Original Article
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; 323:1444-1450November 22, 1990
- Abstract
- Abstract
Background.
Preliminary reports suggest that patients with the acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii pneumonia may benefit from the addition of corticosteroid treatment to antibiotic therapy.
Methods.
We conducted a double-blind, placebo-controlled trial to assess the efficacy of adjunctive corticosteroids in patients with AIDS and severe P. carinii pneumonia. Patients with marked abnormalities in gas exchange who had been treated with antibiotics for less than 72 hours were randomly assigned to receive either methylprednisolone (40 mg) or placebo every 6 hours for 7 days, in addition to treatment for 21 days with trimethoprim–sulfamethoxazole. The primary outcome measures were survival until hospital discharge and the development of respiratory failure.
Results.
Twenty-three patients were enrolled in the study; there were no significant differences in base-line clinical or laboratory measures between the two treatment groups. Of 12 patients treated with corticosteroids, 9 (75 percent) survived until hospital discharge, as compared with only 2 of 11 placebo recipients (18 percent) (P<0.008). Respiratory failure developed in nine placebo recipients, as compared with only three patients treated with corticosteroids (P<0.008). No patient required the interruption or discontinuation of corticosteroid or antibiotic treatment because of toxicity or a complicating event. Because of the marked difference in survival, it was deemed unethical to continue the trial, and the study was terminated.
Conclusions.
Early adjunctive corticosteroid therapy can improve survival and decrease the occurrence of respiratory failure in patients with AIDS and severe P. carinii pneumonia. (N Engl J Med 1990; 323:1444–50.)
Article Activity
- Article
PNEUMOCYSTIS CARINII pneumonia is the most JL common opportunistic infection associated with the acquired immunodeficiency syndrome (AIDS). In approximately 60 to 65 percent of patients with AIDS, it is the AIDS-defining diagnosis; another 20 percent of such patients acquire the disease over the course of their illness.1 The death rate from P. carinii pneumonia approaches 25 percent, making it a major cause of mortality.2 3 4 At present, standard chemotherapy consists of a prolonged course of either trimethoprim–sulfamethoxazole or intravenous pentamidine isethionate (pentamidine).1 , 5 6 7 8 9 10 The predictors of a poor clinical outcome include extensive bilateral pulmonary infiltrates, concurrent pulmonary infections, recurrent P. carinii pneumonia, an elevated serum concentration of lactate dehydrogenase, a decreased serum concentration of albumin, a respiratory rate above 30 per minute, leukocytosis, and an alveolar—arterial oxygen difference of more than 30 mm Hg.11 12 13 In addition, when respiratory failure develops in patients with AIDS because of severe P. carinii pneumonia, their chances of surviving until hospital discharge decrease markedly.14 15 16 17 18
Recently, several reports have suggested that therapy with adjunctive corticosteroids might be beneficial in AIDS-related P. carinii pneumonia if it was given before respiratory failure occurred.19 20 21 22 23 24 We conducted this study to determine whether the early addition of corticosteroids to conventional therapy increases survival, decreases the time to recovery, eliminates the need for intubation, or affects the occurrence of other opportunistic infections in patients with severe P. carinii pneumonia, as compared with patients taking antibiotics alone. Although the anticipated enrollment was 80 patients, the trial was terminated sooner, when a statistically significant difference in survival between corticosteroid and placebo recipients became evident.
Methods
The study participants were selected from among the patients at Jackson Memorial Hospital between June 1989 and May 1990. The study was approved by the hospital's institutional review board, and all subjects gave written informed consent before entering the study. An independent safety-data monitoring committee was formed to review data on safety and efficacy at specific predetermined intervals.
Study Population
The study population consisted of patients with a presumptive diagnosis of severe P. carinii pneumonia who had been treated with antibiotics for less than 72 hours. All the patients were infected with human immunodeficiency virus (HIV) type 1, engaged in behavior placing them at risk for HIV infection, or had oral candidiasis at entry into the study. Severe P. carinii pneumonia was defined as disease that met all the following criteria: a respiratory rate above 30 breaths per minute at rest; an alveolar—arterial oxygen difference above 30 mm Hg while the patient breathed room air; and an arterial partial pressure of oxygen below 75 mm Hg while the patient breathed 35 percent oxygen through a face mask but above 60 mm Hg while the patient breathed 100 percent oxygen through a face mask.
Intubated patients were excluded from the study. In addition, patients were excluded if they had any of the following: a history of hypersensitivity to both trimethoprim–sulfamethoxazole and pentamidine; a serum creatinine level more than three times the upper limit of normal; serum levels of transaminases more than 10 times the upper limit of normal; an absolute neutrophil count below 1×109 cells per liter; and treatment with corticosteroids within a period of two weeks before study entry.
A histologic diagnosis of P. carinii pneumonia was required in all patients, on the basis of sputum examination, bronchoalveolar lavage, or transbronchial biopsy performed during hospitalization. In addition, all sputum samples and bronchoscopy specimens were stained for bacterial pathogens and stained and cultured for fungal and mycobacterial pathogens. One patient in whom the diagnosis of P. carinii pneumonia could not be confirmed was withdrawn from the study and excluded from the analysis of data.
Evaluation before Treatment
The pretreatment evaluation included a medical history, a physical examination, and routine laboratory testing as well as determinations of the serum lactate dehydrogenase level and the presence of HIV p24 antigen, a CD4-cell count, arterial blood gas measurements, and chest roentgenography. An enzyme-linked immunosorbent assay for HIV with Western blot confirmation was performed for all patients with HIV infection undocumented at entry into the study. The level of dyspnea was observed by the investigators and graded as follows: grade 1, dyspnea with exercise; grade 2, dyspnea with mild-to-moderate activity; grade 3, dyspnea at rest; and grade 4, notable respiratory distress, with use of the accessory muscles of respiration. The chest roentgenograms were read by a single radiologist and described as follows: grade 0, clear chest; grade 1, increased interstitial markings; grade 2, diffuse bilateral interstitial infiltrates; grade 3, diffuse interstitial pattern with one or more patchy areas of alveolar consolidation; and grade 4, diffuse alveolar consolidation. Initial Karnofsky status was determined for all patients.25
Treatment Regimen
Trimethoprim–sulfamethoxazole was given for 21 days at a dose of 15 mg of the trimethoprim component per kilogram of body weight per day. The administration of the antibiotic and the modification of treatment in the event of toxicity followed the protocol of Sattler et al.8
The study was designed as a double-blind, placebo-controlled trial. The dose of corticosteroid used was chosen on the basis of the preliminary data of MacFadden et al.20 A block randomization in groups of 10 was used to assign the patients to either placebo or methylprednisolone. The placebo material was indistinguishable in appearance from methylprednisolone, and it was given intravenously as a 100-ml bolus of normal saline every six hours for seven days. Methylprednisolone was given intravenously at a concentration of 40 mg in a 100-ml bolus of normal saline every six hours for seven days. Patients who appeared to have a clinical relapse after seven days of therapy with the study drug received a second course of the same study medication, consisting of three days of a tapering dose. After the completion of therapy, all patients were offered prophylactic treatment for P. carinii pneumonia, as well as anti-HIV treatment with zidovudine.
Follow-up Evaluations and Criteria for Response
The patients were reevaluated after 1, 2, 7, 14, 21, and 28 days and until discharge from the hospital. During therapy all the patients had physical examinations, follow-up blood studies, and chest roentgenography. Patients who underwent intubation during the study were given a score of 5 for dyspnea. Arterial blood gas measurements were recorded as having improved or worsened if the arterial partial pressure of oxygen increased or decreased, respectively, by more than 20 mm Hg from the pretreatment levels. The chest roentgenograms were recorded as being better, unchanged, or worse than those recorded before treatment.
The primary outcome measure for all patients was survival to hospital discharge. The secondary outcome measures included respiratory failure and the completion of antibiotic therapy. Respiratory failure was defined as the presence of either an arterial partial pressure of oxygen below 60 mm Hg while the patient breathed ≥60 percent oxygen through a face mask or a rising partial pressure of carbon dioxide, in addition to a need for intubation. Toxic effects, either from the use of antibiotics or possibly corticosteroids, were documented and graded with respect to severity on a scale of 1 (mild) to 4 (severe). Other opportunistic infections and AIDS-related cancers were recorded whenever they were diagnosed. The patients discharged from the hospital were followed monthly for six months to monitor the development of any illness or recurrences of P. carinii pneumonia possibly related to corticosteroid treatment. All patients were followed for the ascertainment of survival.
Statistical Analysis
In the statistical analysis, continuous data (such as the base-line characteristics of the treatment groups) were compared with use of Student's t-test.26 Significant results were confirmed by the Wilcoxon rank-sum test.26 Dichotomous variables (such as survival to hospital discharge or death or the presence or absence of respiratory failure) were compared by the chi-square test.26 All P values were two-sided.
Our initial projections estimated that 80 patients would be required for the study to have an alpha error of 0.05 with a power of 0.8, assuming a true difference of 0.30 in the proportion of events. In the case of early termination of the study, a P value of less than 0.01 was required for statistical significance at the first interim analysis, in order to control the overall alpha error associated with multiple interim analyses.
Results
The study was terminated at the interim analysis, when the difference between treatment groups with respect to survival to discharge from the hospital reached a P value of less than 0.01.
Study Population
Twenty-four patients were evaluated for entry into the study. One patient with no histologic diagnosis of P. carinii pneumonia was excluded; he later died of pulmonary Kaposi's sarcoma. Twenty-three patients were enrolled in the study, of whom 19 were men and 4 were women. The mean (±SD) age of the patients was 38±11 years. Thirty-five percent reported acquiring HIV infection through homosexual contact, 48 percent through heterosexual contact, 13 percent through intravenous drug use, and 4 percent through infected blood components. There were no significant differences between groups with respect to demographic characteristics.
Twelve patients were assigned to corticosteroid therapy, and 11 patients to placebo. There were no significant differences between groups with respect to any pretreatment characteristic (Table 1Table 1
Pretreatment Characteristics of the Patients According to Treatment Group.). The individual CD4-cell counts, the levels of lactate dehydrogenase and HIV p24 antigen, and the findings on initial chest roentgenography did not correlate with the clinical outcomes. The mean alveolar—arterial oxygen difference when the patient breathed 35 percent oxygen through a face mask was 154 mm Hg in the corticosteroid group and 155 mm Hg in the placebo group at entry into the study, corresponding to a partial pressure of oxygen of approximately 30 mm Hg or an alveolar-arterial oxygen difference of approximately 65 mm Hg when the patient breathed room air. The mean duration of symptoms before hospitalization was 3.0±2.1 weeks in the corticosteroid group and 3.1±1.4 weeks in the placebo group. The number of days of antibiotic treatment before entry into the study averaged 1.1±1.0 in the corticosteroid group and 1.4±1.1 in the placebo group. All the patients but one had dyspnea scores of 4, and all the patients had Karnofsky performance scores of 10 at entry. No patient had received zidovudine or prophylaxis for P. carinii pneumonia before enrollment. Only one patient had had a previous episode of P. carinii pneumonia.Clinical End Points
All the patients were treated with trimethoprim–sulfamethoxazole. None required alternative treatment with pentamidine because of drug toxicity. Eleven patients (48 percent) survived to hospital discharge, including nine in the corticosteroid group and two in the placebo group (P<0.008) — a marked difference in survival between groups (Table 2Table 2
Occurrence of Clinical End Points According to Treatment Group.). One recipient of placebo had a respiratory arrest two hours after receiving his first dose of study medication. Although this patient was included in the data analysis, there was still a statistically significant improvement in survival in the corticosteroid group (P<0.012) when a second analysis was performed from which the patient's data were excluded.Twelve patients (52 percent) had respiratory failure, including three in the corticosteroid group and nine in the placebo group (P<0.008). Ten recipients of corticosteroids completed 21 days of antibiotic therapy, as compared with 4 recipients of placebo (P<0.024), but of these 14 who completed treatment, 3 died before discharge from the hospital (21 percent). Overall survival was 79 percent in those who completed antibiotic treatment.
The average hospital stay for all patients was 17 days (range, 1 to 69). The recipients of placebo spent an average of 13 days in the hospital, as compared with 21 days for the recipients of corticosteroids (P<0.12). The placebo group spent an average of 6.3 days in the intensive care unit (49 percent of the total hospital days), as compared with 1.2 days in the intensive care unit (6 percent of the total hospital days) for the corticosteroid group, and the percentage of time spent in the unit differed significantly between treatment groups (P<0.001). All the patients who survived to hospital discharge had clinical and radiologic improvement by 21 days, as well as improvement in arterial blood gas measurements; after 21 days, 73 percent of these survivors had normal arterial partial pressures of oxygen while breathing room air.
Follow-up observation in the 11 survivors ranged in length from 4 to 14 months. Two patients in the corticosteroid group died during follow-up. Three patients were switched to prophylaxis with inhaled pentamidine because of persistent minor toxic effects of trimethoprim–sulfamethoxazole. No patient had a recurrence of P. carinii pneumonia.
Hospital Course
There were statistically significant differences between groups during the first seven days with respect to fever, mean dyspnea score, and alteration in arterial blood gas measurements (Table 3Table 3
Clinical Measures of the Hospital Course of the Patients, from Entry into the Study through Day 7.*). The recipients of placebo had worsening arterial blood gas measurements during the first week; 67 percent had a worsening in arterial partial pressure of oxygen of 20 mm Hg or more at seven days, as compared with 9 percent of the recipients of corticosteroids (P<0.03). The corticosteroid recipients had a decrease in temperature to normal values almost immediately after starting the study medication, a pattern that was not seen in the placebo recipients. The differences between groups were statistically significant throughout the first seven days (P<0.001 for days 1 through 5 and P<0.01 for days 6 through 7) (Fig. 1Figure 1
Comparison of Clinical Values for Patients during Short-Term Treatment for P. carinii Pneumonia.A). There was an increase in temperature after the discontinuation of corticosteroids that coincided with the development of rashes in some patients and with clinical relapse in others. Levels of lactate dehydrogenase rose during the first 48 hours in the placebo group but remained unchanged during that time in the corticosteroid group and declined persistently thereafter (P<0.06 at both 24 and 48 hours) (Fig. 1B). White-cell counts were higher in the placebo group after 24 hours of treatment (P<0.05) and higher in the corticosteroid group at seven days (P<0.05) (Fig. 1C). Because of the high mortality in the placebo group during the first week of the study, no comparisons between groups were attempted after seven days.Toxicity Data
Toxic effects possibly attributable to treatment are shown in Table 4Table 4
Toxic Effects Possibly Attributable to Treatment with Trimethoprim–Sulfamethoxazole or Methylprednisolone, According to Treatment Group.. The most frequent toxic effects of trimethoprim–sulfamethoxazole were fever and rash, which occurred in five patients and were severe in two. All the patients could be maintained on trimethoprim–sulfamethoxazole with the addition of acetaminophen and diphenhydramine. Elevated results on liver-function tests developed in four patients during treatment; of these, three had concomitant chronic viral hepatitis. In one patient, severe hyperglycemia developed during parenteral hyperalimentation that was sufficient to require the addition of insulin to the hyperalimentation fluid. Hyponatremia developed in two patients, both of whom also had mycobacterial infections. One patient had nausea and vomiting that resolved when his dose of trimethoprim–sulfamethoxazole was reduced to 12 mg of the trimethoprim component per kilogram per day. One patient had a marked increase in blood pressure that resolved when corticosteroid therapy was discontinued and he was switched to oral trimethoprim–sulfamethoxazole.Complications, Other Infections, and Cancers
Two patients (one in each group) had gastrointestinal bleeding that required a transfusion of packed red cells. One patient in the corticosteroid group had a pneumothorax, and another (also in the corticosteroid group), who had a history of an abdominal gunshot wound, had an infarction of his small bowel that required emergency surgical resection. This patient also had deep venous thrombosis that required anticoagulation therapy for three months.
After the withdrawal of corticosteroids, four patients had serious clinical worsening of their P. carinii pneumonia that necessitated the reinstitution and tapering of the medication. Twenty patients had other infections or cancers within six months of entry into the study. These are listed in Table 5Table 5
Distribution of Infections and Cancers According to Treatment Group.* according to the time of diagnosis.Discussion
This double-blind, placebo-controlled trial demonstrates that adjunctive therapy with corticosteroids prevents respiratory failure and improves survival when it is given early to patients with severe P. carinii pneumonia. The results indicate that there is an important role for corticosteroids in the treatment of patients with AIDS and that their use may have dramatic benefits. Our study population was limited to patients who were close to the development of respiratory failure but in whom this condition had not yet occurred, and who had been treated with antibiotics for less than 72 hours. The use of adjunctive intravenous methylprednisolone increased survival, specifically by decreasing the incidence of respiratory failure.
Previous studies of the potential role of adjunctive corticosteroids have reported survival benefits ranging from 0 to 65 percent.19 20 21 22 23 Unfortunately, in most cases the study design has limited the extent to which definitive conclusions can be drawn from these studies. Recently, however, Montaner et al. completed a double-blind, placebo-controlled study that used adjunctive corticosteroids in the treatment of P. carinii pneumonia.24 Their patients had less severe pulmonary disease than those we studied, and because of the crossover design of the study, the patients could not be evaluated for the effect of corticosteroids on respiratory failure or survival. Corticosteroids were associated, however, with decreased respiratory deterioration early in antibiotic therapy in patients with moderately severe disease; those results are concordant with the results in our study.
Because several studies of patients without AIDS have shown no effect of corticosteroid therapy in patients with the adult respiratory distress syndrome (ARDS), we attempted to study a population of patients in whom ARDS had not yet occurred.27 , 28 Since most patients with mild P. carinii pneumonia have good survival outcomes without intervention involving corticosteroids, we excluded this population from our study as well. A limit of 72 hours of antibiotic treatment for entry into the study was set for practical reasons and in order to maintain a uniform study population. Whether the use of the term "early" to describe such adjunctive corticosteroid treatment truly relates to the number of days of antibiotic therapy or simply describes the period before the development of ARDS is unclear from this study.
The clinical response in our patients was characterized by improvements in temperature, dyspnea score, and arterial blood gas measurements, with significant differences between groups during the first week of treatment. After the withdrawal of corticosteroids, 25 percent of the patients had a clinical relapse, with worsening arterial blood gas values and chest roentgenograms and increases in the serum lactate dehydrogenase concentration. When corticosteroid treatment was reinstituted and tapered, all but one of these patients improved and ultimately did well. These findings suggest that a tapering schedule may be warranted, but they do not define an optimal duration of the tapering.
Severe toxic effects of antibiotics were uncommon in our study, and no patient required the substitution of intravenous pentamidine for trimethoprim–sulfamethoxazole. Corticosteroids may have decreased the severity of the most common toxic effects associated with trimethoprim–sulfamethoxazole, enabling patients to complete therapy with one drug and avoid altogether the toxic effects and complications associated with pentamidine. Furthermore, we used a starting dose of trimethoprim–sulfamethoxazole that included 15 mg of the trimethoprim component per kilogram per day and 100 mg of sulfamethoxazole — a dose slightly lower than the standard one, but one that appeared effective in the comparative trial of antibiotic treatment for P. carinii pneumonia conducted by Sattler et al.8
Because of the severity of illness in our study population and the high mortality in our placebo group, we could not assess comparatively the incidence of possible illnesses associated with corticosteroids, such as mycobacterial or viral infections or Kaposi's sarcoma. The number of infections and cancers diagnosed in the recipients of corticosteroids after hospitalization may indicate an effect of corticosteroid treatment or reflect the continued survival of a very immunocompromised population of patients. There was no significant difference in the length of hospitalization between treatment groups, despite the severe mortality in the placebo group. When the amounts of time spent in the intensive care unit were compared, however, the placebo group made significantly more use of the intensive care unit, without improvement in outcome.
Our study shows that early intervention with corticosteroids in patients with AIDS and severe P. carinii pneumonia results in a dramatic survival benefit and a decrease in the incidence of respiratory failure. In addition, treatment with corticosteroids in this population of patients was associated with a decrease in the use of the intensive care unit. On the basis of these findings, we recommend the early use of adjunctive corticosteroids for at least seven days in nonintubated patients with severe P. carinii pneumonia, followed by a tapering dose of corticosteroids. Although we have not identified the optimal dosage or type of corticosteroid to use, 40 mg of methylprednisolone given intravenously every six hours was very effective in our patients. Investigation into the mechanism of action of corticosteroids in the lungs of such patients may provide further insight into the question of which other populations of patients with P. carinii pneumonia might benefit from the use of adjuvant corticosteroids.
Supported in part by a gift from the Alliance Against AIDS, Miami.
We are indebted to Harold Batt, M.D., for assistance in interpreting the chest roentgenograms; to Gordon Dickinson, M.D., Stephen Dittes, M.D., and Richardo Reyes, M.D., for data and safety monitoring; and to Stephen Zimniski, Ph.D., and Ms. Karin Fendl for advice and assistance in the preparation of the manuscript.
Source Information
From the Divisions of General Medicine (S.G., A.M.B., M.A.F.) and Pulmonary Medicine (H.B.), the Department of Medicine, and the Comprehensive AIDS Program (L.L.), University of Miami School of Medicine, and the Department of Pharmacy (O.W.K.), Jackson Memorial Medical Center, Miami. Address reprint requests to Dr. Gagnon at the University of Kansas School of Medicine, 1010 N. Kansas, Wichita, KS 67214.
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