Journal club on Hydrcortisone for Severe Community acquired pneumonia

The role of hydrocortisone for severe community acquired pneumonia

1. Journal Club Presenter; Wondwosen M. (R1) Moderator; Dr. Surafel ( Ass’t Prof. of Int. M) 17, May 2023

2. The acronym CAPE COD C ommunity- A cquired P neumonia: E valuation of CO rticosteroi D s (CAPE COD)

3. Outline Introduction Objective Methodology Statistical Analysis Result Discussion & Conclusion Critical Appraisal

4. Introduction C ommunity-acquired pneumonia remains a major public health issue a leading cause of morbidity and mortality worldwide In US , more than 1.5 million adults are hospitalized for CAP annually In 2019, pneumonia was the ninth leading cause of death in the US and the leading cause of death from infection ( ≈ 50,000 deaths) Pneumonia may lead to intense pulmonary and systemic inflammation , which results in impaired gas exchange , sepsis and organ failure , & ↑ risk of deat h

5. Introduction ctd Mortality of severe CAP has not declined over time and is between 25 and 30% in sub-groups of patient The overall 28-days mortality for inpatients with CAP is about 5% However, in the subgroup admitted to the ICU , it varies from 18 to 54% This I n-hospital case-fatality rate for patients with severe CAP remains unacceptably high

6. The keystones of up-to-date therapy of CAP are antibiotics and supportive treatment , including the correction of hypoxemia There is little to be expected from evolution in antibiotics approach, since CAP’s morbidity and mortality are not due to resistance to antibiotics or poor diffusion of drugs in the lung Introduction ctd

7. Glucocorticoids have powerful antiinflammatory & immunomodulatory activities that mitigate the consequences of pneumonia Corticosteroids (CTx) could down-regulate pulmonary and systemic inflammation accelerate clinical resolution decrease the rate of inflammation-associated systemic complications like ARDS and septic shock reduce the production of inflammatory cytokines Corticosteroids and community-acquired pneumonia

8. Previous studies Two recently published meta-analyses suggested a positive efect of CTx , in terms of survival , when adminstered to severe CAP, with a survival odds ratio of 0.26 [95% CI: 0.11-0.64] and 0.39 [0.17-0.90], respectively However, this positive effect was linked to only four trials gathering less than 300 patients, of which only one was positive (although including only 48 patients) not observed for severe CAP , underlying the necessity to define robust severity criteria for inclusion into such a trial.

9. Previous studies ctd Seven randomized, controlled trials showed that glucocorticoids had positive effects in patients with CAP of varying severity; however, with the exception of one trial, none of these trials showed a between-group difference regarding mortality A meta-analysis of six of these trials suggested that glucocorticoids reduced the time until clinical stabilization and length of hospital stay without improving survival

10. Objective The objective was to evaluate whether early treatment with hydrocortisone reduce s mortality at 28 days among patients admitted to an intensive care unit (ICU) for severe community-acquired pneumoni a

11. Methodology Study Design A phase-III , multicenter, add-on , randomized ,Placebo controlled , double-blind , superiority trial Study Setting At 33 centers in France , From October 28, 2015 , to March 11, 2020 , a total of 5948 patients were assessed for eligibility; of these patients, 800 were enrolled in the trial Timeline Recruitment period: 36 months Patient follow-up: 3 months Total duration: 39 months Exclusion period : 28 days During this period, the subject will not be allowed to participate to another drug trial

12. Etical Isssue and Funding Approved by The ethics committee and T he French regulatory agency Sponsor CHU de Tours 2, boulevard Tonnellé 37044 Tours cedex 9 Funded by the French Ministry of Health ; CAPE CODClinicalTrials.gov number, NCT02517489

13. Randomization methods Allocation sequence generation A computer process was used to generate allocation sequences in a 1:1 ratio Stratification Randomization was stratified on: - (i) centers (ii) use of mechanical ventilation at the time of inclusion Implementation Randomization was centralized and performed electronically

14. Inclusion Criteria Age ≥ 18 years Patients affiliated to social security scheme Admission to an ICU or i ntermediate care unit participating to the trial Diagnosis of CAP suggested by at least two of the following: cough, purulent sputum, chest pain and dyspnea Focal shadowing/infiltrate on chest X-ray or CT-scan Diagnosis of CAP during the 48 hrs post-hospital admission Study drug infusion initiated no longer than 24 hrs post 1 st severity criterion

15. Inclusion Criteria ctd Pt already treated by antibiotics (at least one dose since admission ) Informed consent signed by the pt or its relatives Severity defined by at least one of the following: Pneumonia Severity Index ( PSI) > 130 (Fine class V) Pt placed on mechanical ventilation (invasive or not) for acute respiratory failure, with a PEEP level of 5 cm of water or more Pt treated by high-flow oxygen therapy with a FiO 2 of 50% or more & a PaO 2 /FiO 2 (P/F) ratio lower than 300

16. Exclusion Criteria Pt treated by vasopressors for septic shock at the time of inclusion Clinical history suggesting of aspiration of gastric content Pt treated by invasive mechanical ventilation within 14 days before current hospital admission P t treated by antibiotics for a respiratory infection for more than seven days at the admission to the hospital (except if a pathogen resistant to this antibiotics is isolated) History of cystic fibrosis

17. Exclusion Criteria ctd Post-obstructive pneumonia Pts in which rapid PCR -test is positive for flu Active tuberculosis or fungal infection Active viral hepatitis or active infection with herpes viruses Myelosuppression Decision of withholding mechanical ventilation or endotracheal intubation Hypersensitivity to corticosteroids

18. Exclusion Criteria ctd Pt needing anti-inflammatory corticosteroids or substitutive hydrocortisone for any reason Pts under treatment by more than 15 mg/d of prednisone (or equivalent) for more than 30 days Pt already enrolled in another drug trial with mortality as an end-point Pregnant or breastfeeding woman Patient on judicial protection

19. Primary Outcome Death from any cause by day 28

20. Secondary Outcomes In pts non-invasively ventilated at inclusion , proportion of pts needing endotracheal intubation In pts non-ventilated at inclusion , proportion of pts requiring non- invasive ventilation & proportion of pts needing endotracheal intubation Number of pts with vasopressor therapy initiation from inclusion to D28 ICU and/or intermediate care unit LOS All -causes mortality at D90

21. Secondary Outcomes ctd D28 ventilator-free -days This outcome will be assessed applying the following rules : - The period of interest will begin at the randomization date Patients who die before day 28 will be affected a value Days between two mechanical ventilation episodes will be taken into account A successful extubation will be defined as a spontaneous breathing 48h after extubation

22. D28 vasopressor-free -days This outcome will be assessed applying the following rules : - The period of interest will begin at the randomization date Patients who die before day 28 will be affected a 0 value Days between two vasoconstrictor-therapy episodes will be taken into account Secondary Outcomes ctd

23. Biomarkers : procalcitonin, C-reactive protein and plasmatic concentration o f pro-inflammatory cytokines (IL-6, IL-20, IL-22, IL- 22BP, HBD2, TNF D) at baseline , D3 and D7 P/F ratio measured daily from baseline to D7 , at the end of treatment , at the end of ICU-stay and/or D28 SOFA calculated daily from baseline to D7 , at the end of treatment , at the end of ICU-stay and/or D28 Secondary Outcomes ctd

24. Safety criteria included S econdary infections or gastrointestinal bleeding by day 28 T he daily amount of insulin administered by day 7 W eight gain by day 7

25. Statistical Analysis Sample size 1200 With fixed α to 5% , β to 20% , a bilateral test, an estimated mortality in the control group of 27% 1146 patients are needed to show a relative decrease of mortality of a quarter in the experimental group (i.e. a mortality of 20% ) With two interim analyses , 1165 are needed ( Peto’s rule ) and 1200 to take into account the possibility of pursuit-consent refusal

26. Statistical Analysis ctd. The statistical analyses was performed by the INSERM CIC 1415 unit and supervised by Bruno Giraudeau The statistical analysis conducted according to the intention to treat (ITT) principle Baseline characteristics was reported per group using descriptive statistics The primary outcome w as analyzed using a chi-square test

27. Randomization

28. Randomization ctd.

29. Treatment period

30. Results and Discussion

31. Primary and Secondary Outcomes

32. 29.5% 18.0% 442 Among 442 patients who had not received any mechanical ventilation at baseline ,endotracheal intubation was performed in 18.0% in the hydrocortisone group and in 29.5% in the placebo group (hazard ratio, 0.59; 95% CI, 0.40 to 0.86)

33. 618 27.7% 19.5% Among 618 patients who had received no invasive ventilation at baseline, the cumulative incidence of invasive mechanical ventilation before day 28 was 19.5% in the hydrocortisone group and 27.7% in the placebo group (hazard ratio, 0.69; 95% CI, 0.50 to 0.94)

34. 703 25.0% 15.3% Among the 703 patients who had not received vasopressors at baseline, the cumulative incidence of vasopressor initiation was 15.3% in the hydrocortisone group and 25.0% in the placebo group (hazard ratio, 0.59; 95% CI, 0.43 to 0.82)

35. Safety Outcomes Hydrocortsone Placebo Treatment effect P- value ( CI 95% )

36. Mortality on day 28: Forest plot subgroup analysis

37. Conclusions E arly treatment with hydrocortisone reduced 28-day mortality among patients who had been admitted to the ICU with severe community-acquired pneumonia

38. Questions or comments

39. Critical appraisal Question s Yes No C an’t tell Did the trial address a clearly focused research question? Yes Was the assignment of participants to interventions randomized ? Y es Was allocation to treatment groups concealed ? Y es Apart from the experimental intervention, did each study group receive the same level of care? Y es Were all participants who entered the study accounted for at its conclusion? Y es Were investigator and Sponsor personnel or delegate(s) ‘ blind’ to treatment? Yes Were the study groups similar at the start of the randomized controlled trial? Y es Were the effects of intervention reported comprehensively? Y es

40. Strength Random , double blind ed and multicentered ( 31 centers ) sampling Large sample size Proper stratification to avoid bias Clearly stated primary and secondary outcome Study outcome was impressive Clinically relevant S ufficient period of follow-up Femae proportion was good

41. Limitations All centres from a single country Wide exclusion criteria I t did not reach its recruitment target , because implementation was impacted by the COVID-19 pandemic T he observed mortality of 11.9% in the control group was lower than anticipated (27%) , which may indicate a lower severity of illness than expected A small percentage of immunocompromised patients Lack evaluation of reversibility of glucocorticoid- induced hyperglycemia Did not assess the potential neuropsychological and neuromuscular side effects of glucocorticoids

42. Will the results help locally? Questions Yes No Can’t Tell Can the results be applied to local population? √ Were all important outcomes considered? √ Are the benefits worth the harms and costs? √

43. Thank You