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✅ Let's analyze an important study, the Community-Acquired Pneumonia: Evaluation of Corticosteroids (CAPE COD), whose paper was published on 03/21/2023 in the New England Journal of Medicine (NEJM) (1): Hydrocortisone in Severe Community-Acquired Pneumonia. But first let's understand the relevance of the study.

✴️ ACCESS THE ARTICLE HERE ✴️

This is a phase 3, double-blind, superiority Randomized Controlled Trial, conducted in 31 French centers, which sought to answer the following clinical question: "early treatment with hydrocortisone reduces 28-day mortality in patients admitted to the Intensive Care Unit (UTI) due to severe CAP?"

👉 It is important to emphasize that the criteria for defining the severity of pneumonia were drawn up by the authors themselves, not following the most widely used criteria, such as the ATS.

To be considered severe CAP, the patient had to present at least one of the following criteria:

• Pneumonia Severity Index (PSI) > 130 (Class V).
• Mechanical ventilation (invasive or not) for acute respiratory failure with PEEP of at least 5cm H20.
• High-flow oxygen therapy with an FiO2 of 50% or greater and a PaO2/FiO2 ratio < 300.
• Oxygen therapy with partially rebreathing mask with reservoir, with a PaO2/FiO2 ratio lower than the values specified in the table in the appendix, depending on the flow used.

Judging by the patient data and results of the control group, this definition selected patients with similar severity to another recent study with a similar proposal (2), but which used the ATS criteria to define severe CAP.

Almost 6000 subjects were eligible, but only 800 were included in the study.

🧐 The main reasons for non-inclusion were: patient needed to use corticosteroids due to septic shock or another disease (current or baseline); patient could not use corticosteroids; patient did not meet the severity criteria; patient with specific diagnoses, in which the use of corticosteroids would probably not bring benefit and could pose risks (inhalation pneumonia or influenza).

👉 We believe that the inclusion and exclusion criteria did not compromise the external validity of the study and reflect the clinical practice of CAP in developed countries.

Intervention:

Within 24 hours after reaching one of the severity criteria, patients in the hydrocortisone group received IV medication in continuous infusion at a dose of 200mg/day for the first 4 days. On the fourth day, the medical team decided whether to maintain hydrocortisone for 8 or 14 days, depending on the patient's clinical improvement.

The control group received saline solution according to the same regimen as the hydrocortisone group.

The intervention would be suspended at the time of patient discharge from the ICU, if this occurred before the time of 8 or 14 days. In fact, early withdrawal of the intervention occurred in more than 75% of the patients, with more than half of them undergoing the intervention for 5 days or less.

Outcomes:

👉 Primary outcome: death from any cause by the 28th.

Secondary outcomes:

• Death from any cause by day 90
• Length of stay in the ICU
• Other outcomes

Results:

Before analyzing the results, it is important to emphasize that the study was designed and conducted with great rigor, reducing the risk of bias as much as possible.

Patients were assessed for eligibility from October/2015 to March/2020 and had similar characteristics at baseline.

✴️ By day 28, mortality in the hydrocortisone group was 6.2% [CI 3.9 to 8.6%] versus 11.9% [CI 8.7 to 15.1%] in the control group. This means an absolute risk reduction (ARR) of 5.6% (CI 1.7 to 9.6%), and a relative risk reduction (RRR) of 48%. The number needed to treat (NNT) to obtain this benefit was 18 patients.

Several secondary endpoints also showed statistically and clinically significant benefit in the hydrocortisone group.

✅ Mortality on day 90: 9.3% [CI 6.4 to 12.2] vs 14.7% [CI 11.1 to 18.2]

In patients not receiving MV at baseline:

✅ Incidence of OTI up to the 28th: 18.0% vs 29.5%; Hazard Ratio (HR) of 0.59 (0.40 to 0.86)

✅ NIV until the 28th: 6.8% vs 10.9%; HR from 0.60 (0.32 to 1.15)

In patients who did not receive OTI at baseline:

✅ Incidence of OTI until the 28th: 19.5% vs 27.7%; RH of 0.69 (0.50 to 0.94)

In patients not receiving vasopressors at baseline:

✅ Incidence of starting vasopressors up to day 28: 15.3% vs 25.0%; RH of 0.59 (0.43 to 0.82)

Regarding safety outcomes, there was no difference between groups in rates of secondary infection or gastrointestinal bleeding up to day 28. There was, however, a difference in daily insulin requirements up to day 7, being greater in the hydrocortisone group.

🧐 The subgroup analysis showed some interesting questions:

1. There did not seem to be a greater clinical effect in the group of patients with PSI > 130 versus PSI <= 130.

2. Some groups may benefit more from corticosteroid therapy: patients on MV, patients without isolated microorganisms; older patients; women.

Discussion:

👩 🔬 The CAPE COD study is the largest and best study ever published on the subject. Interestingly, another study (2), whose population and clinical question were similar, with a good number of participants, was also published recently, in 2022, by Meduri et al. In this case, an equivalent dose of methylprednisolone was used in the first 7 days, but treatment with corticosteroids did not alter mortality. We identified some differences between the studies. See below:

👩‍🔬 Our opinion is that the CAPE COD study adds to the evidence that already pointed to an important role for corticosteroids for patients with CAP, in particular critically ill patients.

✍ The reduction in mortality by almost half (48%) and the NNT of 18 lead us to have a low threshold for prescribing hydrocortisone early, preferably in continuous infusion, for up to 1 to 2 weeks (at least 75% of patients underwent the intervention for 8 days or less) in patients admitted to the ICU for CAP.

References:

1) Dequin PF, Meziani F, Quenot JP, et al. Hydrocortisone in Severe Community-Acquired Pneumonia [published online ahead of print, 2023 Mar 21]. N Engl J Med. 2023;10.1056/NEJMoa2215145. doi:10.1056/NEJMoa2215145

2) Meduri, G.U., Shih, MC., Bridges, L. et al. Low-dose methylprednisolone treatment in critically ill patients with severe community-acquired pneumonia. Intensive Care Med 48, 1009–1023 (2022). https://doi.org/10.1007/s00134-022-06684-3

✴️ Xlungers, what did you think of this article?

🤔 Do you already use corticosteroids in severe PAC? If not, has it changed your practice?

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