory conditions who receive corti-costeroids or other therapies—particularly because PCP in patients without AIDS is associated with a high (30 to 50%) mortality rate? Although this proposal is attractive at first glance, several arguments can be made against widespread prophylaxis. 1.In the original reports by Hughes and coworkers,1Hughes WT Kuhn S Chaudhary S Feldman S Verzosa M Aur RJ et al.Successful chemoprophylaxis for Pneumo-cystis carinii pneumonitis.N Engl J Med. 1977; 297: 1419-1426Crossref PubMed Scopus (483) Google Scholar, 2Hughes WT Rivera GK Schell MJ Thornton D Lott L Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis.N Engl J Med. 1987; 316: 1627-1632Crossref PubMed Scopus (323) Google Scholar they noted that trirnethoprim-sulfamethoxazole was well tolerated and associated with a low rate of myelosuppression. In the ensuing years, however, the availability of more potent chemotherapy has led to a more prolonged duration of myelosuppression and—perhaps—a higher likelihood that agents such as trimelhoprim-sulfamethoxazole will contribute to clinically significant myelosuppression.2.Occasional reports have suggested poor tolerance of trirnethoprim-sulfamethoxazole in otherwise normal hosts. In an outbreak of Salmonella infection among hospital dietary workers, the investigators opted to treat all 50 employees with a 2-week course of trirnethoprim-sulfamethoxazole. To their surprise, adverse reactions developed in 16 subjects (32%).9Linnemann Jr, CC Cannon CG Staneck JL McNeely BL Prolonged hospital epidemic of salmonellosis: use of trimethoprim-sulfamethoxazole for control.Infect Control. 1985; 6: 221-225PubMed Google Scholar3.The antibacterial activity of trirnethoprim-sulfamethoxazole may create an additional problem. My colleagues and I have administered PCP prophylaxis to many patients who were receiving chemotherapy. In such patients, hospitalizations for neutropenia and fever are often complicated because the trirnethoprim-sulfamethoxazole may influence blood culture results. Similarly, culture results in patients with postoperative wound infections may be un-revealing; consequently, prolonged courses of broad-spectrum empiric therapy may be given. Conclusion.—So to whom should prophylaxis be given? Yale and Limper suggest consideration of prophylaxis in patients receiving “prolonged daily systemic corticosteroid therapy,” similar to our reported recommendation.3Sepkowitz KA Brown AE Armstrong D Pneumocystis carinii pneumonia without acquired immonodeficiency syndrome: more patients, same risk [editorial].Arch Intern Med. 1995; 155: 1125-1128Crossref PubMed Scopus (155) Google Scholar When asked to be more specific, however, all authors intentionally equivocate. We have previously recommended that any patient with an underlying immunologic disorder, such as that conferred by chemotherapy, transplantation, or an inflammatory disorder, who receives the equivalent of at least 20 mg of prednisone a day for more than a month be given prophylaxis.3Sepkowitz KA Brown AE Armstrong D Pneumocystis carinii pneumonia without acquired immonodeficiency syndrome: more patients, same risk [editorial].Arch Intern Med. 1995; 155: 1125-1128Crossref PubMed Scopus (155) Google Scholar In contrast, prophylaxis is unnecessary in patients receiving identical doses of corticostcroids who have no underlying immunologic disorder, such as those with asthma. Because of the difficulties in diagnosing PCP, as well as the current inability to understand how much corticosteroid is too much, a more specific recommendation cannot be given. CorrectionMayo Clinic ProceedingsVol. 71Issue 3PreviewIn the January 1996 issue of the Mayo Clinic Proceedings in an editorial entitled “Pneumocystis carinii Pneumonia Without Acquired Immunodeficiency Syndrome” by Sepkowitz (Mayo Clin Proc 1996; 71:102–103), the last sentence in the third paragraph on page 102 should have read as follows: Full-Text PDF
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