Bozzette et al: Corticosteroids for Severe PCP in AIDS (1995)

“We conclude that the early addition of corticosteroids to the therapeutic regimen for Pneumocystis pneumonia in patients with AIDS and moderate-to-severe impairment of oxygenation reduces the risks of respiratory failure and death.”

  • Samuel A. Bozzette, M.D., Ph.D., et al.

1. Publication Details

  • Trial Title: A Controlled Trial of Early Adjunctive Treatment with Corticosteroids for Pneumocystis carinii Pneumonia in the Acquired Immunodeficiency Syndrome
  • Citation: Bozzette SA, Sattler FR, Chiu J, 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(21):1451-1457. DOI: 10.1056/NEJM199011223232104. Note: The definitive trial by Bozzette on this topic was published in 1990.
  • Published: November 22, 1990, in The New England Journal of Medicine
  • Author: Samuel A. Bozzette, M.D., Ph.D.
  • Funding: National Institute of Allergy and Infectious Diseases (NIAID).

2. Keywords

  • AIDS, Pneumocystis carinii Pneumonia (PCP), Corticosteroids, Respiratory Failure, Randomized Controlled Trial

3. The Clinical Question

  • In patients with AIDS and moderate-to-severe Pneumocystis carinii pneumonia (PCP) (Population), does the early addition of corticosteroids (Intervention) compared to standard therapy alone (Comparison) reduce the incidence of respiratory failure or death (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Pneumocystis carinii pneumonia (PCP) was a leading cause of death in patients with the acquired immunodeficiency syndrome (AIDS). Treatment with antimicrobial agents like trimethoprim-sulfamethoxazole or pentamidine was standard, but many patients still experienced clinical deterioration and respiratory failure, thought to be due to an intense inflammatory response in the lungs.
  • Knowledge Gap: It was hypothesized that corticosteroids, by dampening this inflammatory response, could improve outcomes. However, there was significant concern about using potent immunosuppressants in an already severely immunocompromised patient population. High-quality evidence was needed to determine the risk-benefit balance.
  • Proposed Hypothesis: The authors hypothesized that early adjunctive treatment with corticosteroids would reduce the risk of respiratory failure and death in patients with AIDS and moderate-to-severe PCP.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: Multiple medical centers in the United States.
  • Trial Period: Enrollment ran from November 1988 to November 1989.
  • Population:
    • Inclusion Criteria: Adult patients with AIDS and confirmed PCP who had moderate-to-severe impairment of oxygenation (defined as a PaO2 < 75 mm Hg on room air or an alveolar-arterial oxygen gradient > 35 mm Hg).
    • Exclusion Criteria: Included active infection for which corticosteroids would be contraindicated.
  • Intervention: Patients received a tapering course of corticosteroids (prednisone or intravenous methylprednisolone) in addition to standard anti-PCP therapy.
  • Control: Patients received a matching placebo in addition to standard anti-PCP therapy.
  • Management Common to Both Groups: All patients received standard antimicrobial therapy for PCP (trimethoprim-sulfamethoxazole or pentamidine).
  • Power and Sample Size: The authors calculated that a sample size of 226 patients would be required to have 90% power to detect a 50% reduction in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: A composite of respiratory failure, the need for mechanical ventilation, or death.
    • Secondary Outcomes: Included overall mortality, rates of adverse events, and long-term survival.

6. Key Results

  • Enrollment and Baseline: 251 patients were randomized (128 to corticosteroids and 123 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early by the data and safety monitoring board after an interim analysis showed a significant benefit in the corticosteroid group.
  • Primary Outcome: The risk of the primary composite outcome (respiratory failure or death) was significantly lower in the corticosteroid group. The event occurred in 29 of 128 patients (22.6%) in the steroid group, compared with 53 of 123 patients (43.1%) in the placebo group (p=0.001).
  • Secondary Outcomes: The risk of death was also significantly lower in the corticosteroid group.
  • Adverse Events: There was no significant difference in the overall rate of adverse events or secondary infections between the two groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients who met the composite endpoint between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates of the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.001 is well below the 0.05 threshold, indicating that the observed difference in the primary outcome is highly statistically significant and very unlikely to be due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 43.1% – 22.6% = 20.5%.
      • Clinical Meaning: For every 100 patients with moderate-to-severe PCP treated with corticosteroids, about 21 were saved from respiratory failure or death.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.205 = 4.9, which is rounded up to 5.
      • Clinical Meaning: You would need to treat only 5 patients with corticosteroids to prevent one additional case of respiratory failure or death.
  • Subgroup Analyses: The benefit was consistent across different subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing bias and provided high-quality evidence.
  • Generalizability: The inclusion of patients from multiple centers increases the applicability of the findings.
  • Statistical Power: The study was adequately powered and found a large, significant effect.
  • Patient-Centered Outcomes: The primary outcome was a composite of death and respiratory failure, which are highly clinically relevant endpoints.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias.
  • External Validity (Generalizability): The findings are specific to patients with moderate-to-severe PCP and do not apply to those with mild disease. The study was conducted before the era of highly active antiretroviral therapy (HAART).
  • Other: The trial was stopped early for benefit, which can sometimes lead to an overestimation of the true treatment effect.

10. Conclusion of the Authors

  • The early addition of corticosteroids to standard therapy for moderate-to-severe PCP in patients with AIDS is an effective and safe intervention that reduces the risk of respiratory failure and death.

11. To Summarize

  • Impact on Current Practice: This was a landmark, practice-changing trial that established adjunctive corticosteroids as the standard of care for moderate-to-severe PCP in patients with AIDS, a recommendation that stands to this day.
  • Specific Recommendations:
    • Patient Selection: For adult patients with AIDS and moderate-to-severe PCP (PaO2 < 75 mm Hg on room air).
    • Actionable Intervention: Administer a tapering course of corticosteroids early in the treatment course.
    • Expected Benefit: This intervention can be expected to prevent one case of respiratory failure or death for every 5 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that steroids should be given for mild PCP, where the risks likely outweigh the benefits.
  • Implementation Caveats: The timing is crucial; the benefit was seen with early administration of corticosteroids.

12. Context and Related Studies

  • Building on Previous Evidence: The Bozzette et al. trial (1990) was the definitive study that provided high-quality evidence to support a practice that was based on physiological theory but was controversial due to safety concerns.
  • Influence on Subsequent Research: The definitive positive result of this trial was so practice-changing that it has not been ethically feasible to repeat a placebo-controlled trial in this population. Its findings were rapidly incorporated into international guidelines.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question.
  • Future Directions: Subsequent research has focused on the role of steroids in other opportunistic infections and on the management of PCP in the era of modern antiretroviral therapy.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a major cause of mortality in the AIDS epidemic.
  • Methods: The multicenter, double-blind RCT design was of high quality and appropriate for minimizing bias. The patient population and outcomes were well-defined.
  • Results: The study reported a large and both statistically and clinically significant benefit (NNT of 5). The confidence interval for the effect was narrow and did not cross the line of no effect.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The high external validity for the specific population studied has made its findings a durable standard of care for decades.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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