Marwan Bouras,Jordi Rello,Antoine Roquilly
Steroids in severe community-acquired pneumonia: dangerous, worthless, or miracle cure? The roller coaster of clinical trials
Steroids in severe community-acquired pneumonia: dangerous, worthless, or miracle cure? The roller coaster of clinical trials

Community-acquired pneumonia (CAP) was the leading cause of infectious diseases and the second cause of disability-adjusted life-years in the world in 2019, even before the COVID-19 pandemic. CAP is classically induced by virulent bacteria (such as Streptococcus pneumoniae) or respiratory viruses (influenza), and new pathogenic viruses such as SARS-CoV-2 (COVID-19) can rapidly diffuse in the population. The mortality rate reaches around 25% of patients receiving mechanical ventilation for CAP [1]. Steroidal therapy has been proposed as an adjuvant treatment option to dampen inflammation-induced lung injuries. In 2011, one of the first randomized, placebo-controlled trials showed that 5 mg of dexamethasone was associated with a reduced length of hospital stay [2] but without difference in all other patients' outcomes. In another study, 50 mg/day of prednisone for 7 days reduced the time to clinical stability with no increase in complications but failed to improve patient outcomes [3]. In 2021, a meta-analysis evaluating the use of corticosteroids as adjunctive therapy in community-acquired pneumonia concluded that although corticosteroids were not associated with a decrease in mortality, however, steroids were associated with decreased disease progression, i.e. fewer admission to intensive care units or requirement for mechanical ventilation [4]. So, after more than a decade of research, this therapeutical option remained a highly debated topic among healthcare professionals. Two recent trials, the CAPE COD trial [5] and the ESCAPe trial [6], provided important information to delineate better the place of corticosteroids in CAP patients. In the ESCAPe trial [6], Meduri et al. randomized 586 critically ill patients in 42 American hospitals to receive 40 mg/day of methylprednisolone or placebo for 20 days with a tapering plan and observed no significant difference in 60-day mortality (16% vs. 18% [95%CI: -8−5%], p = 0.61) or any other secondary outcomes. The CAPE COD trial is a multicenter, double-blind, placebo-controlled trial in 31 French ICUs evaluating 200 mg/day infusion of hydrocortisone for 8 or 14 days with a planned taper in patients admitted in ICU with severe non-viral CAP. Yet the trial was stopped early due to the COVID-19 pandemic, the authors reported a significant decrease in mortality, with 6.2% of the hydrocortisone group and 11.9% of the placebo group dead at 28 days (absolute difference −5.6% [95%CI: −9.6 to −1.7%], p = 0.006). It is unusual for a disease as severe CAP to have two randomized trials of such high quality published in less than six months. However, the two trials have different conclusions and should be analyzed cautiously. First, the inclusion criteria were different between the two studies, notably viral CAP were excluded from the French study, notably because steroids were associated with unfavorable outcome in severe influenza pneumonia [7]. Corticosteroids have attracted much attention during the SARS-CoV-2 pandemic. DEXA-ARDS, a randomized multicenter study involving 17 ICUs in Spain, showed an increase of 4.8 ventilator-free days ([95%CI: 2.5–7.03], p < 0001) within 28 days in the intervention arm as well as a decreased mortality rate [8]. Other randomized controlled trials in both viral and non-viral settings have demonstrated a clear benefit in the intervention arms treated with dexamethasone [9]. However, this has led to overprescribing corticosteroids for non-severe pneumonia without any inflammatory signs, in which administering corticosteroids may be dangerous [10]. It is likely that steroids do not meet all CAP patient needs, and the use of biomarkers could be interesting in selecting subgroups of patients. In the Stern et al. systematic review, the mortality benefit was only seen in patients with severe pneumonia, and data on viral pneumonia were of poor quality [11]. C-Reactive Protein (CRP) can be useful in evaluating the inflammatory response. In 2015, Torres et al. also found a decrease in treatment failure with 0.5 mg/kg methylprednisolone in patients presenting with severe CAP and a high inflammatory response (CRP > 150 mg/L) [12], at the expense of improved resolution of chest-X rays opacities, supporting the development of personalized corticoids therapy. In subgroup analyses of the CAPE COD trial, hydrocortisone was most effective in inflammatory patients with CRP > 150 mg/L (relative risk −7.4, [95%CI −12.9−1.7%]), which is the same threshold as Torres’ study [12]. Another significant difference between the two recent RCTs is the timing for corticosteroid administration. The ESCAPe trial allowed for randomization up to 72–96 h after hospital admission, while in the CAPE COD trial, patients in the hydrocortisone group received intravenous hydrocortisone administered continuously within 24 h after the onset of any severity criterion. We propose that the observation that an early administration effect may be beneficial can be explained by the glucocorticoid receptor's (GR) mechanisms of action. GR is a transcription factor expressed in most cells. After binding steroids, the GR translocates to the nucleus and exerts both genomic and non-genomic effects (notably in mitochondria) [13]. During inflammation, epigenetic modifications alter the possibility for GR to regulate the transcription of inflammatory genes. During the first hours of inflammation, steroids reduce inflammatory cytokine production, neutrophils, and T cell recruitment and adhesion [13]. In later days, steroids can have opposite effects on the inflammatory response by reducing anti-inflammatory cytokines secretion or increasing phagocytic capacity [14]. Sex differences in outcomes of infections (particularly tuberculosis), graft dysfunction, and survival in solid organ transplant recipients and ICU patients are consistently reported [15]. Interestingly, in the USA trial up to 96% of the cohort were male, compared with 69% among pneumonia patients in the French study. A subgroup analysis suggested potentially better benefits among females. Because the inflammatory response is modulated by progesterone and other sexual hormones, further studies should elucidate the interaction between steroids, biological sex, and inflammation in patients with pneumonia. Finally, even if the ESCAPe trial did not reach significance, probably due to a lack of power because the inclusions were stopped early due to low recruitment, both trials showed a decrease in mortality. These results strengthened the results of a 2017 Cochrane systematic review in which the relative risk of death was 0.66 in CAP patients treated with steroids (95%CI: 0.47–0.92) [11]. Recent guidelines suggest using corticosteroids in severe CAP if a shock is present [16]. The comparison of these two recent study designs and results suggests that corticosteroids may be beneficial in severe CAP patients with an inflammatory state (which could be defined by CRP level), but the treatment should be administrated early during the disease time course. These trials also confirm that using low-dose corticosteroids in severe CAP is safe in addition to antimicrobial therapy, but influenza viral pneumonia should be excluded. These results should not be extrapolated to hospital-acquired pneumonia, even if corticosteroids have been proposed to prevent hospital-acquired pneumonia after major surgery or trauma because of the very different pathophysiology between VAP and CAP [17]. In the early 21st century, the old therapeutic paradigm that the right antibiotic at the right time (and source control if empyema) is enough is broken by the high mortality of pneumococcal pneumonia who underwent mechanical ventilation. Outcomes are an interaction of bacterial burden, virulence factors associated with different serotypes [18], age, comorbidities and host immune response [19]. This is likely to change the way we approach pneumonia and sepsis. First, it is needed to identify potential immune deficits and the concept of immunocompromised host pneumonia with different phenotypes is required. Second, quick identification of the causative pathogen and measuring the number of copies with metagenomics should become the standard of care. Amongst influenza pneumonia, the presence of immunoparalysis was a major mortality driver [20], being the opposite in COVID-19. We learned that heterogeneity was partly explained by early specific host response dysregulations which should be considered to design targeted approaches to adjunctive therapy. Time has arrived to consider all these variables for a personalized approach.

AR received a grant and personal fees from MSD. The authors declare having no other conflict of interest.