Critical Care Alert: CAPE-COD Trial

ARTICLE: Dequin PF, Meziani F, et. al (CRICS-TriGGERSep Network). Hydrocortisone in Severe Community-Acquired Pneumonia. N Engl J Med. 2023 Mar 21. doi: 10.1056/NEJMoa2215145. Epub ahead of print. PMID: 36942789.

The Community-Acquired Pneumonia: Evaluation of Corticosteroids (CAPE-COD) trial was designed to study early treatment with hydrocortisone in patients admitted to the ICU for severe community-acquired pneumonia and evaluate whether the anti-inflammatory/immunomodulatory effects of glucocorticoids would reduce mortality at 28 days. 

BACKGROUND
In the United States, more than 1.5 million adults are hospitalized annually for community-acquired pneumonia (CAP). In 2019, pneumonia was both the ninth leading cause of death in the United States and the leading cause of death from infection - with approximately 50,000 deaths. In high-income countries, the monthly rate of death in hospitalized patients with CAP is 10-12% and 30% for those who are mechanically ventilated.¹ 

Glucocorticoid use has been previously studied in the treatment of pneumonia given that the severity of illness appears tied to the intense pulmonary and systemic inflammation that impairs gas exchange and leads to sepsis and organ failure.¹ Glucocorticoids have strong anti-inflammatory and immunomodulatory effects which could mitigate these harms. The 2005 trial, “Hydrocortisone Infusion for Severe Community-Acquired Pneumonia,” published by the American Journal of Respiratory and Critical Care Medicine, showed that a 7-day course of low-dose IV hydrocortisone significantly reduced duration of mechanical ventilation, hospital length of stay, and mortality in-hospital.² In 2010, the same journal published “Efficacy of Corticosteroids in Community-Acquired Pneumonia,” which showed that prednisolone at 40 mg daily for 7 days did not improve outcomes, but concluded that “A benefit in more severely ill patients cannot be excluded.”³ In 2011, The Lancet evaluated dexamethasone as an adjunct that could reduce hospital stay in non-immunocompromised patients.⁴ Then a 2015 article, “Effect of Corticosteroids on Treatment Failure Among Hospitalized Patients with Severe Community-Acquired Pneumonia and High Inflammatory Response,” showed that acute use of methylprednisolone compared with placebo decreased treatment failure - and if replicated may support corticosteroids as an adjunctive treatment.⁵ 

Over the years, the results of 7 of these randomized trials - like the ones listed above - and a meta-analysis of 6 of them suggested glucocorticoids reduced time for clinical stabilization and hospital length of stay but did not improve survival. Meta-analysis of trials that were deemed to have a risk of bias or were open label did have some moderate quality of evidence for decreased mortality.¹ Therefore, the CAPE COD trial was conducted in order to further evaluate this question of reduced mortality.

DESIGN
Double-blind, randomized, controlled superiority trial of 800 patients conducted in 31 French centers by members of the Clinical Research in Intensive Care and Sepsis-Trial Group for Global Evaluation and Research in Sepsis Network. Randomization was assigned in a 1:1 ratio, via computer-generation of a random list, to receive hydrocortisone or a placebo. 

The severity of pneumonia was defined by at least 1 of 4 criteria:

1. Initiation of mechanical ventilation with a PEEP of at least 5
2. Initiation of oxygen through HFNC with a PaO2:FiO2 <300 (with an FiO2 of 50% or more)
3. Initiation of oxygen through a non-rebreathing mask with a PaO2:FiO2 <300
4. Score >130 on the Pulmonary Severity Index 

Testing for a causative pathogen was left to the discretion of the medical team. Testing for influenza during epidemic periods was recommended. 

Patients received standard therapy for pneumonia, including antibiotics and supportive care. Respiratory support was left to the medical team. Within 24 hours of development of severe pneumonia criteria - patients in the hydrocortisone group received 200 mg/daily IV for four days. On the fourth day, the medical team would decide to administer hydrocortisone for 8 or 14 days, depending on the patient’s condition. Hydrocortisone was tapered and treatment was discontinued by the time of discharge. Patients in the control group received IV saline as their placebo. 

Statistical Analysis: It was estimated that enrollment of 1,146 patients would provide 80% power to detect a 25% relative reduction in mortality by day 28 (mortality was estimated at 27% in the placebo group and 20.25% in the hydrocortisone group). A p value of <.049 was considered statistically significant and the rates of death by day 28 and 90 were reported as point estimates with a 95% confidence interval. The chi-square test was used to analyze 28-day mortality. 

INCLUSION CRITERIA

• Adult patients 18 years or above, admitted to one of the participating ICUs or intermediate care units for severe CAP (see criteria above), which was diagnosed via clinical (at least two of the following: cough, purulent sputum, chest pain, dyspnea) and radiologic (focal shadowing/infiltrate on CXR or CT scan) evidence.
• Diagnosis of CAP had to occur during the 48 hours post-hospital admission and the study drug infusion had to be initiated no longer than 24 hours post first severity criterion
• Patient already treated by antibiotics (at least one dose since admission to the hospital

EXCLUSION CRITERIA

• Do-not-intubate order
• Pneumonia secondary to influenza or aspiration
• Vasopressor therapy for septic shock on initial presentation
• Previous intubation within 2 weeks of admission
• Previous antibiotics for more than 1 week prior to admission
• History of cystic fibrosis, myelosuppression
• Active TB or fungal infection, viral hepatitis or active infection with herpes virus
• Pregnant/breastfeeding women
• Decision of withholding mechanical ventilation or endotracheal intubation
• Patients needing anti-inflammatory corticosteroids or substitutive hydrocortisone for any reason
• Patients under treatment by more than 15 mg/d of prednisone (or equivalent) for more than 30 days
• Hypersensitivity to corticosteroids

PRIMARY OUTCOME

• Death from any cause by day 28 

SECONDARY OUTCOMES

• Death from any cause by day 90
• Length of ICU stay
• Noninvasive ventilation or endotracheal intubation among patients with no baseline ventilatory needs
• Endotracheal intubation among patients with baseline noninvasive ventilatory needs
• Initiation of vasopressor therapy by day 28
• Number of ventilator-free and vasopressor-free days by day 28
• Change in the PaO2:FiO2 ratio by day 7
• SOFA score change by day 7
• Quality of life by day 90, measured by a SF-36 Health Survey

SAFETY OUTCOMES

• Secondary infections (e.g., ventilator-associated pneumonia, bloodstream infection) or gastrointestinal bleeding by day 28
• Median daily dose of insulin administered by day 7 in patients receiving insulin therapy
• Median weight change from baseline by day 7 

KEY RESULTS

• 5,948 patients, between October 28th, 2015 - March 11th, 2020, were assessed for eligibility, and 800 were enrolled. 
• 401 patients were assigned to the hydrocortisone group, 1 died before treatment. 399 patients were assigned to the placebo group, 2 withdrew consent, and 2 did not have the legal capacity to give consent. Therefore, 795 patients were analyzed. 
• 6.8% (54) patients were included solely for a score of >130 on the PSI. 
• Patient population characteristics: both groups had similar characteristics, including a median age of 67, around 70% male enrollment, around 30% female enrollment, and similar percentages for the type of respiratory support patients required. Comorbidities included COPD, asthma, diabetes, immunosuppression. 

PRIMARY OUTCOME RESULT
Death by day 28 had occurred in 25 of the 400 hydrocortisone grouped patients (6.2%; 95% confidence interval 3.9-8.6) and in 47 of 395 placebo grouped patients (11.9%; 95% confidence interval 8.7-15.1). This had an absolute difference of 5.6% with a P value of .006 and a 95% CI of -9.6 to -1.7. 

SECONDARY OUTCOMES RESULTS

• Mortality at day 90: 9.3% in the hydrocortisone group vs. 14.7% in the placebo group (absolute difference, −5.4 percentage points; 95% CI, −9.9 to −0.8)
• By day 28 around 90% of patients were discharged from the hydrocortisone group and around 80% of patients were discharged from the placebo group (hazard ratio, 1.33; 95% CI, 1.16 to 1.52) 
• Among 442 patients who do not receive any ventilation at baseline, endotracheal intubation was done in 18% of hydrocortisone grouped patients vs. 29.5% in the placebo group (hazard ratio, 0.59; 95% CI, 0.40 to 0.86)
• Among 618 patients with no invasive ventilation at baseline, the incidence of invasive mechanical ventilation before day 28 was 19.5% for hydrocortisone and 27.7% for placebo (hazard ratio, 0.69; 95% CI, 0.50 to 0.94)
• Among 703 patients with no baseline vasopressor need, the incidence of initiation was 15.3% in the hydrocortisone group and 25% in the placebo group (hazard ratio, 0.59; 95% CI, 0.43 to 0.82)
• Further secondary outcome information can be found in the supplemental appendix. Among the supplemental data - there is evidence of hydrocortisone being beneficial amongst patients with a CRP level > 15 mg/dL.

SAFETY OUTCOME RESULTS
During the first 28 days after randomization:

• 169 serious adverse events occurred in 151 of 795 patients (19%)
• 70 in the hydrocortisone group 
• 99 in the placebo group
• ICU-acquired infections occurred in 9.8% of the hydrocortisone group and in 11.1% of the placebo group (hazard ratio, 0.87; 95% CI, 0.57 to 1.34; p value 0.54)
• Occurrence of GI bleed was 2.2% in the hydrocortisone group and 3.3% in the placebo group (hazard ratio, 0.68; 95% CI, 0.29 to 1.59; p value 0.38)
• By day 7, patients required an average of 35.5U of insulin daily in the hydrocortisone group and 20.5U in the placebo group (median difference, 8.7; 95% CI, 4.0 to 13.8; p value > 0.001)
• By day 7, median weight change from baseline was 2.0 kg in the hydrocortisone group and 1.0 kg in the placebo group (median difference, 1.0; 95% CI, 0 to 2.0; p value 0.18)

LIMITATIONS

• Observed mortality of 11.9% in the control group was lower than the anticipated 27% - indicating a potentially less severely ill population than expected. 
• Standardized pathogen testing was not mandated - no pathogen was isolated in 44.9% of patients. 
• A small percentage of immunocompromised patients were included in the study and these results should be applied with caution to this population
• Though the hydrocortisone group experienced higher doses of insulin use by 7 days, the authors did not evaluate the reversibility of glucocorticoid-induced hyperglycemia 
• The administration of continuous IV hydrocortisone with tapering doses compared to other regimens is not supported by a high level of evidence.

EM TAKE-AWAYS

• Hydrocortisone benefited severely ill pneumonia patients requiring ICU level care that did not have a contraindication to steroids, though this study excluded those who presented in septic shock requiring vasopressors. Consider hydrocortisone for admitted patients boarding in the ED who meet these inclusion criteria.
• CRP and other markers of inflammatory response could potentially be used to assess if a patient would benefit from steroids.

REFERENCES

1. Dequin PF, Meziani F, et. al (CRICS-TriGGERSep Network). Hydrocortisone in Severe Community-Acquired Pneumonia. N Engl J Med. 2023 Mar 21. doi: 10.1056/NEJMoa2215145. Epub ahead of print. PMID: 36942789.
2. Confalonieri M, Urbino R, Potena A, et al. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med. 2005;171(3):242-248. 
3. Snijders D, Daniels JM, de Graaff CS, van der Werf TS, Boersma WG. Efficacy of corticosteroids in community-acquired pneumonia: a randomized double-blinded clinical trial. Am J Respir Crit Care Med. 2010;181(9):975-982. 
4. Meijvis SC, Hardeman H, Remmelts HH, et al. Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. Lancet. 2011;377(9782):2023-2030. 
5. Torres A, Sibila O, Ferrer M, et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA. 2015;313(7):677-686.