Download PDF
Semin Respir Crit Care Med 2016; 37(06): 913-922
DOI: 10.1055/s-0036-1593538
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Nonantibiotic Adjunctive Therapies for Community-Acquired Pneumonia (Corticosteroids and Beyond): Where Are We with Them?

Oriol Sibila
1   Respiratory Department, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona (UAB), Barcelona, Spain
2   Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
,
Ana Rodrigo-Troyano
1   Respiratory Department, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona (UAB), Barcelona, Spain
2   Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
,
Antoni Torres
3   Pulmonolgy Department, Respiratory Institute (ICR), Hospital Clinic of Barcelona, Spain
4   Centro de Investigación Biomedica En Red - Enfermedades Respiratorias, Barcelona, Spain
› Author Affiliations
Further Information

Publication History

Publication Date:
13 December 2016 (online)

   Permissions and Reprints

Abstract

Community-acquired pneumonia (CAP) is a leading cause of hospitalization, morbidity, and mortality. Despite advances in antibiotic treatments, mortality among patients with CAP is still high. For this reason, interest has been focused on nonantibiotic therapeutic measures directed to the host response rather than the microorganism. The development of an efficacious adjunctive treatment has important implications for reducing mortality in CAP. Some clinical studies performed in the last decade have shown a clinically beneficial effect of corticosteroids, possibly by diminishing local and systemic inflammatory host response. Recent meta-analyses showed faster resolution of symptoms, shorter time to clinically stability, reduction of mechanical ventilation needed, and reduction of mortality in the most severe population, although some methodological limitations must be taken into account. In addition, some studies using statins also suggested improved outcomes due to its anti-inflammatory effect in CAP, although this requires further research. Other adjunctive therapies such as immunoglobulins and stem cells are being explored, but are not yet in the stage of clinical trials. In summary, the use of corticosteroids and other adjuvant treatments are promising in CAP, but more studies are needed to determine their impact on mortality.

Keywords

community-acquired pneumonia - corticosteroids - statins - immunoglobulins
 

  • References

  • 1 Jemal A, Ward E, Hao Y, Thun M. Trends in the leading causes of death in the United States, 1970-2002. JAMA 2005; 294 (10) 1255-1259
    CrossrefPubMedGoogle Scholar
  • 2 Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 1997; 349 (9064) 1498-1504
    CrossrefPubMedGoogle Scholar
  • 3 Heron M, Hoyert DL, Murphy SL, Xu J, Kochanek KD, Tejada-Vera B. Deaths: final data for 2006. Natl Vital Stat Rep 2009; 57 (14) 1-134
    PubMedGoogle Scholar
  • 4 Shindo Y, Ito R, Kobayashi D , et al; Central Japan Lung Study Group. Risk factors for 30-day mortality in patients with pneumonia who receive appropriate initial antibiotics: an observational cohort study. Lancet Infect Dis 2015; 15 (9) 1055-1065
    CrossrefPubMedGoogle Scholar
  • 5 Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms in sepsis. Nat Rev Immunol 2008; 8 (10) 776-787
    CrossrefPubMedGoogle Scholar
  • 6 Kellum JA, Kong L, Fink MP , et al; GenIMS Investigators. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med 2007; 167 (15) 1655-1663
    CrossrefPubMedGoogle Scholar
  • 7 Yende S, D'Angelo G, Kellum JA , et al; GenIMS Investigators. Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis. Am J Respir Crit Care Med 2008; 177 (11) 1242-1247
    CrossrefPubMedGoogle Scholar
  • 8 Wunderink RG. Adjunctive therapy in community-acquired pneumonia. Semin Respir Crit Care Med 2009; 30 (2) 146-153
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Montón C, Ewig S, Torres A , et al. Role of glucocorticoids on inflammatory response in nonimmunosuppressed patients with pneumonia: a pilot study. Eur Respir J 1999; 14 (1) 218-220
    CrossrefPubMedGoogle Scholar
  • 10 Sibila O, Ferrer M, Agustí C, Torres A. Corticosteroids as adjunctive treatment in community-acquired pneumonia. Minerva Anestesiol 2014; 80 (12) 1336-1344
    PubMedGoogle Scholar
  • 11 Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med 2005; 353 (16) 1711-1723
    CrossrefPubMedGoogle Scholar
  • 12 Webster JI, Tonelli L, Sternberg EM. Neuroendocrine regulation of immunity. Annu Rev Immunol 2002; 20: 125-163
    CrossrefPubMedGoogle Scholar
  • 13 Baldwin Jr AS. Series introduction: the transcription factor NF-kappaB and human disease. J Clin Invest 2001; 107 (1) 3-6
    CrossrefPubMedGoogle Scholar
  • 14 Edwards MR, Bartlett NW, Clarke D, Birrell M, Belvisi M, Johnston SL. Targeting the NF-kappaB pathway in asthma and chronic obstructive pulmonary disease. Pharmacol Ther 2009; 121 (1) 1-13
    CrossrefPubMedGoogle Scholar
  • 15 Sibila O, Luna CM, Agustí C , et al. Effects of glucocorticoids in ventilated piglets with severe pneumonia. Eur Respir J 2008; 32 (4) 1037-1046
    CrossrefPubMedGoogle Scholar
  • 16 Meduri GU, Kanangat S, Bronze M , et al. Effects of methylprednisolone on intracellular bacterial growth. Clin Diagn Lab Immunol 2001; 8 (6) 1156-1163
    CrossrefPubMedGoogle Scholar
  • 17 Li Y, Cui X, Li X , et al. Risk of death does not alter the efficacy of hydrocortisone therapy in a mouse E. coli pneumonia model: risk and corticosteroids in sepsis. Intensive Care Med 2008; 34 (3) 568-577
    CrossrefPubMedGoogle Scholar
  • 18 Tagliabue C, Salvatore CM, Techasaensiri C , et al. The impact of steroids given with macrolide therapy on experimental Mycoplasma pneumoniae respiratory infection. J Infect Dis 2008; 198 (8) 1180-1188
    CrossrefPubMedGoogle Scholar
  • 19 Menéndez R, Cavalcanti M, Reyes S , et al. Markers of treatment failure in hospitalised community acquired pneumonia. Thorax 2008; 63 (5) 447-452
    CrossrefPubMedGoogle Scholar
  • 20 Ramírez P, Ferrer M, Martí V , et al. Inflammatory biomarkers and prediction for intensive care unit admission in severe community-acquired pneumonia. Crit Care Med 2011; 39 (10) 2211-2217
    CrossrefPubMedGoogle Scholar
  • 21 Menéndez R, Martínez R, Reyes S , et al. Biomarkers improve mortality prediction by prognostic scales in community-acquired pneumonia. Thorax 2009; 64 (7) 587-591
    CrossrefPubMedGoogle Scholar
  • 22 Garcia-Vidal C, Calbo E, Pascual V, Ferrer C, Quintana S, Garau J. Effects of systemic steroids in patients with severe community-acquired pneumonia. Eur Respir J 2007; 30 (5) 951-956
    CrossrefPubMedGoogle Scholar
  • 23 Salluh JIF, Soares M, Coelho LM , et al. Impact of systemic corticosteroids on the clinical course and outcomes of patients with severe community-acquired pneumonia: a cohort study. J Crit Care 2011; 26 (2) 193-200
    CrossrefPubMedGoogle Scholar
  • 24 Tagami T, Matsui H, Horiguchi H, Fushimi K, Yasunaga H. Low-dose corticosteroid use and mortality in severe community-acquired pneumonia patients. Eur Respir J 2015; 45 (2) 463-472
    CrossrefPubMedGoogle Scholar
  • 25 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 (3) 242-248
    CrossrefPubMedGoogle Scholar
  • 26 Snijders D, Daniels JMA, de Graaff CS, van der Werf TS, Boersma WG. Efficacy of corticosteroids in community-acquired pneumonia: a randomized double-blinded clinical trial. Am J Respir Crit Care Med 2010; 181 (9) 975-982
    CrossrefPubMedGoogle Scholar
  • 27 Meijvis SCA, Hardeman H, Remmelts HHF , et al. Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. Lancet 2011; 377 (9782) 2023-2030
    CrossrefPubMedGoogle Scholar
  • 28 Fernández-Serrano S, Dorca J, Garcia-Vidal C , et al. Effect of corticosteroids on the clinical course of community-acquired pneumonia: a randomized controlled trial. Crit Care 2011; 15 (2) R96
    CrossrefPubMedGoogle Scholar
  • 29 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 (7) 677-686
    CrossrefPubMedGoogle Scholar
  • 30 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 (9977) 1511-1518
    CrossrefPubMedGoogle Scholar
  • 31 Chen Y, Li K, Pu H, Wu T. Corticosteroids for pneumonia. Cochrane Database Syst Rev 2011; (3) CD007720
    PubMedGoogle Scholar
  • 32 Nie W, Zhang Y, Cheng J, Xiu Q. Corticosteroids in the treatment of community-acquired pneumonia in adults: a meta-analysis. PLoS ONE 2012; 7 (10) e47926
    CrossrefPubMedGoogle Scholar
  • 33 Marti C, Grosgurin O, Harbarth S , et al. Adjunctive corticotherapy for community acquired pneumonia: a systematic review and meta-analysis. PLoS ONE 2015; 10 (12) e0144032
    CrossrefPubMedGoogle Scholar
  • 34 Wan Y-D, Sun T-W, Liu Z-Q, Zhang S-G, Wang L-X, Kan Q-C. Efficacy and safety of corticosteroids for community-acquired pneumonia: a systematic review and meta-analysis. Chest 2016; 149 (1) 209-219
    CrossrefPubMedGoogle Scholar
  • 35 Siemieniuk RAC, 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 (7) 519-528
    CrossrefPubMedGoogle Scholar
  • 36 Baigent C, Keech A, Kearney PM , et al; Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366 (9493) 1267-1278
    CrossrefPubMedGoogle Scholar
  • 37 Hou W, Lv J, Perkovic V , et al. Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidney disease: a systematic review and meta-analysis. Eur Heart J 2013; 34 (24) 1807-1817
    CrossrefPubMedGoogle Scholar
  • 38 Gutierrez J, Ramirez G, Rundek T, Sacco RL. Statin therapy in the prevention of recurrent cardiovascular events: a sex-based meta-analysis. Arch Intern Med 2012; 172 (12) 909-919
    CrossrefPubMedGoogle Scholar
  • 39 Blanco-Colio LM, Tuñón J, Martín-Ventura JL, Egido J. Anti-inflammatory and immunomodulatory effects of statins. Kidney Int 2003; 63 (1) 12-23
    CrossrefPubMedGoogle Scholar
  • 40 Ascer E, Bertolami MC, Venturinelli ML , et al. Atorvastatin reduces proinflammatory markers in hypercholesterolemic patients. Atherosclerosis 2004; 177 (1) 161-166
    CrossrefPubMedGoogle Scholar
  • 41 Novack V, Eisinger M, Frenkel A , et al. The effects of statin therapy on inflammatory cytokines in patients with bacterial infections: a randomized double-blind placebo controlled clinical trial. Intensive Care Med 2009; 35 (7) 1255-1260
    CrossrefPubMedGoogle Scholar
  • 42 Almog Y, Shefer A, Novack V , et al. Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation 2004; 110 (7) 880-885
    CrossrefPubMedGoogle Scholar
  • 43 Merx MW, Liehn EA, Graf J , et al. Statin treatment after onset of sepsis in a murine model improves survival. Circulation 2005; 112 (1) 117-124
    CrossrefPubMedGoogle Scholar
  • 44 Jerwood S, Cohen J. Unexpected antimicrobial effect of statins. J Antimicrob Chemother 2008; 61 (2) 362-364
    PubMedGoogle Scholar
  • 45 van de Garde EMW, Hak E, Souverein PC, Hoes AW, van den Bosch JM, Leufkens HG. Statin treatment and reduced risk of pneumonia in patients with diabetes. Thorax 2006; 61 (11) 957-961
    CrossrefPubMedGoogle Scholar
  • 46 Chung S-D, Tsai M-C, Lin H-C, Kang J-H. Statin use and clinical outcomes among pneumonia patients. Clin Microbiol Infect 2014; 20 (9) 879-885
    CrossrefPubMedGoogle Scholar
  • 47 Polgreen LA, Cook EA, Brooks JM, Tang Y, Polgreen PM. Increased statin prescribing does not lower pneumonia risk. Clin Infect Dis 2015; 60 (12) 1760-1766
    CrossrefPubMedGoogle Scholar
  • 48 Makris D, Manoulakas E, Komnos A , et al. Effect of pravastatin on the frequency of ventilator-associated pneumonia and on intensive care unit mortality: open-label, randomized study. Crit Care Med 2011; 39 (11) 2440-2446
    CrossrefPubMedGoogle Scholar
  • 49 Papazian L, Roch A, Charles P-E , et al; STATIN-VAP Study Group. Effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomized clinical trial. JAMA 2013; 310 (16) 1692-1700
    CrossrefPubMedGoogle Scholar
  • 50 Viasus D, Garcia-Vidal C, Simonetti AF , et al. The effect of simvastatin on inflammatory cytokines in community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. BMJ Open 2015; 5 (1) e006251
    CrossrefPubMedGoogle Scholar
  • 51 Kreymann KG, de Heer G, Nierhaus A, Kluge S. Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit Care Med 2007; 35 (12) 2677-2685
    CrossrefPubMedGoogle Scholar
  • 52 Taccone FS, Stordeur P, De Backer D, Creteur J, Vincent J-L. Gamma-globulin levels in patients with community-acquired septic shock. Shock 2009; 32 (4) 379-385
    CrossrefPubMedGoogle Scholar
  • 53 de la Torre MC, Bolíbar I, Vendrell M , et al. Serum immunoglobulins in the infected and convalescent phases in community-acquired pneumonia. Respir Med 2013; 107 (12) 2038-2045
    CrossrefPubMedGoogle Scholar
  • 54 Shankar-Hari M, Spencer J, Sewell WA, Rowan KM, Singer M. Bench-to-bedside review: immunoglobulin therapy for sepsis - biological plausibility from a critical care perspective. Crit Care 2012; 16 (2) 206
    PubMedGoogle Scholar
  • 55 Werdan K, Pilz G, Bujdoso O , et al; Score-Based Immunoglobulin Therapy of Sepsis (SBITS) Study Group. Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study. Crit Care Med 2007; 35 (12) 2693-2701
    CrossrefPubMedGoogle Scholar
  • 56 Alejandria MM, Lansang MAD, Dans LF, Mantaring III JB. Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database Syst Rev 2013; (9) CD001090
    PubMedGoogle Scholar
  • 57 Welte T, Dellinger RP, Ebelt H , et al. Concept for a study design in patients with severe community-acquired pneumonia: a randomised controlled trial with a novel IGM-enriched immunoglobulin preparation - the CIGMA study. Respir Med 2015; 109 (6) 758-767
    CrossrefPubMedGoogle Scholar
  • 58 Gupta N, Krasnodembskaya A, Kapetanaki M , et al. Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia. Thorax 2012; 67 (6) 533-539
    CrossrefPubMedGoogle Scholar
  • 59 Asmussen S, Ito H, Traber DL , et al. Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia. Thorax 2014; 69 (9) 819-825
    CrossrefPubMedGoogle Scholar
  • 60 Hackstein H, Lippitsch A, Krug P , et al. Prospectively defined murine mesenchymal stem cells inhibit Klebsiella pneumoniae-induced acute lung injury and improve pneumonia survival. Respir Res 2015; 16: 123
    CrossrefPubMedGoogle Scholar
  • 61 Marik P, Kraus P, Sribante J, Havlik I, Lipman J, Johnson DW. Hydrocortisone and tumor necrosis factor in severe community-acquired pneumonia. A randomized controlled study. Chest 1993; 104 (2) 389-392
    CrossrefPubMedGoogle Scholar
  • 62 McHardy VU, Schonell ME. Ampicillin dosage and use of prednisolone in treatment of pneumonia: co-operative controlled trial. BMJ 1972; 4 (5840) 569-573
    CrossrefPubMedGoogle Scholar
  • 63 Mikami K, Suzuki M, Kitagawa H , et al. Efficacy of corticosteroids in the treatment of community-acquired pneumonia requiring hospitalization. Lung 2007; 185 (5) 249-255
    CrossrefPubMedGoogle Scholar
  • 64 van Woensel JBM, van Aalderen WMC, de Weerd W , et al. Dexamethasone for treatment of patients mechanically ventilated for lower respiratory tract infection caused by respiratory syncytial virus. Thorax 2003; 58 (5) 383-387
    CrossrefPubMedGoogle Scholar
  • 65 Cao LF, Lu YM, Ma HG, Ma M. Budesonide inhaling auxiliary therapy after mycoplasma pneumoniae infection of children. Int J Respir 2007; 27 (8) 567–569
    PubMedGoogle Scholar
  • 66 Wagner Jr HN, Bennett Jr IL, Lasagna L, Cluff LE, Rosenthal MB, Mirick GS. The effect of hydrocortisone upon the course of pneumococcal pneumonia treated with penicillin. Bull Johns Hopkins Hosp 1956; 98 (3) 197-215
    PubMedGoogle Scholar
  • 67 Sabry N, Omar E. Corticosteroids and ICU course of community acquired pneumonia in Egyptian settings. Pharmacol Pharm 2011; 2: 73-81
    CrossrefPubMedGoogle Scholar
  • 68 Bennett IL, Findland M, Hamburger M, Kass E, Lepper M, Waisbren B. The effectiveness of hydrocortisone in the management of severe infections. JAMA 1963; 183 (6) 462-465
    CrossrefPubMedGoogle Scholar
  • 69 Klastersky J, Cappel R, Debusscher L. Effectiveness of betamethasone in management of severe infections. A double-blind study. N Engl J Med 1971; 284 (22) 1248-1250
    CrossrefPubMedGoogle Scholar
  • 70 Nafae RM, Ragab MI, Amany FM, Rashed SB. Adjuvant role of corticosteroids in the treatment of community-acquired pneumonia. Egypt J Chest Dis Tuberc 2013; 62 (3) 439-445
    PubMedGoogle Scholar
  • 71 El Ghamrawy A, Shokeir M, Esmat A. Effects of low dose hydrocortisone in ICU patients with severe community acquired pneumonia. Egypt J Chest Dis Tuberc 2006; 5: 91-99
    PubMedGoogle Scholar
  • 72 Chon GR, Lim C-M, Koh Y, Hong S-B. Analysis of systemic corticosteroid usage and survival in patients requiring mechanical ventilation for severe community-acquired pneumonia. J Infect Chemother 2011; 17 (4) 449-455
    CrossrefPubMedGoogle Scholar
  • 73 Ugajin M, Yamaki K, Hirasawa N, Kobayashi T, Yagi T. Impact and indication of early systemic corticosteroids for very severe community-acquired pneumonia. Int J Gen Med 2013; 6: 693-701
    PubMedGoogle Scholar
  • 74 Polverino E, Cillóniz C, Dambrava P , et al. Systemic corticosteroids for community-acquired pneumonia: reasons for use and lack of benefit on outcome. Respirology 2013; 18 (2) 263-271
    CrossrefPubMedGoogle Scholar