Corticosteroids and hospital-acquired pneumonia

Abstract

Hospital-acquired pneumonia (HAP) is a serious infection with high mortality rates, especially in critically ill patients. The role of corticosteroids as adjunctive therapy in this population is debated. These agents have anti-inflammatory and immunomodulatory properties, which have the potential to reduce pulmonary inflammation and improve oxygenation. However, the risk of secondary infections and metabolic complications that their use may entail is a matter for concern, given their impact on patients’ outcome. In this review, we discuss the current scientific evidence on the use of corticosteroids as adjunctive therapy for patients with HAP and VAP, its implications for patients’ clinical outcomes, and the possible effects. Corticosteroids are not recommended as standard therapy for HAP/VAP but may be beneficial in selected subgroups of patients.

Background

Hospital-acquired pneumonia (HAP) is a lung infection that develops at least 48 h after hospital admission in patients who were not incubating the infection at the time of admission. It is one of the most common and severe hospital-acquired infections, with high morbidity and mortality rates, especially among critically ill patients [1, 2]. A major subtype of HAP is ventilator-associated pneumonia (VAP) which develops in intubated patients undergoing artificial ventilation for at least 48–72 h [3, 4] (Fig. 1).

Fig. 1.

Overview of hospital-acquired pneumonia (HAP)

Corticosteroid use as adjunctive treatment for HAP and VAP patients remains controversial, in view of the lack of clinical evidence and the presence of contradictory reports [5, 6]. The anti-inflammatory and immunomodulatory properties of corticosteroids may reduce the lung inflammation, improve oxygenation, and potentially shorten the period of mechanical ventilation, but the side effects of these agents may argue against their use.

This review focus on the use corticosteroids as adjunctive therapy, meaning their administration together with antibiotics for the treatment of patients with HAP and VAP. The implications for patients’ clinical outcomes and the potential effects are also discussed.

Epidemiology and main pathogens in HAP and VAP

Hospital-acquired infections are a major health threat globally and are associated with significant morbidity, mortality and healthcare costs [7]. HAP is one of the most common hospital-acquired infections, associated with prolonged hospital stay, complications and increased hospital mortality. It is important to emphasize that HAP and VAP are common complications in hospitalized and mechanically ventilated patients, especially in those who are immunocompromised, post-surgical, and older patients. Mortality rates ranging between 20% and 35%; in the case of VAP, this mortality may reach up to 50% in high-risk groups.

Over the past decade, there was a reduction in some healthcare-associated infections, while pneumonia remain a common cause of infection in hospital and ICU settings, especially during respiratory viral pandemics such as COVID-19 [8–12].

Several factors may affect the identification of different microbial aetiologies in HAP/VAP. These include the duration of mechanical ventilation, ICU and hospital stay, previous hospitalization, previous antimicrobial therapy and local microbial ecology. In general, Gram-negative bacteria are the predominant microorganisms causing HAP/VAP, being reported in between 50% and 80% of cases with definite aetiology. Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacterales are the most frequently reported, albeit with notable geographical variations. The second most frequently identified group of bacteria are Gram-positive bacteria, among which Staphylococcus aureus is predominant. Opportunistic pathogens such as fungi are also reported as pathogens in VAP, especially in recent years. Table 1. show the most common pathogens involved in HAP and VAP.

Table 1.

Pathogens associated with nosocomial pneumonia (HAP/VAP) [9, 13, 14].

Category	Pathogen	Key Characteristics
Gram-negative bacteria	Pseudomonas aeruginosa	High risk of antibiotic resistance, frequent in intensive care units
	Klebsiella pneumoniae	May produce extended-spectrum β-lactamases (ESBL) and carbapenemases (KPC)
	Escherichia coli	Associated with nosocomial pneumonia and often antibiotic-resistant
	Acinetobacter baumannii	Highly antibiotic-resistant, common in intensive care patients
	Enterobacter spp.	May develop resistance to β-lactams
Gram-positive bacteria	Staphylococcus aureus methicillin resistant (MRSA)	Methicillin-resistant strain (MRSA), dangerous and widespread in hospital settings
	Streptococcus pneumoniae	More common in HAP than in VAP
	Enterococcus spp.	Less common, but relevant in immunocompromised patients
Less common pathogens	Legionella pneumophila	More frequent in immunocompromised patients or those exposed to contaminated water systems
	Aspergillus spp.	Important in immunosuppressed patients
	Respiratory viruses (SARS-CoV-2, Influenza A/B, adenovirus)	Primarily affects patients with immune impairment

Abbreviations: ESBL Extended-spectrum β-lactamases, KPC Carbapenemases, MRSA Methicillin-resistant strain

Drug-resistant pathogens are a group of concern in the management of HAP and VAP [14–18]. Multidrug-resistant (MDR) Gram-negative pathogens such as extended-spectrum-β-lactamase producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE) and MDR P. aeruginosa, including carbapenem-resistant strains, are associated with worse outcomes, mainly because of inappropriate or delayed antimicrobial therapy. Risk factors for this group of pathogens include the presence of septic shock, diabetes mellitus, chronic obstructive pulmonary disease (COPD), cystic fibrosis, renal impairment, severe liver disease, immunosuppression, chronic dialysis, site of care ecology with high levels of MDR pathogens, previous use of antibiotics, recent prolonged hospitalization (>5 days) and previous colonization by MDR pathogens.

Corticosteroids in HAP/VAP: safety considerations and preventive insights

There is no gold standard for the diagnosis of HAP and VAP. The use of corticosteroids can alter the presence of fever due to their strong antipyretic and anti-inflammatory effect, their ability to induce leucocytosis and reduce macrophages, and their effect on pulmonary infiltration. They also have an effect on biomarkers such as C-reactive protein [19, 20], which makes the diagnosis of HAP and VAP more challenging due to the difficulty of distinguishing the effects of corticosteroids from a true infection. This may delay the clinical suspicion of pneumonia, and may also explain why patients who received corticosteroids present higher pathogen burdens [5, 21].

The use of corticosteroids in clinical settings has been linked to a higher risk of HAP and VAP [22]. This connection is especially clear in critically ill patients, where corticosteroid use is often essential for treating severe conditions, but can also make patients more vulnerable to infections. During the COVID-19 pandemic there was an increase in the research into corticosteroids and their effects in critically ill patients. Some studies have found a link between the use of corticosteroids and the increased risk of developing HAP/VAP [23–28], while others reported that low doses of corticosteroids prevent pneumonia may prevent pneumonia or have not effect on the risk of HAP/VAP [29–35].

Several studies have shown an increased risk of VAP and ICU-acquired respiratory tract infections in COVID-19 patients treated with corticosteroids. A retrospective multicentre study in 15 ICUs in France found a higher incidence of VAP in the early corticosteroid group (aHR: 1.29, 95% CI 1.05–1.58, p = 0.016) [25]. Similarly, a propensity-matched study from Italy reported VAP in 56% of patients who received dexamethasone versus 34% in those who did not (RR: 1.61, 95% CI: 1.26–2.10, p = 0.0001) [36]. In a large multicentre prospective study of 3,777 severe COVID-19 patients, 17.1% of those who received dexamethasone developed ICU-acquired respiratory infections, compared with 13.2% of those who did not (p = 0.014). While mortality rates were not consistently different between groups, corticosteroid-treated patients often had longer ICU stays and were more frequently infected by multidrug-resistant bacteria [27].

Although these studies showed that the use of corticosteroids increases the risk of VAP and ICU-respiratory tract infections, a retrospective multicentre study of 36 European ICUs analysing data from 545 COVID-19 patients, of whom 191 (35%) received corticosteroids, did not find a significant association between corticosteroid use and the risk of VAP [23].

There are also reports of higher secondary infection rates in COVID-19 patients and in those affected by the earlier SARS and influenza A H1N1 pandemics. A multicentre study of 28 ICUs in Korea, analysing 245 critically ill patients with influenza A H1N1, showed higher 90-day mortality (58% vs. 27%, p < 0.001) and secondary bacterial pneumonia (57% vs. 22%, p < 0.001) in patients who received corticosteroids [37]. Another prospective study in 220 ICU patients with influenza A H1N1 reported that early corticosteroid use was not associated with increased mortality but was linked to higher risk of HAP (26.2% vs. 13.8%, p < 0.05; OR 2.2) [28]. In cases of HAP, P. aeruginosa, Acinetobacter baumannii and S. pneumoniae were the most frequent pathogens identified.

Importantly, the risk of secondary bacterial infections from corticosteroids use may vary depending on the type of pneumonia. Studies in severe viral pneumonia, especially those caused by influenza virus, have shown that corticosteroids can increase the risk of bacterial superinfection and mortality [38–40]. However, this risk appears to be less significant in bacterial pneumonia, such as most cases of HAP and VAP, especially when corticosteroids are used in low doses for a short duration and together with an appropriate antibiotic therapy [41]. Because of this, the etiology of pneumonia should always be considered when evaluating the potential risks of corticosteroid use, because what happen in viral infections may not the same for bacterial pneumonia.

It is important to mention the methodological challenges facing studies focusing on the use of corticosteroids, such as the differences in the definitions of these agents, broad classifications of immunosuppression, and case-mix diversity, all of which complicate the accurate evaluation of their impact on HAP and VAP.

In 2011, the results of the HYPOLYTE trial were published, a study that assessed the efficacy of hydrocortisone in reducing HAP in 150 severely ill patients from seven French ICUs. In the study, Hydrocortisone was given as 200 mg/day via continuous IV infusion for 5 days. The dose was then reduced to 100 mg on day 6, and 50 mg on day 7 before stopping treatment. The study found that hydrocortisone significantly reduced HAP (35.6% vs. 51.3%; HR 0.51; p = 0.007). The authors reported more mechanical ventilation-free days in the hydrocortisone group, but no significant difference in mortality was observed (p = 0.44). These results suggest that the use of hydrocortisone in trauma patients reduces the risk of HAP without increasing mortality [33].

In 2014, a double-blind, phase 3 placebo-controlled trial was carried out at 19 French ICUs investigating the use of hydrocortisone plus fludrocortisone for pneumonia prevention. The study found that the use of corticosteroids reduced HAP from 53% (placebo) to 45% (steroid group), though the results did not reach statistical significance (HR 0.75, 95% CI 0.55–1.03, p = 0.07) [42].

Corticosteroids for the treatment of HAP and VAP (Table 2)

Table 2.

Summary of key studies evaluating corticosteroids in pulmonary infections

Study/Desing	Population	Intervention	Main Findings	Leve lof Evidence
Scaravilli et al. [36] /Propensity-matched retrospective cohort	316 mechanically ventilated COVID-19 ICU patients (158 DEXA+, 158 DEXA−)	Dexamethasone 6 mg/day IV × 10 days	VAP was more frequent in DEXA + group (56% vs. 34%, RR 1.61, p = 0.0001). DEXA + had higher VAP incidence rate and longer ICU/MV durations, but mortality was similar. VAP was linked to higher mortality overall. 28% of VAPs were due to MDR bacteria	Level III (Moderate quality observational evidence)
Lamouche et al. [25] /Multicenter retrospective cohort	670 COVID-19 ARDS patients on MV ≥ 48 h in 15 ICUs	Early corticosteroids (within 24 h of ICU admission)	Early corticosteroids increased VAP risk (aHR 1.29, p = 0.016). VAP was independently associated with increased mortality (aHR 1.86, p = 0.0003). No difference in antibiotic resistance.	Level III (observational, adjusted for confounding)
Saura et al. [23] /Multicenter retrospective cohort (36 ICUs, Europe).	545 COVID-19 patients on MV > 48 h	Adjuvant corticosteroids	No significant overall association between corticosteroids and VAP (p = 0.082). Early use showed non-significant trend toward reduced VAP; later use associated with increased VAP risk (HR 1.94 at day 21).	Level III (observational, adjusted with time-varying analysis)
Roquilly et al. [33] /Multicenter randomized double-blind placebo-controlled trial	149 ICU trauma patients requiring mechanical ventilation	IV hydrocortisone 200 mg/day × 5 days, tapering to day 7	Hydrocortisone reduced HAP (35.6% vs. 51.3%, HR 0.51, p = 0.007) and increased MV-free days. No mortality difference.	Level I (Randomized Controlled Trial)
Lansbury et al. [38] /Systematic review and meta-analysis	30 studies (29 observational, 1 RCT) on patients with influenza	Corticosteroids (varied regimens; mostly high-dose)	Corticosteroid use was associated with increased mortality (OR 3.90; aHR 1.49) and hospital-acquired infections (OR 2.74).	Level II (systematic review of mostly low-quality observational studies)
Zhou et al. [39] /Systematic review and meta-analysis	19 studies (18 observational, 1 RCT); 6637 patients with influenza pneumonia or ARDS	Systemic corticosteroids (varied regimens)	Corticosteroids were associated with higher mortality (OR 1.53) and more nosocomial infections (OR 3.15).	Level II (systematic review with mostly observational data)
Reyes et al. [27] /Multicenter, prospective cohort study	3777 adult ICU patients with confirmed COVID-19	Dexamethasone treatment within 24 h of ICU admission (54.7% of patients)	Higher VAP incidence in dexamethasone group (17.1% vs. 13.2%, p = 0.014). Dexamethasone was an independent risk factor for ICU-RTI (OR 1.64; 95% CI 1.37–1.97; p < 0.001)	Level II (Prospective cohort study with PSM and regression analysis)
Martin-Loeches et al. [50] /Prospective, observational, multicenter study	220 ICU patients with confirmed (H1N1)v influenza A infection	Corticosteroid therapy at ICU admission (57.3% of patients)	HAP was more frequent in corticosteroid group (26.2% vs. 13.8%, OR 2.2, p < 0.05)	Level II (Prospective observational study with adjusted analysis)
Ranzani et al. [5] /Prospective, observational study	316 critically ill patients with ICU-acquired pneumonia	Prior systemic corticosteroid use at pneumonia onset (40% of patients)	Steroid use associated with reduced 28-day survival (adjusted HR 2.503; 95% CI 1.176–5.330; p = 0.017). Decreased inflammatory response and higher bacterial burden in steroid group	Level II (Prospective observational study with adjusted analysis)
Wafy et al. [58] /Randomized Controlled Trial (RCT)	50 patients with severe/very severe HAP (per Pneumonia Severity Index)	Adjunctive systemic steroids (Group I)	Improved oxygenation by Day 7 in steroid group. Reduced time to clinical stability and hospital stay. No significant difference in ICU mortality or duration of mechanical ventilation. No significant increase in steroid-related complications	Level I (Randomized Controlled Trial)
Pirraccchio et al. [41] /Narrative review including multiple RCTs and meta-analyses	Critically ill adults with severe pulmonary infections (COVID-19, CAP, PCP, ARDS)	Low-dose corticosteroids (≤ 400 mg hydrocortisone equivalent/day)	Severe COVID-19 requiring oxygen or mechanical ventilation, dexamethasone 6 mg daily for 10 days significantly reduced 28-day mortality Severe bacterial CAP low-dose corticosteroids decreased 30-day mortality HIV-positive patients with moderate to severe Pneumocystis pneumonia, corticosteroid reduced mortality ARDS patients, corticosteroids decreased in-hospital mortality	Level I (Multiple RCTs and meta-analyses)

Corticosteroids and their immunomodulatory properties can be beneficial in certain contexts, particularly in cases of severity, but they may also promote opportunistic infections and the action of drug-resistant pathogens in HAP and VAP [43, 44]. Recent scientific evidence suggests a beneficial effect of corticosteroids associated with the dose and duration of the treatment. A systematic review by Pirracchio et al. [41] showed that low-dose corticosteroids (≤400 mg/day hydrocortisone equivalent) administered early (within 24–36 hours) and for a limited duration (5–14 days) are associated with improved outcomes in patients with severe pneumonia, ARDS, and sepsis, with fewer adverse effects such as secondary infections. In contrast, higher doses (e.g., dexamethasone ≥12 mg/day) have been associated with an increased mortality in viral pneumonias and greater risk of complications. For example, results from the RECOVERY follow-up trial demonstrated increased mortality in hospitalized COVID-19 patients receiving 20mg/day compared to standard dose of 6 mg/day, The results of COVIDICUS and COVID STEROIDS 2 trials reported no mortality benefit of 12 mg or 20 mg daily vs 6 mg daily in patients with severe COVID-19 or ARDS [45, 46]. These findings showed that treatment with corticosteroids should be individualized and consider both clinical severity and timing, particularly in HAP/VAP, where most cases are bacterial and may respond differently than viral infections.

In the case of bacteria, the identification of S. aureus including MRSA is reported to be more frequent in patients receiving corticosteroids [47, 48]. During the severe acute respiratory syndrome (SARS), influenza A H1N1, and COVID-19 pandemics there were reports of an increase of secondary bacterial pneumonia, mainly due to S. aureus in patients received corticosteroids [49–53]. The use of corticosteroids is also linked to nosocomial Legionella pneumonia, and to the increase in the detection of fungal and opportunistic infections such as Aspergillus sp., and Pneumocystis jirovecii and viral reactivations such as cytomegalovirus reactivation [54–57].

It is difficult to reach firm conclusions regarding the effect of corticosteroids on the outcomes of patients with HAP and VAP, due to the lack of scientific evidence. As we mentioned above, the use of corticosteroids affects the clinical presentation of pneumonia, thus creating a challenge for the diagnosis, and affects the pathogen profile of patients with HAP and VAP. All these points should be taken account during patients’ clinical and microbiological evaluation.

Regarding the impact of corticosteroid use on mortality in patients with HAP and VAP, most studies report higher mortality rates in patients administered corticosteroids. Some, however, have reported a beneficial effect: for example, a recent randomized controlled trial assessing the effect of adjunctive steroids in 50 patients with severe HAP, including VAP [58] found improved oxygenation by day 7 in the steroid group, and accelerated clinical stability. There were no significant differences regarding ICU mortality, duration of mechanical ventilation, or length of hospital stay. Another retrospective study evaluated the effect of corticosteroid use on 28-day survival in 316 ICU-acquired pneumonia patients, of whom 125 (40%) received corticosteroids [5]. In that study, patients receiving corticosteroids had lower 28-day survival, lower systemic inflammation and higher bacterial loads at the time of diagnosis. A subgroup analysis revealed a higher mortality risk in patients with non-ventilator ICU-acquired pneumonia, and in patients with mild organ dysfunction without an identified bacterial cause. No significant effect on overall mortality risk was observed.

An ongoing phase III clinical trial is currently assessing whether the addition of dexamethasone improves outcomes in critically ill patients with severe HAP and high inflammatory response [58]. The experimental group received dexamethasone 0.2mg/kg/day for 5- 7 days plus standard antimicrobial therapy, while the control group were administered placebo plus standard antimicrobial therapy. The main outcomes are the clinical cure rate at the test-of-cure visit (day 8–10 post-randomization or at ICU discharge) and all-cause of mortality at 28 days. The study started in 2024 and will finish in 2026. The results of this clinical trial will provide more information on the use of corticosteroids in the treatment of patients with HAP.

Discussion

The use of corticosteroids as adjunctive therapy for HAP and VAP is controversial, above all because of the lack of clinical evidence. During the COVID-19 pandemic there was an increase in the research into corticosteroids and the studies published provided evidence on the outcomes of their use and the association with microbial aetiology. Corticosteroid use has advantages and disadvantages: while the anti-inflammatory and immunomodulatory effects offer potentially benefits, mainly related to the reduction in lung inflammation, improved oxygenation, and shorter mechanical ventilation duration, the potential side effects include conditions such as immunosuppression, hyperglycaemia, myopathy, increased secondary infections, and other metabolic complications.

The scientific evidence on the impact of corticosteroids in the outcomes of patients with HAP and VAP is conflicting. While some studies reported a reduced risk of pneumonia in patients administered corticosteroids, others reported no such effect; still others report improved outcomes in patients with HAP and VAP. Studies of mechanically ventilated patients with severe COVID-19 have shown that corticosteroid use increases the risk of VAP especially in the case of dexamethasone. Future research into the effect of corticosteroids in specific populations (i.e., HAP or VAP) is warranted, since there are differences in the severity and in the microbial aetiology, especially regarding drug-resistant pathogens.

In general, given that the scientific evidence is controversial, a personalized approach based on severity of disease, previous comorbidities, and risk of complications remains vital. Future studies with larger sample sizes in specific settings are needed to be able to reach firm conclusions regarding the effect of corticosteroids as adjunctive therapy and its future recommendations.

Conclusions

Nosocomial pneumonia is one of the most common and severe hospital-acquired infections, with mortality rates reaching up to 71% in patients with ventilator-associated pneumonia (VAP). Anti-inflammatory and immunomodulatory effects of corticosteroids may reduce lung damage and improve oxygenation and may also shorten the duration of mechanical ventilation in critically ill patients. However, there is a risk of side effects such as increased risk of secondary infections (bacterial superinfections, candidiasis), and metabolic and muscular complications, including hyperglycemia, myopathy, osteoporosis, and immunosuppression.

In conclusion, corticosteroids are not recommended as standard therapy for HAP/VAP but may be beneficial in selected subgroups (e.g., ARDS). Large-scale prospective clinical trials (e.g., DExa-HAP VAP) are needed to clarify their current impact.

Abbreviations

HAP

Hospital-acquired pneumonia

ICU

Intensive Care Unit

NV-HAP

Non-ventilated hospital-acquired pneumonia

V-HAP

Ventilated-HAP

ICU-AP

ICU-acquired pneumonia

VAP

Ventilator-associated pneumonia

ESBL

Extended-spectrum β-lactamases

KPC

Carbapenemases

MRSA

Methicillin-resistant strain

MDR

Multidrug-resistant

CRE

Carbapenem-resistant Enterobacterales

COPD

Chronic obstructive pulmonary disease

aHR

Adjusted hazard ratio

CI

Confidential interval

ARDS

Acute respiratory distress syndrome

Authors’ contributions

All authors wrote the main manuscript text, prepared figures and tables and reviewed the manuscript.

Funding

This study was supported by CIBER de Enfermedades Respiratorias (CIBERES CB06/06/0028), and by 2009 Support to Research Groups of Catalonia 911, IDIBAPS. The funders had no role in the conception, literature selection, analysis, interpretation, writing of the manuscript, or the decision to submit the article for publication.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.