The principle action of corticosteroids is the inhibition of the expression and action of several cytokines involved in the
immune inflammatory response to pneumonia [6]. It is known that, in CAP patients, the
use of systemic adjunctive corticosteroid therapy attenuates the local and systemic inflammatory response [7], and may potentially reduce the development of acute respiratory distress syndrome (ARDS),
sepsis and mortality. Sibila et al. [8], in a study of Pseudomonas aeruginosa pneumonia in mechanically ventilated piglets, observed a lower lung bacterial
burden and less severe histological pneumonia in piglets treated with corticosteroids plus antibiotics compared to antibiotics
alone.
Several randomized controlled trials (RCT) have been performed in humans, the majority of which included hospitalized patients
with non‐severe CAP. The results of these trials have been negative [9], or have
demonstrated a reduction in length of stay [10] or time to clinical stability
[11]. To date, four studies have been performed in patients with severe CAP
[12–15]. A meta‐analysis published by
Nie et al. [16] showed that in a subgroup of patients with severe CAP, steroids
reduced mortality. More recently, a meta‐analysis [17] showed that the use of
systemic corticosteroids in CAP was associated with a moderate reduction in the need for mechanical ventilation, development of
ARDS and, with high certainty, a reduction in time to clinical stability and duration of hospitalization. This study also showed a
possible reduction in mortality, but this effect was seen mainly in the subgroup of patients with severe pneumonia.
However, most of these RCTs had important limitations: a) the inclusion of many patients with low severity without ICU
admission, which makes it difficult to demonstrate differences in clinical outcomes, such as treatment failure and mortality,
because of the rates of these outcomes; and b) the inclusion of patients regardless of the initial level of inflammation. To date,
this latter variable has not been taken into account in the any of the RCTs. CAP patients with a marked inflammatory response have
high levels of C‐reactive protein (CRP), higher rates of treatment failure [18] and
worse mortality rates [19]. Furthermore, there are marked differences in variables in
the majority of RCTs, regardless of dosages, type and length of steroid treatment, which makes it very difficult to compare
results. The primary end‐points are different between studies, and some of them, such as length of stay or even time to clinical
stability, are ‘soft’ endpoints: length of stay depends on other variables and clinical stability is driven by the persistence of
fever which is, in fact, down‐regulated by corticosteroids.
More recently, Torres et al. [20] performed an RCT comparing methylprednisolone (0.5 mg/kg every 12 h for 5 days) vs. placebo, with important specific characteristics: a) the authors
included only patients with severe CAP with major or minor modified criteria of the American Thoracic Society, or with a Pneumonia
Severity Index (PSI) risk class V; b) they chose patients with a large systemic inflammatory response, with a threshold for serum
levels of CRP of 15 mg/dl; c) treatment failure was defined as early (clinical deterioration indicated by the development of
shock, need for invasive mechanical ventilation, not present at baseline, or death, within 72 h) or late (radiographic
progression or persistence of respiratory failure, development of shock, need for invasive mechanical ventilation not present at
baseline, or death, between 72 and 120 h after treatment initiation), and was the primary end‐point, rather than
mortality. In addition, it is known that treatment failure in CAP is associated with higher mortality, as previously shown in the
study by Menendez et al. [21].
The principal results showed a decrease in the treatment failure rate from 31 to 13%
(p = 0.02). Corticosteroids reduced the risk of treatment failure with an odds ratio of 0.34. Mortality did not differ
significantly between groups, but the study was not designed to find differences in mortality (10% in the methylprednisolone arm
vs. 15% in the placebo arm, p = 0.37). The reduction in treatment failure was more evident in
late treatment failure (3% vs. 25%, p = 0.001), and especially in radiographic progression, which was one of the variables
included in the composite definition of late treatment failure (2% vs. 15%, p = 0.007). The rates of adverse effects were small
and similar between arms. A limitation of this study was the long recruitment period (8 years) and the use of methylprednisolone
for 5 days only, with an abrupt interruption of the treatment.
The results of this study, which found fewer treatment failures, particularly late treatment failure, and less radiographic
progression, may be explained by stopping of the progression to ARDS or a potential blocking of the Jarisch‐Herxheimer reaction,
which is thought to be due to high concentrations of cytokines released after the initiation of antibiotics, possibly through the
release of endotoxins or other bacterial mediators in patients with a high bacterial burden, as occurs in meningococcal disease
[22].