The potential use of oral corticosteroids in patients with community-acquired pneumonia (CAP) has become extremely topical. In the past 12 months we have had two randomized controlled trials (1,2), three meta-analysis (3-5) and a significant number of associated editorials and commentaries. While the randomized controlled trials could be described as mildly positive at best, the meta-analyses, and particularly the paper by Siemieniuk and colleagues (4), have been much more vocal in their support of steroid therapy.
That CAP is both a common and serious health problem is undisputed. CAP has also been a frequent focus of quality of care measurement with not only institutional inpatient mortality targeted, but also a host of surrogate measures selected on the basis of some association with adverse outcome (e.g., performing blood cultures and timing of antibiotic therapy). Unfortunately a large proportion of the mortality in CAP is probably not preventable as it occurs in elderly patients with multiple comorbidities in whom significant limits in the ceiling of care (e.g., not for resuscitation, not for intensive care etc.) are (almost always appropriately) in place. There remains however a significant cohort of patients who die despite all attempts to treat them, and this remains a major source of frustration and angst to clinicians and the families of those who succumb.
In the group of patients who die despite all attempts to cure them, multi-organ failure from severe sepsis is the usual scenario. Given that sepsis is generally thought to be driven by an excessive or uncontrolled pro-inflammatory response (6), suppression of the immune system with high doses of corticosteroids would seem a logical therapy to trial. Unfortunately despite a number of small trials suggesting therapeutic benefit, large scale randomized trials have found no benefit of immunosuppressive doses of corticosteroids in either septic shock or acute lung injury and are therefore not recommended as standard therapy (7). As with many interventions it is likely that within the broad group of patients with sepsis, steroids have a net beneficial effect in some and a net harmful effect in others. Proponents of steroids have argued that it is patients with pneumonia may be in the beneficial group.
Proponents of meta-analysis argue that this methodology helps tease out whether there is a real benefit (or harm) of a therapy hidden by under powering of the clinical trials conducted so far. The problem with the approach of meta-analysis is that even one “outlier” study can significantly influence the outcome when added to a number of studies with neutral (i.e., negative) results. In the case of CAP and steroids the problematic paper is Confalonieri and colleagues (8) which demonstrated a remarkable benefit of steroids that no one has been able to repeat or even come anywhere near the efficacy demonstrated and therefore its credibility as an estimate of the likelihood of benefit of steroids is questionable particularly in the context of all the other randomized studies now published. Examining the Forrest plot in Siemieniuk and colleagues (4) it is immediately apparent that if the Confalonieri et al. paper is excluded as an aberrant outlier the overall analysis is minimal to no benefit (8).
The counter argument to the meta-analysis of Siemieniuk and colleagues being flawed because of the bias introduced by the Confalonieri et al. study is that there is no evidence of harm, so why not give steroids anyway? Personally I think this is a dangerous path to follow, driven as it is by desperation (the need to do something) rather than clear evidence of benefit.
While I am sure that future studies will tease out subgroups of patients with CAP that will have a net positive benefit from high dose corticosteroids, I am equally sure that there are many other things with a likely much higher benefit for patients with CAP that we have evidence for but are currently not doing well. Compliance with the standard “sepsis bundle” approach outlined in the Surviving Sepsis campaign (7) is associated with better outcomes in patients with CAP (9,10), and includes rapid administration of antibiotics, fluid resuscitation and correction of electrolyte abnormalities and hyperglycemia. Inclusion of a macrolide in combination with a beta-lactam remains the optimal standard therapy in sick patients based on current evidence (11). Early mobilization improves mortality (12), but is not part of routine care in most hospitals. Acute myocardial infarction occurs in up to 10% of patients who are severely ill with pneumonia (13-15), and anti-platelet therapy appears to significant reduce the risk (16-18), but again is not part of the standard of care. Pulmonary emboli are also a significant contributor to adverse patient outcomes (19), but thrombosis prophylaxis is also not routine in many hospitals (20,21).
In summary, the interest surrounding the use of immunosuppressant doses of corticosteroids is driven much more by clinician frustration in their inability to change patient outcomes than it is by the current strength of the data. I am sure that future research will identify patients that will benefit from steroid immunosuppressant therapy, but much greater gains are already available through careful and rigorous application of optimal treatment bundles that include rapid antibiotic therapy and fluid resuscitation, early mobilization, myocardial ischaemic and venous thrombosis prophylaxis and attention to other comorbidities such as hyperglycemia and electrolyte abnormalities. When all of these are routinely covered in all individuals then steroids may find their place.
Acknowledgements
None.
Footnotes
Provenance: This is a Guest Editorial commissioned by the Section Editor Wan-Jie Gu (Department of Anesthesiology, Affiliated Drum Tower Hospital, Medical College of Nanjing University, China).
Conflicts of Interest: The author has no conflicts of interest to declare.
References
- 1.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;313:677-86. [DOI] [PubMed] [Google Scholar]
- 2.Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2015;385:1511-8. [DOI] [PubMed] [Google Scholar]
- 3.Horita N, Otsuka T, Haranaga S, et al. Adjunctive Systemic Corticosteroids for Hospitalized Community-Acquired Pneumonia: Systematic Review and Meta-Analysis 2015 Update. Sci Rep 2015;5:14061. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Siemieniuk RA, Meade MO, Alonso-Coello P, et al. Corticosteroid Therapy for Patients Hospitalized With Community-Acquired Pneumonia: A Systematic Review and Meta-analysis. Ann Intern Med 2015;163:519-28. [DOI] [PubMed] [Google Scholar]
- 5.Chen LP, Chen JH, Chen Y, et al. Efficacy and safety of glucocorticoids in the treatment of community-acquired pneumonia: A meta-analysis of randomized controlled trials. World J Emerg Med 2015;6:172-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet 2005;365:63-78. [DOI] [PubMed] [Google Scholar]
- 7.Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 2013;39:165-228. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.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;171:242-8. [DOI] [PubMed] [Google Scholar]
- 9.Hortmann M, Heppner HJ, Popp S, et al. Reduction of mortality in community-acquired pneumonia after implementing standardized care bundles in the emergency department. Eur J Emerg Med 2014;21:429-35. [DOI] [PubMed] [Google Scholar]
- 10.Fätkenheuer G, Preuss M, Salzberger B, et al. Long-term outcome and quality of care of patients with Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect Dis 2004;23:157-62. [DOI] [PubMed] [Google Scholar]
- 11.Wunderink RG, Waterer GW. Community-acquired pneumonia. N Engl J Med 2014;370:1863. [DOI] [PubMed] [Google Scholar]
- 12.Carratalà J, Garcia-Vidal C, Ortega L, et al. Effect of a 3-step critical pathway to reduce duration of intravenous antibiotic therapy and length of stay in community-acquired pneumonia: a randomized controlled trial. Arch Intern Med 2012;172:922-8. [DOI] [PubMed] [Google Scholar]
- 13.Ramirez J, Aliberti S, Mirsaeidi M, et al. Acute myocardial infarction in hospitalized patients with community-acquired pneumonia. Clin Infect Dis 2008;47:182-7. [DOI] [PubMed] [Google Scholar]
- 14.Perry TW, Pugh MJ, Waterer GW, et al. Incidence of cardiovascular events after hospital admission for pneumonia. Am J Med 2011;124:244-51. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Musher DM, Rueda AM, Kaka AS, et al. The association between pneumococcal pneumonia and acute cardiac events. Clin Infect Dis 2007;45:158-65. [DOI] [PubMed] [Google Scholar]
- 16.Oz F, Gul S, Kaya MG, et al. Does aspirin use prevent acute coronary syndrome in patients with pneumonia: multicenter prospective randomized trial. Coron Artery Dis 2013;24:231-7. [DOI] [PubMed] [Google Scholar]
- 17.Falcone M, Russo A, Cangemi R, et al. Lower mortality rate in elderly patients with community-onset pneumonia on treatment with aspirin. J Am Heart Assoc 2015;4:e001595. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Storey RF, James SK, Siegbahn A, et al. Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study. Platelets 2014;25:517-25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Chen YG, Lin TY, Huang WY, et al. Association between pneumococcal pneumonia and venous thromboembolism in hospitalized patients: A nationwide population-based study. Respirology 2015;20:799-804. [DOI] [PubMed] [Google Scholar]
- 20.Rifkin WD, Burger A, Holmboe ES, et al. Comparison of hospitalists and nonhospitalists regarding core measures of pneumonia care. Am J Manag Care 2007;13:129-32. [PubMed] [Google Scholar]
- 21.Jancar P, Morgan T, Mrhar A, et al. Venous thromboembolism prophylaxis in hospitalized patients with pneumonia: a prospective survey. Wien Klin Wochenschr 2009;121:318-23. [DOI] [PubMed] [Google Scholar]