Original Article
A Controlled Trial of Early Adjunctive Treatment with Corticosteroids for Pneumocystis carinii Pneumonia in the Acquired Immunodeficiency Syndrome
N Engl J Med 1990; 323:1451-1457November 22, 1990
- Abstract
- Abstract
Background.
Pneumocystis carinii pneumonia remains a common cause of serious morbidity and mortality in patients with the acquired immunodeficiency syndrome (AIDS). The extensive lung injury that accompanies pneumocystis-associated respiratory failure and the reports of clinical benefit from the use of adjunctive corticosteroids provided the rationale for this prospective multicenter trial.
Methods.
A total of 333 patients with AIDS and pneumocystis pneumonia received standard treatment and were randomly assigned to receive either corticosteroids (beginning with the equivalent of 40 mg of prednisone twice daily) or no additional therapy. The primary end points in this unblinded trial were the occurrence of respiratory failure (hypoxemia ratio [partial pressure of arterial oxygen divided by fraction of inspired oxygen] <75, intubation, or death), death, and dose-limiting toxicity of the initial standard therapy.
Results.
Of the patients with confirmed or presumed pneumocystis pneumonia (n = 225 and n = 26, respectively), those assigned to treatment with corticosteroids had a lower cumulative risk at 31 days of respiratory failure (0.14 vs. 0.30, P = 0.004) and of death (0.11 vs. 0.23, P = 0.009), as well as a lower risk of death within 84 days (0.16 vs. 0.26, P = 0.026). The frequency of dose-limiting toxicity of the standard therapy was similar in the two treatment groups. Intention-to-treat analyses of the entire cohort confirmed these findings. Clinical benefit could not be demonstrated, however, for patients with mild disease (hypoxemia ratio, >350), equivalent to a partial pressure of oxygen >75 torr on room air. The patients assigned to corticosteroid treatment had an excess of localized herpetic lesions (26 percent vs. 15 percent, P = 0.04) but not of other infections or of neoplasms.
Conclusions.
Early adjunctive treatment with corticosteroids reduces the risks of respiratory failure and death in patients with AIDS and moderate-to-severe pneumocystis pneumonia. Because the adverse effects are few, corticosteroids should be included as part of the initial treatment for persons with AIDS who have moderate-to-severe pneumocystis pneumonia. (N Engl J Med 1990; 323:1451–7.)
Article Activity
- Article
PNEUMOCYSTIS CARINII pneumonia remains a common cause of serious morbidity and mortality in patients with the acquired immunodeficiency syndrome (AIDS).1 2 3 4 5 6 7 8 The extensive lung injury found in patients with respiratory failure due to pneumocystis pneumonia and the antiinflammatory actions of corticosteroids provide a rationale for evaluating the efficacy of adjunctive treatment with corticosteroids.9 10 11 12 13 14 15 16 Clinical evidence in patients who do not have AIDS suggests that although corticosteroids increase the vulnerability to pneumocystis pneumonia, they may reduce the symptoms of infection.17 , 18 In patients with AIDS and pneumocystis pneumonia, reports have suggested that adjunctive treatment with corticosteroids can reduce signs and symptoms, improve lung function, and increase tolerance for antipneumocystis therapy.19 20 21 22 23 24 25 26 27
Although physiologic benefit from adjunctive treatment with corticosteroids has been documented, prospective studies must establish improvement in clinical outcomes, particularly given the concern that corticosteroids may result in the exacerbation or development of opportunistic conditions.28 29 30 31 We conducted a multicenter, randomized, controlled trial of the use of early adjunctive corticosteroids in patients with human immunodeficiency virus (HIV) infection and pneumocystis pneumonia.
Methods
Patient Selection
The patients had received fewer than 36 hours of therapy for HIV-related pneumocystis pneumonia that was either presumed or confirmed. Patients were excluded from the study if they were under 18 years of age or had a documented intolerance to corticosteroids. They were also excluded if they were receiving mechanical ventilation or had a hypoxemia ratio of less than 75. The hypoxemia ratio was calculated as the partial pressure of arterial oxygen divided by the fraction of inspired oxygen. All the patients gave written informed consent before enrollment. The protocol and consent forms were reviewed and approved by the institutional review boards at each institution.
Study Design
This was a randomized, nonblinded clinical trial. The patients were stratified according to center, initial form of antipneumocystis therapy, and severity of illness, as indicated by their initial hypoxemia ratio. The seventy strata were defined as follows: stratum 1, mild (hypoxemia ratio, >350); stratum 2, moderate (hypoxemia ratio, >250 and ≤350); and stratum 3, severe (hypoxemia ratio, ≤250 but >75). The randomization was prepared centrally, with blocks of four patients per stratum and a 1:1 proportion; it was carried out by means of sealed envelopes at the study sites.
The patients were treated with the form of standard therapy selected by their primary physicians. The acceptable standard treatments were oral or parenteral trimethoprim–sulfamethoxazole (15 to 20 mg of the trimethoprim component per kilogram of body weight per day), parenteral pentamidine (3 to 4 mg per kilogram per day), or oral dapsone ( 100 mg per day) plus trimethoprim ( 15 to 20 mg per kilogram per day). The patients randomly assigned to corticosteroid treatment received prednisone (40 mg twice a day for five days, followed by 40 mg daily for five days, followed by 20 mg daily for the duration of antipneumocystis therapy). Patients unable to take oral medication received parenteral methylprednisolone (75 percent of the respective prednisone doses). Patients considered by their physicians to have had no response or to have had intolerance to the initial therapy could be switched to another form of standard therapy. Patients in whom respiratory failure developed could receive corticosteroids on the orders of their primary physicians.
Patients were classified as negative for the disease if no P. carinii was found when adequate specimens obtained at bronchoscopy were examined by standard techniques. Patients who did not undergo these procedures or for whom the diagnosis was not confirmed by examination of sputum were classified as having presumed disease. Patients for whom there was morphologic confirmation of the diagnosis according to the standard criteria used by the pathologists at each participating center were classified as having confirmed disease.
Assessments and End Points
The patients were evaluated at base line and on study days 3, 6, 10, 14, 21, and 84 for the presence of fever (temperature, >38°C [100.5°F]), respiratory symptoms, the occurrence and progression of other disease, and untoward effects of drug treatment. The laboratory evaluation included a random determination of the base-line cortisol level, serial measurements of arterial blood gases, and complete blood counts.
The primary end point of the study was respiratory failure, which was defined as being indicated by death, the institution of mechanical ventilation, or a hypoxemia ratio of less than 75 at a scheduled evaluation (equivalent to a partial pressure of arterial oxygen of less than 60 torr, with a mask delivering 80 percent oxygen). The secondary end points were death and toxicity from antipneumocystis therapy sufficient to necessitate the termination of treatment.
Statistical Analysis
The calculation of sample size called for a total of 240 patients with confirmed pneumocystis pneumonia, in order to permit the detection of a reduction in the risk of an unfavorable outcome from 30 percent to 15 percent, with a beta error of 0.20 and a two-tailed alpha error of 0.05. We estimated that 340 patients would be needed to ensure the recruitment of 240 patients with confirmed disease.
The treatment groups were compared by the chi-square test, the t-test, or the Mann—Whitney statistic, as appropriate. The MantelHaenszel procedure was used as appropriate to adjust for center.32 Survival curves were produced by the Kaplan–Meier product-limit method, and the risks of unfavorable outcomes were compared by the Wilcoxon test.33 Univariate Cox models were used to derive estimated relative hazards for the survival data.34 The effects of base-line covariates on the risks of unfavorable outcomes were determined by fitting Cox proportional-hazards models.35 Significant predictors were identified by an examination of the global chi-square of the log-likelihood ratios in a series of models. The occurrence of symptoms and signs was evaluated by comparing the proportions of observations during which the sign or symptom was present in each treatment group. Distance-weighted least-squares smoothing was used to estimate the risk of an unfavorable outcome across a range of partial pressures of oxygen as measured at presentation.36
Results
Subjects
Between June 17, 1987, and June 16, 1989, 333 patients were entered in the randomized trial. Five patients did not meet the criteria for entry into the study because they already had respiratory failure. Seventy-seven were classified as negative for pneumocystis pneumonia, and 26 were classified as having presumed disease. Of these 26, 13 (50 percent) had respiratory failure before bronchoscopy could be performed, and 11 of these 13 (85 percent) subsequently died. The remaining 225 patients had confirmed pneumocystis pneumonia.
The most clinically relevant group of enrollees excluded only the 82 patients who either did not meet the entry criteria or were demonstrated to be negative for pneumocystis pneumonia. Therefore, this report focuses on the 251 patients with confirmed or presumed disease (225 and 26 patients, respectively). Of these patients, 123 (49 percent) were assigned to receive standard therapy plus adjunctive corticosteroids and 128 (51 percent) to receive standard treatment alone. The base-line characteristics of the two treatment groups were similar (Table 1Table 1
Base-Line Characteristics of 251 Patients with Presumed or Confirmed Pneumocystis Pneumonia, According to Treatment-Group Assignment.). In the corticosteroid group, one (1 percent) and three (2 percent) patients were lost to follow-up after 21 and 84 days of the study, respectively; in the standard-treatment group, five (4 percent) and seven (6 percent) patients were lost after the corresponding intervals.Occurrence of Unfavorable Outcomes
Forty-one of the 251 patients ( 16 percent) died during the acute episode of pneumocystis. One death was due to sepsis with Staphylococcus aureus; the other 40 deaths were related to pneumocystis pneumonia. Seven additional patients received mechanical ventilation, and in seven more hypoxemia ratios of less than 75 were recorded at a scheduled evaluation, but the patients were not intubated. Thus, respiratory failure occurred in 55 of the 251 patients (22 percent). Thirty-seven of these events (67 percent) took place during the first four days on which the patient was studied.
The cumulative risks of respiratory failure on day 21 (the last scheduled evaluation of the acute episode) were 0.13 and 0.28 in the corticosteroid and the standard-treatment groups, respectively (P = 0.004). The cumulative risks of death were 0.09 and 0.18, respectively (P = 0.024) (Fig. 1Figure 1
Cumulative Risk of an Unfavorable Outcome over a Period of 31 Days.). The corresponding cumulative risks at the time of the last pneumocystis-related death on day 31 were 0.14 in the corticosteroid group and 0.30 in the standard-treatment group for respiratory failure (P = 0.004) and 0.11 and 0.23, respectively, for death (P = 0.009) (Fig. 1). The cumulative risks of death on day 84 were 0.16 and 0.26, respectively (P = 0.026).The cumulative risk of dose-limiting toxicity from antipneumocystis therapy after 21 days was 0.22 in the corticosteroid group and 0.31 in the standard-treatment group (P = 0.12). However, the median duration of therapy, which indicates both efficacy and toxicity, was longer in the corticosteroid group among the 201 patients (80 percent) initially treated with trimethoprim–sulfamethoxazole (20.5 vs. 14 days for the standard-treatment group, P = 0.002). Sixty-nine of 98 such patients in the corticosteroid group (70 percent) completed at least 14 days of therapy, but only 56 of 103 patients in the standard-treatment group (54 percent) did so (P = 0.03).
In both treatment groups, the crude risk of an unfavorable outcome was low for the patients in stratum 1, who were less severely ill (Table 2Table 2
Crude Risk of an Unfavorable Outcome after 31 Days of Follow-up, According to Severity of Pneumocystis Pneumonia.). This risk and the difference in risk between the two treatment groups increased with increasing severity of disease (Table 2 and Fig. 2Figure 2
Probability of Death from Respiratory Causes, According to Initial Hypoxemia Ratio.).The patients taking corticosteroids had a lower risk of respiratory failure and death in the subsidiary analyses of all 333 patients enrolled (the intention-to-treat analysis), of the 328 eligible patients, and of the 225 patients with confirmed pneumocystis pneumonia (Table 3Table 3
Estimated Cumulative Risk of an Unfavorable Outcome, According to Eligibility for the Study and Type of Diagnosis of Pneumocystis Pneumonia.). Trends indicating a benefit from corticosteroids were also observed in each subgroup in an analysis performed according to center and type of initial antipneumocystis therapy.Effect on Signs and Symptoms
The symptoms that were observed less often in the corticosteroid group than in the standard-treatment group included fever (34 percent vs. 49 percent, P<0.001), cough (54 percent vs. 68 percent, P<0.001), and dyspnea at rest (29 percent vs. 40 percent, P = 0.01). Chest pain was present to a similar extent in the two treatment groups (25 percent vs. 28 percent, P = 0.16). None of the recorded symptoms were more frequent in the corticosteroid group.
Incidence of Other Conditions and Recurrence
After 84 days of study, there was a higher incidence of focal reactivation of herpesviruses in the corticosteroid group (32 of 123 patients, or 26 percent) than in the standard-treatment group (19 of 128 patients, or 15 percent; P = 0.04) (Table 4Table 4
Incidence of Infections and Cancers.). There was also a trend toward an increase in the incidence of oral thrush after 84 days (Table 4). The incidence of other HIV-associated opportunistic conditions was similar in both treatment groups after both 21 and 84 days of follow-up (Table 4). The effect of corticosteroids on the severity of preexisting conditions was not measured systematically.Information on the use of maintenance therapy and the rate of recurrence of pneumocystis pneumonia after 84 days was available for 178 of the 210 patients who survived the acute episode (85 percent). There were confirmed relapses in 4 of 95 patients (4 percent) in the corticosteroid group and in 4 of 83 patients (5 percent) in the standard-treatment group (P = 0.54), whereas there were unconfirmed relapses in 5 patients (5 percent) and 3 patients (4 percent), respectively (P = 0.80) — a total of nine relapses (9 percent) and seven relapses (8 percent) in the respective groups (P = 0.79).
Multivariate Analysis
The effect of corticosteroids in relation to other prognostic factors was examined with multivariate Cox proportional-hazards modeling. The significant independent predictors of respiratory failure were lower hypoxemia ratios at entry and random assignment to Standard treatment alone. These variables and enrollment at center 3 were significant independent predictors of death during the acute episode. Covariates that were not independently predictive of either outcome included age, risk group, race, history of pneumocystis pneumonia, symptom duration, type of initial primary treatment, presence of other opportunistic or bacterial infection, and initial concentrations of hemoglobin and cortisol.
Effect on Pulmonary Function
The mean hypoxemia ratio on day 3 of the study declined by 41 in the standard-treatment group but increased by 4 in the corticosteroid group (P = 0.01) (Fig. 3Figure 3
Changes in the Hypoxemia Ratio over Time.). Thereafter, oxygenation was improved in both groups, with consistently more improvement in the corticosteroid group. The mean change from base line over the 21 days of observation was an increase of 66 in the corticosteroid group and of 17 in the standard-treatment group (P<0.001).Treatment of Respiratory Failure
Among the patients whose hypoxemia ratio declined to less than 75, mechanical ventilation was used in 5 of 10 (50 percent) in the corticosteroid group and in 15 of 26 (58 percent) in the standard-treatment group (P = 0.48). The patients receiving mechanical ventilation had similar median hypoxemia ratios at the last scheduled arterial blood gas measurement before intubation (205 vs. 214, P = 0.52).
High doses of parenteral corticosteroids were prescribed for "rescue" at the discretion of the primary physician in 7 of 17 patients (41 percent) in the corticosteroid group and 19 of 38 patients (50 percent) in the standard-treatment group in whom respiratory failure developed (P = 0.55). The short-term mortality among the patients who received such therapy after respiratory failure, as compared with that among those who did not, was 11 of 16 (69 percent) as compared with 5 of 7 (71 percent) at center 1 (P = 0.25), 2 of 2 (100 percent) as compared with 15 of 16 (94 percent) at center 3 (P = 0.89), and 4 of 8 (50 percent) as compared with 3 of 6 (50 percent) at all the other centers (P = 0.70). Furthermore, in the 55 patients in whom respiratory failure developed, multivariate Cox modeling showed that neither the original treatment-group assignment nor the use of high-dose corticosteroids was a significant predictor of survival.
Discussion
In this study, the early use of adjunctive corticosteroids in patients with HIV infection and pneumocystis pneumonia was associated with a reduction by approximately half in the risk of acute respiratory failure and death. The benefit in survival persisted over at least 84 days. Outcomes improved for patients with moderate-to-severe lung dysfunction at presentation (Table 2). The benefit appeared to increase with increasing severity of pulmonary dysfunction at presentation (Fig. 3) — a finding corroborated by the strong effect of corticosteroids in a recently concluded double-blind trial in 23 patients with severe pneumocystis pneumonia.37 In accordance with previous observations, the risk of respiratory failure was low, and no deaths from respiratory causes were observed in the patients who presented with mild disease.4
The use of adjunctive corticosteroids did not significantly reduce the treatment-limiting toxicity of anti-pneumocystis therapy. However, the patients in the corticosteroid group who received trimethoprim — sulfamethoxazole were still more likely to complete an adequate course in the initial anti-pneumocystis therapy than their counterparts in the standard-treatment group, because the initial therapy was less often discontinued or changed because of treatment failure or a perception of such failure. No adverse effects directly attributable to treatment with corticosteroids were observed, and except for an increase in the reactivation of localized herpetic lesions, there were no significant differences between the treatment groups in the incidence of other morbid conditions.
Because this study was not blinded, there is a possibility that bias may account for these results.38 Bias in the selection of subgroups for analysis or the ascertainment of end points is ruled out by the significant survival benefit demonstrated in the strict intention-to-treat analysis. Systematic differences in the medical care of patients cannot be ruled out definitively, but several factors make such differences unlikely; among them are the consistent benefit demonstrated at a number of institutions, the consistent use of mechanical ventilation and high-dose corticosteroids for rescue in patients with respiratory failure, and the uniformly poor prognosis of patients with respiratory failure within institutions, regardless of original treatment assignment or use of rescue corticosteroids. Multivariate analysis was used to adjust for possible confounding, but treatment-group assignment remained highly predictive of outcome. Finally, loss to follow-up was slightly more frequent in the corticosteroid group, but all patients lost to follow-up were well at their last evaluation.
Most cases of respiratory failure occurred in association with early deterioration in oxygenation during the first few days of therapy. Thus, the prevention of such early deterioration appears to provide a physiologic basis for the improvement in clinical outcomes in the corticosteroid group (Fig. 2). This effect is consistent with the protective effect of early corticosteroid administration demonstrated previously in animal models of the respiratory distress syndrome39 and in patients with pneumocystis pneumonia.28 Furthermore, the finding of superior oxygenation in the corticosteroid group throughout this study was consistent with a previous report of persistently superior exercise tolerance in patients treated with adjunctive corticosteroids early in their illness.28
Over the next decade, approximately 750,000 episodes of pneumocystis pneumonia can be expected to cause more than 175,000 deaths in the United States and Western Europe.40 The number of cases and fatalities can be reduced by identifying persons at risk and providing them with effective prophylaxis.41 Our data indicate that mortality attributable to pneumocystis pneumonia can be reduced further by the use of an inexpensive course of adjunctive corticosteroids in persons with moderate-to-severe disease. Initial therapy for HIV-related pneumocystis pneumonia in persons with hypoxemia ratios of less than 350 (equivalent to a partial pressure of oxygen of 74 torr while a person is breathing room air) should include prednisone or its equivalent in the dosages used in this trial. Vigorous attempts should be made to confirm the diagnosis in all such patients, in order to avoid adverse effects related to the masking of unsuspected infections, such as tuberculosis and pulmonary cryptococcosis.
Supported by the California University-Wide AIDS Research Program.
*The following additional members of the California Collaborative Treatment Group participated in this study: University of California, San Diego — Vinh Nguyen, M.D., Ben Freeman, L.V.N., and Michael Pate, R.N.; University of Southern California — Karen Kinn, R.N., Ronn Bill, C.R.T.T., and Sheila Tenn, R.N.; University of California, Irvine — Sheila Fitzgibbons, R.N., P.H.N., M.P.A.; Kaiser Permanente Medical Center, Los Angeles — Paul Turner, M.D., and Joel Ruskin, M.D.; Stanford University and Santa Clara Valley Hospital — Stanley Derisinski, M.D., Thomas Merigan, M.D., and David Stevens, M.D.
We are indebted to the medical house staff, the pulmonary physicians, and the physicians and nurses treating patients with AIDS at our institutions; to the participants in this study; to Melville Klauber, Ph.D., for his assistance in the initiation of the study; and to Susan Ellenberg, Ph.D., and David Feigal, M.D., for their advice in planning the analysis of the data.
Source Information
From the Departments of Medicine (S.A.B., A.W.W., A.B., J.N., J. Coffman, B.C., T.-C.M., D.D.R., J.A.M.), Pathology (D.D.R.), and Mathematics (I.A.), University of California, San Diego; the Department of Medicine, University of Southern California and Los Angeles County Hospital, Los Angeles (F.R.S., C.H., B.A., C.T.B., J.L.); the Department of Medicine, University of California, Irvine (J. Chiu, R.L., J.G.T.); the Department of Medicine, Kaiser Permanente Medical Center, Los Angeles (D.G., D.N.); and the Department of Medicine, Stanford University and Santa Clara Valley Hospital, San Jose, Calif. (C.K.). Address reprint requests to Dr. Bozzette at the Division of Infectious Diseases, Box H208, University of California-San Diego Medical Center, 225 Dickinson St., San Diego, CA 92103.
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