Semin Respir Crit Care Med 2016; 37(06): 806-818
DOI: 10.1055/s-0036-1592074
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Role of Streptococcus pneumoniae in Community-Acquired Pneumonia

Charles Feldman
1   Division of Pulmonology, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa
2   Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
,
Ronald Anderson
3   Department of Immunology, Institute for Cellular and Molecular Medicine, Pretoria, South Africa
4   Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
› Author Affiliations
Further Information

Publication History

Publication Date:
13 December 2016 (online)

Abstract

Streptococcus pneumoniae (the pneumococcus) remains one of the most common causes of bacterial community-acquired pneumonia (CAP), encompassing infections mild enough to be treated on an outpatient basis, as well as those requiring hospital care, or even intensive care unit admission. This microorganism is associated with a significant burden of disease, causing substantial morbidity and mortality worldwide, and generating considerable health-care costs. The reason that pneumococcal CAP remains such a common cause of disease relates to the presence of several risk factors for this infection in patients throughout the world. Such risk factors include extremes of age, lifestyle factors, including smoking and alcohol abuse, and various underlying comorbid conditions, including congenital and acquired immunodeficiencies. This article will review various aspects of pneumococcal CAP, including the burden of pneumococcal disease, risk factors for pneumococcal infection, the occurrence of cardiovascular events in patients with pneumococcal CAP, the apparently pivotal role of pneumolysin, a major virulence factor of the pneumococcus, in the pathogenesis of severe infection and associated cardiac dysfunction, empiric antibiotic treatment for pneumococcal CAP, as well as adjunctive therapies, specifically those which target pneumolysin, and, finally, the mortality of such infections.

 
  • References

  • 1 File Jr TM, Marrie TJ. Burden of community-acquired pneumonia in North American adults. Postgrad Med 2010; 122 (2) 130-141
  • 2 Isturiz RE, Luna CM, Ramirez J. Clinical and economic burden of pneumonia among adults in Latin America. Int J Infect Dis 2010; 14 (10) e852-e856
  • 3 Shibl AM, Memish ZA, Ibrahim E, Kanj SS. Burden of adult community-acquired pneumonia in the Middle East/North Africa region. Rev Med Microbiol 2010; 21 (1) 11-20
  • 4 Song JH, Thamlikitkul V, Hsueh P-R. Clinical and economic burden of community-acquired pneumonia amongst adults in the Asia-Pacific region. Int J Antimicrob Agents 2011; 38 (2) 108-117
  • 5 Welte T, Torres A, Nathwani D. Clinical and economic burden of community-acquired pneumonia among adults in Europe. Thorax 2012; 67 (1) 71-79
  • 6 Lozano R, Naghavi M, Foreman K , et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380 (9859) 2095-2128
  • 7 Nunes MC, von Gottberg A, de Gouveia L , et al. Persistent high burden of invasive pneumococcal disease in South African HIV-infected adults in the era of an antiretroviral treatment program. PLoS ONE 2011; 6 (11) e27929
  • 8 Chavanet P. Pneumococcus infections: is the burden still as heavy?. Med Mal Infect 2012; 42 (4) 149-153
  • 9 Blasi F, Mantero M, Santus P, Tarsia P. Understanding the burden of pneumococcal disease in adults. Clin Microbiol Infect 2012; 18 (Suppl. 05) 7-14
  • 10 Ludwig E, Bonanni P, Rohde G, Sayiner A, Torres A. The remaining challenges of pneumococcal disease in adults. Eur Respir Rev 2012; 21 (123) 57-65
  • 11 Drijkoningen JJ, Rohde GG. Pneumococcal infection in adults: burden of disease. Clin Microbiol Infect 2014; 20 (Suppl. 05) 45-51
  • 12 Said MA, Johnson HL, Nonyane BA , et al; AGEDD Adult Pneumococcal Burden Study Team. Estimating the burden of pneumococcal pneumonia among adults: a systematic review and meta-analysis of diagnostic techniques. PLoS ONE 2013; 8 (4) e60273
  • 13 Sanz Herrero F, Blanquer Olivas J. Microbiology and risk factors for community-acquired pneumonia. Semin Respir Crit Care Med 2012; 33 (3) 220-231
  • 14 Feldman C, Anderson R. Antibiotic resistance of pathogens causing community-acquired pneumonia. Semin Respir Crit Care Med 2012; 33 (3) 232-243
  • 15 Cilloniz C, Albert RK, Liapikou A , et al. The effect of macrolide resistance on the presentation and outcome of patients hospitalized for Streptococcus pneumoniae pneumonia. Am J Respir Crit Care Med 2015; 191 (11) 1265-1272
  • 16 Cillóniz C, Ardanuy C, Vila J, Torres A. What is the clinical relevance of drug-resistant pneumococcus?. Curr Opin Pulm Med 2016; 22 (3) 227-234
  • 17 Torres A, Peetermans WE, Viegi G, Blasi F. Risk factors for community-acquired pneumonia in adults in Europe: a literature review. Thorax 2013; 68 (11) 1057-1065
  • 18 Nuorti JP, Butler JC, Farley MM , et al; Active Bacterial Core Surveillance Team. Cigarette smoking and invasive pneumococcal disease. N Engl J Med 2000; 342 (10) 681-689
  • 19 Kyaw MH, Rose Jr CE, Fry AM , et al; Active Bacterial Core Surveillance Program of the Emerging Infections Program Network. The influence of chronic illnesses on the incidence of invasive pneumococcal disease in adults. J Infect Dis 2005; 192 (3) 377-386
  • 20 Lynch III JP, Zhanel GG. Streptococcus pneumoniae: epidemiology and risk factors, evolution of antimicrobial resistance, and impact of vaccines. Curr Opin Pulm Med 2010; 16 (3) 217-225
  • 21 Chidiac C. Pneumococcal infections and adult with risk factors. Med Mal Infect 2012; 42 (10) 517-524
  • 22 van Hoek AJ, Andrews N, Waight PA , et al. The effect of underlying clinical conditions on the risk of developing invasive pneumococcal disease in England. J Infect 2012; 65 (1) 17-24
  • 23 Obert J, Burgel P-R. Pneumococcal infections: association with asthma and COPD. Med Mal Infect 2012; 42 (5) 188-192
  • 24 Boikos C, Quach C. Risk of invasive pneumococcal disease in children and adults with asthma: a systematic review. Vaccine 2013; 31 (42) 4820-4826
  • 25 Aspa J, Rajas O. Invasive pneumococcal disease and pneumococcal pneumonia: A review of the pertinent clinical issues. Clin Pulm Med 2014; 21 (2) 76-80
  • 26 Bello S, Menéndez R, Torres A , et al. Tobacco smoking increases the risk for death from pneumococcal pneumonia. Chest 2014; 146 (4) 1029-1037
  • 27 Torres A, Blasi F, Dartois N, Akova M. Which individuals are at increased risk of pneumococcal disease and why? Impact of COPD, asthma, smoking, diabetes, and/or chronic heart disease on community-acquired pneumonia and invasive pneumococcal disease. Thorax 2015; 70 (10) 984-989
  • 28 Gili-Miner M, López-Méndez J, Béjar-Prado L, Ramírez-Ramírez G, Vilches-Arenas Á, Sala-Turrens J. Alcohol use disorders and community-acquired pneumococcal pneumonia: associated mortality, prolonged hospital stay and increased hospital spending. Arch Bronconeumol 2015; 51 (11) 564-570
  • 29 Feldman C, Anderson R. Bacterial respiratory infections complicating human immunodeficiency virus. Semin Respir Crit Care Med 2016; 37 (2) 214-229
  • 30 Brundage JF. Interactions between influenza and bacterial respiratory pathogens: implications for pandemic preparedness. Lancet Infect Dis 2006; 6 (5) 303-312
  • 31 van der Sluijs KF, van der Poll T, Lutter R, Juffermans NP, Schultz MJ. Bench-to-bedside review: bacterial pneumonia with influenza - pathogenesis and clinical implications. Crit Care 2010; 14 (2) 219
  • 32 McCullers JA. The co-pathogenesis of influenza viruses with bacteria in the lung. Nat Rev Microbiol 2014; 12 (4) 252-262
  • 33 Robinson KM, Kolls JK, Alcorn JF. The immunology of influenza virus-associated bacterial pneumonia. Curr Opin Immunol 2015; 34: 59-67
  • 34 McCullers JA, Rehg JE. Lethal synergism between influenza virus and Streptococcus pneumoniae: characterization of a mouse model and the role of platelet-activating factor receptor. J Infect Dis 2002; 186 (3) 341-350
  • 35 Madhi SA, Klugman KP ; Vaccine Trialist Group. A role for Streptococcus pneumoniae in virus-associated pneumonia. Nat Med 2004; 10 (8) 811-813
  • 36 McCullers JA. Insights into the interaction between influenza virus and pneumococcus. Clin Microbiol Rev 2006; 19 (3) 571-582
  • 37 Klugman KP, Chien YW, Madhi SA. Pneumococcal pneumonia and influenza: a deadly combination. Vaccine 2009; 27 (Suppl. 03) C9-C14
  • 38 Kuster SP, Tuite AR, Kwong JC, McGeer A, Fisman DN ; Toronto Invasive Bacterial Diseases Network Investigators. Evaluation of coseasonality of influenza and invasive pneumococcal disease: results from prospective surveillance. PLoS Med 2011; 8 (6) e1001042
  • 39 Alicino C, Iudici R, Alberti M, Durando P. The dangerous synergism between influenza and Streptococcus pneumoniae and innovative perspectives of vaccine prevention. J Prev Med Hyg 2011; 52 (3) 102-106
  • 40 Davis BM, Aiello AE, Dawid S, Rohani P, Shrestha S, Foxman B. Influenza and community-acquired pneumonia interactions: the impact of order and time of infection on population patterns. Am J Epidemiol 2012; 175 (5) 363-367
  • 41 Vernatter J, Pirofski L-A. Current concepts in host-microbe interaction leading to pneumococcal pneumonia. Curr Opin Infect Dis 2013; 26 (3) 277-283
  • 42 Wolter N, Cohen C, Tempia S , et al. HIV and influenza virus infections are associated with increased blood pneumococcal load: a prospective, hospital-based observational study in South Africa, 2009-2011. J Infect Dis 2014; 209 (1) 56-65
  • 43 Christenson B, Hedlund J, Lundbergh P, Örtqvist A. Additive preventive effect of influenza and pneumococcal vaccines in elderly persons. Eur Respir J 2004; 23 (3) 363-368
  • 44 Blay A, Bessler H, Lahad A, Waitman DA, Djaldetti M. Does pneumococcal vaccine reduce influenza morbidity in humans?. Vaccine 2007; 25 (6) 1071-1075
  • 45 Chien YW, Klugman KP, Morens DM. Efficacy of whole-cell killed bacterial vaccines in preventing pneumonia and death during the 1918 influenza pandemic. J Infect Dis 2010; 202 (11) 1639-1648
  • 46 Crowe S, Utley M, Walker G, Grove P, Pagel C. A model to evaluate mass vaccination against pneumococcus as a countermeasure against pandemic influenza. Vaccine 2011; 29 (31) 5065-5077
  • 47 Chien Y-W, Levin BR, Klugman KP. The anticipated severity of a “1918-like” influenza pandemic in contemporary populations: the contribution of antibacterial interventions. PLoS ONE 2012; 7 (1) e29219
  • 48 Gilchrist SA, Nanni A, Levine O. Benefits and effectiveness of administering pneumococcal polysaccharide vaccine with seasonal influenza vaccine: an approach for policymakers. Am J Public Health 2012; 102 (4) 596-605
  • 49 Chang YC, Chou YJ, Liu JY, Yeh TF, Huang N. Additive benefits of pneumococcal and influenza vaccines among elderly persons aged 75 years or older in Taiwan—a representative population-based comparative study. J Infect 2012; 65 (3) 231-238
  • 50 McGarry LJ, Gilmore KE, Rubin JL, Klugman KP, Strutton DR, Weinstein MC. Impact of 13-valent pneumococcal conjugate vaccine (PCV13) in a pandemic similar to the 2009 H1N1 in the United States. BMC Infect Dis 2013; 13: 229
  • 51 Domínguez A, Castilla J, Godoy P , et al; CIBERESP Cases and Controls in Pandemic Influenza Working Group Spain. Benefit of conjugate pneumococcal vaccination in preventing influenza hospitalization in children: a case-control study. Pediatr Infect Dis J 2013; 32 (4) 330-334
  • 52 Klugman KP, Madhi SA. Pneumococcal vaccines and flu preparedness. Science 2007; 316 (5821) 49-50
  • 53 Corrales-Medina VF, Musher DM, Shachkina S, Chirinos JA. Acute pneumonia and the cardiovascular system. Lancet 2013; 381 (9865) 496-505
  • 54 Krüger S, Frechen D. Cardiovascular complications and comorbidities in CAP. In: Chalmers JD, Pletz MW, Aliberti S, eds. Community-Acquired Pneumonia. Norwich, UK: European Respiratory Society Publications. Eur Respir Monogr 2014; 63: 256-265
  • 55 Feldman C, Anderson R. Community-acquired pneumonia: Pathogenesis of acute cardiac events and potential adjunctive therapies. Chest 2015; 148 (2) 523-532
  • 56 Brown AO, Millett ERC, Quint JK, Orihuela CJ. Cardiotoxicity during invasive pneumococcal disease. Am J Respir Crit Care Med 2015; 191 (7) 739-745
  • 57 Arnold FW, Ramirez JA. The burden of cardiac complications in patients with community-acquired pneumonia. J Clin Outcomes Manag 2016; 23 (4) 173-180
  • 58 Musher DM, Rueda AM, Kaka AS, Mapara SM. The association between pneumococcal pneumonia and acute cardiac events. Clin Infect Dis 2007; 45 (2) 158-165
  • 59 Eurich DT, Johnstone JJ, Minhas-Sandhu JK, Marrie TJ, Majumdar SR. Pneumococcal vaccination and risk of acute coronary syndromes in patients with pneumonia: population-based cohort study. Heart 2012; 98 (14) 1072-1077
  • 60 Prina E, Ranzani OT, Torres A. Community-acquired pneumonia. Lancet 2015; 386 (9998) 1097-1108
  • 61 Mueller C, Laule-Kilian K, Scholer A, Perruchoud AP. B-type natriuretic peptide for risk stratification in community-acquired pneumonia. J Intern Med 2005; 258 (4) 391-393
  • 62 Christ-Crain M, Breidthardt T, Stolz D , et al. Use of B-type natriuretic peptide in the risk stratification of community-acquired pneumonia. J Intern Med 2008; 264 (2) 166-176
  • 63 Jeong KY, Kim K, Kim TY , et al. Prognostic value of N-terminal pro-brain natriuretic peptide in hospitalised patients with community-acquired pneumonia. Emerg Med J 2011; 28 (2) 122-127
  • 64 Krüger S, Ewig S, Kunde J, Hartmann O, Suttorp N, Welte T ; CAPNETZ Study Group. Pro-atrial natriuretic peptide and pro-vasopressin for predicting short-term and long-term survival in community-acquired pneumonia: results from the German Competence Network CAPNETZ. Thorax 2010; 65 (3) 208-214
  • 65 Nowak A, Breidthardt T, Christ-Crain M , et al. Direct comparison of three natriuretic peptides for prediction of short- and long-term mortality in patients with community-acquired pneumonia. Chest 2012; 141 (4) 974-982
  • 66 Kolditz M, Ewig S, Höffken G. Management-based risk prediction in community-acquired pneumonia by scores and biomarkers. Eur Respir J 2013; 41 (4) 974-984
  • 67 Florin TA, Ambroggio L. Biomarkers for community-acquired pneumonia in the emergency department. Curr Infect Dis Rep 2014; 16 (12) 451
  • 68 Chang CL, Mills GD, Karalus NC , et al. Biomarkers of cardiac dysfunction and mortality from community-acquired pneumonia in adults. PLoS ONE 2013; 8 (5) e62612
  • 69 Viasus D, Del Rio-Pertuz G, Simonetti AF , et al. Biomarkers for predicting short-term mortality in community-acquired pneumonia: a systematic review and meta-analysis. J Infect 2016; 72 (3) 273-282
  • 70 Mitchell TJ, Dalziel CE. The biology of pneumolysin. In: Anderluh G, Gilbert R, , eds. MACPF/CDC Proteins – Agents of Defence, Attack and Invasion. Dordrecht: Springer; 2014: 145-160
  • 71 Price KE, Camilli A. Pneumolysin localizes to the cell wall of Streptococcus pneumoniae . J Bacteriol 2009; 191 (7) 2163-2168
  • 72 Feldman C, Mitchell TJ, Andrew PW , et al. The effect of Streptococcus pneumoniae pneumolysin on human respiratory epithelium in vitro. Microb Pathog 1990; 9 (4) 275-284
  • 73 Feldman C, Munro NC, Jeffery PK , et al. Pneumolysin induces the salient histologic features of pneumococcal infection in the rat lung in vivo. Am J Respir Cell Mol Biol 1991; 5 (5) 416-423
  • 74 Canvin JR, Marvin AP, Sivakumaran M , et al. The role of pneumolysin and autolysin in the pathology of pneumonia and septicemia in mice infected with a type 2 pneumococcus. J Infect Dis 1995; 172 (1) 119-123
  • 75 Kadioglu A, Gingles NA, Grattan K, Kerr A, Mitchell TJ, Andrew PW. Host cellular immune response to pneumococcal lung infection in mice. Infect Immun 2000; 68 (2) 492-501
  • 76 Witzenrath M, Gutbier B, Hocke AC , et al. Role of pneumolysin for the development of acute lung injury in pneumococcal pneumonia. Crit Care Med 2006; 34 (7) 1947-1954
  • 77 García-Suárez MdelM, Flórez N, Astudillo A , et al. The role of pneumolysin in mediating lung damage in a lethal pneumococcal pneumonia murine model. Respir Res 2007; 8: 3
  • 78 Karlström A, Boyd KL, English BK, McCullers JA. Treatment with protein synthesis inhibitors improves outcomes of secondary bacterial pneumonia after influenza. J Infect Dis 2009; 199 (3) 311-319
  • 79 Hotomi M, Yuasa J, Briles DE, Yamanaka N. Pneumolysin plays a key role at the initial step of establishing pneumococcal nasal colonization. Folia Microbiol (Praha) 2016; 61 (5) 375-383
  • 80 Aberdein JD, Cole J, Bewley MA, Marriott HM, Dockrell DH. Alveolar macrophages in pulmonary host defence the unrecognized role of apoptosis as a mechanism of intracellular bacterial killing. Clin Exp Immunol 2013; 174 (2) 193-202
  • 81 Bewley MA, Naughton M, Preston J , et al. Pneumolysin activates macrophage lysosomal membrane permeabilization and executes apoptosis by distinct mechanisms without membrane pore formation. MBio 2014; 5 (5) e01710-e01714
  • 82 González-Juarbe N, Gilley RP, Hinojosa CA , et al. Pore-forming toxins induce macrophage necroptosis during acute bacterial pneumonia. PLoS Pathog 2015; 11 (12) e1005337
  • 83 Littmann M, Albiger B, Frentzen A, Normark S, Henriques-Normark B, Plant L. Streptococcus pneumoniae evades human dendritic cell surveillance by pneumolysin expression. EMBO Mol Med 2009; 1 (4) 211-222
  • 84 Colino J, Snapper CM. Two distinct mechanisms for induction of dendritic cell apoptosis in response to intact Streptococcus pneumoniae. J Immunol 2003; 171 (5) 2354-2365
  • 85 Davies LC, Jenkins SJ, Allen JE, Taylor PR. Tissue-resident macrophages. Nat Immunol 2013; 14 (10) 986-995
  • 86 Aggarwal NR, King LS, D'Alessio FR. Diverse macrophage populations mediate acute lung inflammation and resolution. Am J Physiol Lung Cell Mol Physiol 2014; 306 (8) L709-L725
  • 87 Tarassishin L, Suh HS, Lee SC. Interferon regulatory factor 3 plays an anti-inflammatory role in microglia by activating the PI3K/Akt pathway. J Neuroinflammation 2011; 8: 187
  • 88 Günthner R, Anders HJ. Interferon-regulatory factors determine macrophage phenotype polarization. Mediators Inflamm 2013; 2013: 731023
  • 89 Pelegrin P, Surprenant A. Dynamics of macrophage polarization reveal new mechanism to inhibit IL-1β release through pyrophosphates. EMBO J 2009; 28 (14) 2114-2127
  • 90 Liu W, Zhang X, Zhao M , et al. Activation in M1 but not M2 macrophages contributes to cardiac remodeling after myocardial infarction in rats: a critical role of the calcium sensing receptor/NRLP3 inflammasome. Cell Physiol Biochem 2015; 35 (6) 2483-2500
  • 91 Hwang I, Yang J, Hong S , et al. Non-transcriptional regulation of NLRP3 inflammasome signaling by IL-4. Immunol Cell Biol 2015; 93 (6) 591-599
  • 92 Witzenrath M, Pache F, Lorenz D , et al. The NLRP3 inflammasome is differentially activated by pneumolysin variants and contributes to host defense in pneumococcal pneumonia. J Immunol 2011; 187 (1) 434-440
  • 93 McNeela EA, Burke A, Neill DR , et al. Pneumolysin activates the NLRP3 inflammasome and promotes proinflammatory cytokines independently of TLR4. PLoS Pathog 2010; 6 (11) e1001191
  • 94 Harvey RM, Hughes CE, Paton AW, Trappetti C, Tweten RK, Paton JC. The impact of pneumolysin on the macrophage response to Streptococcus pneumoniae is strain-dependent. PLoS ONE 2014; 9 (8) e103625
  • 95 Lemon JK, Miller MR, Weiser JN. Sensing of interleukin-1 cytokines during Streptococcus pneumoniae colonization contributes to macrophage recruitment and bacterial clearance. Infect Immun 2015; 83 (8) 3204-3212
  • 96 Karmakar M, Katsnelson M, Malak HA , et al. Neutrophil IL-1β processing induced by pneumolysin is mediated by the NLRP3/ASC inflammasome and caspase-1 activation and is dependent on K+ efflux. J Immunol 2015; 194 (4) 1763-1775
  • 97 Kim JY, Paton JC, Briles DE, Rhee DK, Pyo S. Streptococcus pneumoniae induces pyroptosis through the regulation of autophagy in murine microglia. Oncotarget 2015; 6 (42) 44161-44178
  • 98 Lemon JK, Weiser JN. Degradation products of the extracellular pathogen Streptococcus pneumoniae access the cytosol via its pore-forming toxin. MBio 2015; 6 (1) e02110-e02114
  • 99 Di Paolo NC, Doronin K, Baldwin LK, Papayannopoulou T, Shayakhmetov DM. The transcription factor IRF3 triggers “defensive suicide” necrosis in response to viral and bacterial pathogens. Cell Reports 2013; 3 (6) 1840-1846
  • 100 Ali YM, Kenawy HI, Muhammad A, Sim RB, Andrew PW, Schwaeble WJ. Human L-ficolin, a recognition molecule of the lectin activation pathway of complement, activates complement by binding to pneumolysin, the major toxin of Streptococcus pneumoniae. PLoS ONE 2013; 8 (12) e82583
  • 101 Muñoz-Planillo R, Kuffa P, Martínez-Colón G, Smith BL, Rajendiran TM, Núñez G. K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 2013; 38 (6) 1142-1153
  • 102 Shoma S, Tsuchiya K, Kawamura I , et al. Critical involvement of pneumolysin in production of interleukin-1α and caspase-1-dependent cytokines in infection with Streptococcus pneumoniae in vitro: a novel function of pneumolysin in caspase-1 activation. Infect Immun 2008; 76 (4) 1547-1557
  • 103 Grailer JJ, Canning BA, Kalbitz M , et al. Critical role for the NLRP3 inflammasome during acute lung injury. J Immunol 2014; 192 (12) 5974-5983
  • 104 Brinkmann V, Reichard U, Goosmann C , et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303 (5663) 1532-1535
  • 105 Nel JG, Theron AJ, Pool R , et al. Neutrophil extracellular traps and their role in health and disease. S Afr J Sci 2016; 112 (1/2) :Art# 2015-0072
  • 106 G. Nel J, Theron AJ, Durandt C , et al. Pneumolysin activates neutrophil extracellular trap formation. Clin Exp Immunol 2016; 184 (3) 358-367
  • 107 Wartha F, Beiter K, Albiger B , et al. Capsule and D-alanylated lipoteichoic acids protect Streptococcus pneumoniae against neutrophil extracellular traps. Cell Microbiol 2007; 9 (5) 1162-1171
  • 108 Beiter K, Wartha F, Albiger B, Normark S, Zychlinsky A, Henriques-Normark B. An endonuclease allows Streptococcus pneumoniae to escape from neutrophil extracellular traps. Curr Biol 2006; 16 (4) 401-407
  • 109 Saffarzadeh M, Juenemann C, Queisser MA , et al. Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones. PLoS ONE 2012; 7 (2) e32366
  • 110 Ward PA, Grailer JJ. Acute lung injury and the role of histones. Transl Respir Med 2014; 2: 1
  • 111 Sreeramkumar V, Adrover JM, Ballesteros I , et al. Neutrophils scan for activated platelets to initiate inflammation. Science 2014; 346 (6214) 1234-1238
  • 112 Witzenrath M, Gutbier B, Owen JS , et al. Role of platelet-activating factor in pneumolysin-induced acute lung injury. Crit Care Med 2007; 35 (7) 1756-1762
  • 113 Howard KM. Differential expression of platelet-activating factor acetylhydrolase in lung macrophages. Am J Physiol Lung Cell Mol Physiol 2009; 297 (6) L1141-L1150
  • 114 Spreer A, Kerstan H, Böttcher T , et al. Reduced release of pneumolysin by Streptococcus pneumoniae in vitro and in vivo after treatment with nonbacteriolytic antibiotics in comparison to ceftriaxone. Antimicrob Agents Chemother 2003; 47 (8) 2649-2654
  • 115 Wall EC, Gordon SB, Hussain S , et al. Persistence of pneumolysin in the cerebrospinal fluid of patients with pneumococcal meningitis is associated with mortality. Clin Infect Dis 2012; 54 (5) 701-705
  • 116 Anderson R, Nel JG, Theron AJ , et al. Pneumolysin triggers the production of platelet-activating factor by human neutrophils in vitro. . Thorax 2015; 70 (Suppl. 03) A49
  • 117 Ohkuni H, Nagamune H, Ozaki N , et al. Characterization of recombinant Streptococcus mitis-derived human platelet aggregation factor. APMIS 2012; 120 (1) 56-71
  • 118 Varga-Szabo D, Braun A, Nieswandt B. Calcium signaling in platelets. J Thromb Haemost 2009; 7 (7) 1057-1066
  • 119 Nel JG, Durandt C, Mitchell TJ, Feldman C, Anderson R, Tintinger GR. Pneumolysin mediates platelet activation in vitro . Lung 2016; 194 (4) 589-593
  • 120 Etulain J, Martinod K, Wong SL, Cifuni SM, Schattner M, Wagner DD. P-selectin promotes neutrophil extracellular trap formation in mice. Blood 2015; 126 (2) 242-246
  • 121 Caudrillier A, Kessenbrock K, Gilliss BM , et al. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J Clin Invest 2012; 122 (7) 2661-2671
  • 122 Feldman C, Anderson R. Prevalence, pathogenesis, therapy and prevention of cardiovascular events in patients with community-acquired pneumonia. Pneumonia 2016; 8: 11
  • 123 Brown AO, Mann B, Gao G , et al. Streptococcus pneumoniae translocates into the myocardium and forms unique microlesions that disrupt cardiac function. PLoS Pathog 2014; 10 (9) e1004383
  • 124 Alhamdi Y, Neill DR, Abrams ST , et al. Circulating pneumolysin is a potent inducer of cardiac injury during pneumococcal infection. PLoS Pathog 2015; 11 (5) e1004836
  • 125 Alhamdi Y, Abrams ST, Cheng Z , et al. Circulating histones are major mediators of cardiac injury in patients with sepsis. Crit Care Med 2015; 43 (10) 2094-2103
  • 126 Alhamdi Y, Zi M, Abrams ST , et al. Circulating histone concentrations differentially affect the predominance of left or right ventricular dysfunction in critical illness. Crit Care Med 2016; 44 (5) e278-e288
  • 127 Borissoff JI, ten Cate H. From neutrophil extracellular traps release to thrombosis: an overshooting host-defense mechanism?. J Thromb Haemost 2011; 9 (9) 1791-1794
  • 128 Mangold A, Alias S, Scherz T , et al. Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size. Circ Res 2015; 116 (7) 1182-1192
  • 129 Stakos DA, Kambas K, Konstantinidis T , et al. Expression of functional tissue factor by neutrophil extracellular traps in culprit artery of acute myocardial infarction. Eur Heart J 2015; 36 (22) 1405-1414
  • 130 Lam F, Cruz M, Parikh K, Rumbaut R. Histones stimulate ultra-large von Willebrand factor release from endothelium: a potential contributor to the prothrombotic state in sepsis. FASEB J 2015; 29 (1) :supplement 631.13
  • 131 Merten M, Thiagarajan P. P-selectin in arterial thrombosis. Z Kardiol 2004; 93 (11) 855-863
  • 132 Woodhead M, Noor M. Empirical antibiotic management of adult CAP. In: Chalmers JD, Pletz MW, Aliberti S, eds. Community-Acquired Pneumonia. Norwich, UK: European Respiratory Society Publications. Eur Respir Monogr 2014; 63: 140-154
  • 133 Mandell LA, Wunderink RG, Anzueto A , et al; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 (Suppl. 02) S27-S72
  • 134 Woodhead M, Blasi F, Ewig S , et al; Joint Taskforce of the European Respiratory Society and European Society for Clinical Microbiology and Infectious Diseases. Guidelines for the management of adult lower respiratory tract infections—full version. Clin Microbiol Infect 2011; 17 (Suppl. 06) E1-E59
  • 135 Waterer GW, Somes GW, Wunderink RG. Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia. Arch Intern Med 2001; 161 (15) 1837-1842
  • 136 Baddour LM, Yu VL, Klugman KP , et al; International Pneumococcal Study Group. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. Am J Respir Crit Care Med 2004; 170 (4) 440-444
  • 137 Gattarello S, Borgatta B, Solé-Violán J , et al; Community-Acquired Pneumonia en la Unidad de Cuidados Intensivos II Study Investigators*. Decrease in mortality in severe community-acquired pneumococcal pneumonia: impact of improving antibiotic strategies (2000-2013). Chest 2014; 146 (1) 22-31
  • 138 Gattarello S. What is new in antibiotic therapy in community-acquired pneumonia? An evidence-based approach focusing on combined therapy. Curr Infect Dis Rep 2015; 17 (10) 501
  • 139 Emmet O'Brien M, Restrepo MI, Martin-Loeches I. Update on the combination effect of macrolide antibiotics in community-acquired pneumonia. Respir Investig 2015; 53 (5) 201-209
  • 140 García-Suárez MdelM, Cima-Cabal MD, Flórez N , et al. Protection against pneumococcal pneumonia in mice by monoclonal antibodies to pneumolysin. Infect Immun 2004; 72 (8) 4534-4540
  • 141 Henry BD, Neill DR, Becker KA , et al. Engineered liposomes sequester bacterial exotoxins and protect from severe invasive infections in mice. Nat Biotechnol 2015; 33 (1) 81-88
  • 142 Li H, Zhao X, Wang J , et al. β-sitosterol interacts with pneumolysin to prevent Streptococcus pneumoniae infection. Sci Rep 2015; 5: 17668
  • 143 Zhao X, Li H, Wang J , et al. Verbascoside alleviates pneumococcal pneumonia by reducing pneumolysin oligomers. Mol Pharmacol 2016; 89 (3) 376-387
  • 144 Fukuda Y, Yanagihara K, Higashiyama Y , et al. Effects of macrolides on pneumolysin of macrolide-resistant Streptococcus pneumoniae . Eur Respir J 2006; 27 (5) 1020-1025
  • 145 Anderson R, Steel HC, Cockeran R , et al. Comparison of the effects of macrolides, amoxicillin, ceftriaxone, doxycycline, tobramycin and fluoroquinolones, on the production of pneumolysin by Streptococcus pneumoniae in vitro. J Antimicrob Chemother 2007; 60 (5) 1155-1158
  • 146 Anderson R, Steel HC, Cockeran R , et al. Clarithromycin alone and in combination with ceftriaxone inhibits the production of pneumolysin by both macrolide-susceptible and macrolide-resistant strains of Streptococcus pneumoniae . J Antimicrob Chemother 2007; 59 (2) 224-229
  • 147 Cockeran R, Steel HC, Wolter N , et al. Effects of clarithromycin at sub-minimum inhibitory concentrations on early ermB gene expression, metabolic activity and growth of an erm(B)-expressing macrolide-resistant strain of Streptococcus pneumoniae. . Open J Respir Dis 2012; 2 (1) :Paper ID 17694
  • 148 Hirst RA, Mohammed BJ, Mitchell TJ, Andrew PW, O'Callaghan C. Streptococcus pneumoniae-induced inhibition of rat ependymal cilia is attenuated by antipneumolysin antibody. Infect Immun 2004; 72 (11) 6694-6698
  • 149 Rae N, Finch S, Chalmers JD. Cardiovascular disease as a complication of community-acquired pneumonia. Curr Opin Pulm Med 2016; 22 (3) 212-218
  • 150 Trac MH, McArthur E, Jandoc R , et al. Macrolide antibiotics and the risk of ventricular arrhythmia in older adults. CMAJ 2016; 188 (7) E120-E129
  • 151 Statt S, Ruan JW, Hung LY , et al. Statin-conferred enhanced cellular resistance against bacterial pore-forming toxins in airway epithelial cells. Am J Respir Cell Mol Biol 2015; 53 (5) 689-702
  • 152 Rosch JW, Boyd AR, Hinojosa E , et al. Statins protect against fulminant pneumococcal infection and cytolysin toxicity in a mouse model of sickle cell disease. J Clin Invest 2010; 120 (2) 627-635
  • 153 Havers F, Bramley AM, Finelli L , et al. Statin use and hospital length of stay among adults hospitalized with community-acquired pneumonia. Clin Infect Dis 2016; 62 (12) 1471-1478
  • 154 Steel HC, Theron AJ, Cockeran R, Anderson R, Feldman C. Pathogen- and host-directed anti-inflammatory activities of macrolide antibiotics. Mediators Inflamm 2012; 2012: 584262
  • 155 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 (7) 519-528
  • 156 Feldman C, Anderson R. Corticosteroids in the adjunctive therapy of community-acquired pneumonia: an appraisal of recent meta-analyses of clinical trials. J Thorac Dis 2016; 8 (3) E162-E171
  • 157 Berjohn CM, Fishman NO, Joffe MM, Edelstein PH, Metlay JP. Treatment and outcomes for patients with bacteremic pneumococcal pneumonia. Medicine (Baltimore) 2008; 87 (3) 160-166
  • 158 Mongardon N, Max A, Bouglé A , et al. Epidemiology and outcome of severe pneumococcal pneumonia admitted to intensive care unit: a multicenter study. Crit Care 2012; 16 (4) R155
  • 159 Weinberger DM, Harboe ZB, Sanders EA , et al. Association of serotype with risk of death due to pneumococcal pneumonia: a meta-analysis. Clin Infect Dis 2010; 51 (6) 692-699
  • 160 Luján M, Gallego M, Belmonte Y , et al. Influence of pneumococcal serotype group on outcome in adults with bacteraemic pneumonia. Eur Respir J 2010; 36 (5) 1073-1079
  • 161 Mortensen EM, Metersky ML. Long-term mortality after pneumonia. Semin Respir Crit Care Med 2012; 33 (3) 319-324