病因学
肺炎链球菌(也称为肺炎球菌)是各种严重程度 CAP 和不同年龄 CAP 患者中最常见的致病病原体。[13]Rice LB. Antimicrobial resistance in gram-positive bacteria. Am J Med. 2006 Jun;119(suppl 1):S11-9. http://www.ncbi.nlm.nih.gov/pubmed/16735146?tool=bestpractice.com [14]Cillóniz C, Ewig S, Polverino E, et al. Microbial aetiology of community-acquired pneumonia and its relation to severity. Thorax. 2011 Apr;66(4):340-6. http://thorax.bmj.com/content/66/4/340.long http://www.ncbi.nlm.nih.gov/pubmed/21257985?tool=bestpractice.com [15]Cillóniz C, Ewig S, Polverino E, et al. Community-acquired pneumonia in outpatients: aetiology and outcomes. Eur Respir J. 2012 Oct;40(4):931-8. http://erj.ersjournals.com/content/40/4/931.long http://www.ncbi.nlm.nih.gov/pubmed/22267760?tool=bestpractice.com [16]Cilloniz C, Torres A, Polverino E, et al. Community-acquired lung respiratory infections in HIV-infected patients: microbial aetiology and outcome. Eur Respir J. 2014 Jun;43(6):1698-708. http://erj.ersjournals.com/content/43/6/1698.long http://www.ncbi.nlm.nih.gov/pubmed/24525448?tool=bestpractice.com [17]Almirall J, Boixeda R, Bolíbar I, et al. Differences in the etiology of community-acquired pneumonia according to site of care: a population-based study. Respir Med. 2007 Oct;101(10):2168-75. http://www.resmedjournal.com/article/S0954-6111%2807%2900194-1/fulltext http://www.ncbi.nlm.nih.gov/pubmed/17629472?tool=bestpractice.com 然而,其他研究已发现流行性感冒病毒是成年人患 CAP 的最常见原因。[7]Alimi Y, Lim WS, Lansbury L, et al. Systematic review of respiratory viral pathogens identified in adults with community-acquired pneumonia in Europe. J Clin Virol. 2017 Oct;95:26-35. http://www.ncbi.nlm.nih.gov/pubmed/28837859?tool=bestpractice.com [18]Jain S, Self WH, Wunderink RG, et al. Community-acquired pneumonia requiring hospitalization among US adults. N Engl J Med. 2015 Jul 30;373(5):415-27. http://www.nejm.org/doi/full/10.1056/NEJMoa1500245 http://www.ncbi.nlm.nih.gov/pubmed/26172429?tool=bestpractice.com 在欧洲和美国,肺炎链球菌引起的 CAP 大约占总病例数的 30% 至 35%。[14]Cillóniz C, Ewig S, Polverino E, et al. Microbial aetiology of community-acquired pneumonia and its relation to severity. Thorax. 2011 Apr;66(4):340-6. http://thorax.bmj.com/content/66/4/340.long http://www.ncbi.nlm.nih.gov/pubmed/21257985?tool=bestpractice.com [19]Almirall J, Bolíbar I, Vidal J, et al. Epidemiology of community-acquired pneumonia in adults: a population-based study. Eur Respir J. 2000 Apr;15(4):757-63. http://erj.ersjournals.com/content/15/4/757.long http://www.ncbi.nlm.nih.gov/pubmed/10780770?tool=bestpractice.com 其他细菌性病因包括:流感嗜血杆菌、金黄色葡萄球菌(包括 MRSA)、A 族链球菌和军团菌属。例如,在免疫功能正常的 CAP 患者中,有 2%-6% 是由嗜肺军团菌(特别是 1 血清组)引起。[20]Mandell LA, Marrie TJ, Grossman RF, et al; The Canadian Community-Acquired Pneumonia Working Group. Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. Clin Infect Dis. 2000 Aug;31(2):383-421. http://cid.oxfordjournals.org/content/31/2/383.full http://www.ncbi.nlm.nih.gov/pubmed/10987698?tool=bestpractice.com
非典型细菌也是常见病因,不过其发生频率因年度和流行情况而异。[17]Almirall J, Boixeda R, Bolíbar I, et al. Differences in the etiology of community-acquired pneumonia according to site of care: a population-based study. Respir Med. 2007 Oct;101(10):2168-75. http://www.resmedjournal.com/article/S0954-6111%2807%2900194-1/fulltext http://www.ncbi.nlm.nih.gov/pubmed/17629472?tool=bestpractice.com [21]Marchello C, Dale AP, Thai TN, et al. Prevalence of atypical pathogens in patients with cough and community-acquired pneumonia: a meta-analysis. Ann Fam Med. 2016 Nov;14(6):552-66. http://www.annfammed.org/content/14/6/552.long http://www.ncbi.nlm.nih.gov/pubmed/28376442?tool=bestpractice.com 社区获得性肺炎中,非典型病原体的全球发病率约为 22%,但此病的发病率因地区而异。[22]Arnold FW, Summersgill JT, Ramirez JA. Role of atypical pathogens in the etiology of community-acquired pneumonia. Semin Respir Crit Care Med. 2016 Dec;37(6):819-28. http://www.ncbi.nlm.nih.gov/pubmed/27960206?tool=bestpractice.com 常报道的非典型细菌包括:肺炎支原体、肺炎衣原体、鹦鹉热衣原体和贝纳柯克斯体。[1]Lim WS, Baudouin SV, George RC, et al; Pneumonia Guidelines Committee of the BTS Standards of Care Committee. British Thoracic Society guidelines for the management of community acquired pneumonia in adults: update 2009. Thorax. 2009 Oct;64(suppl 3):iii1-55. https://thorax.bmj.com/content/64/Suppl_3/iii1.long http://www.ncbi.nlm.nih.gov/pubmed/19783532?tool=bestpractice.com 这些病原体在疾病早期很难诊断,而且对 β-内酰胺类药物以外的抗生素(例如,大环内酯类、四环素类或氟喹诺酮类)敏感。[1]Lim WS, Baudouin SV, George RC, et al; Pneumonia Guidelines Committee of the BTS Standards of Care Committee. British Thoracic Society guidelines for the management of community acquired pneumonia in adults: update 2009. Thorax. 2009 Oct;64(suppl 3):iii1-55. https://thorax.bmj.com/content/64/Suppl_3/iii1.long http://www.ncbi.nlm.nih.gov/pubmed/19783532?tool=bestpractice.com
门诊治疗和住院治疗的 CAP 患者中,因肺炎支原体致病的比例分别高达 37% 和 10%。[14]Cillóniz C, Ewig S, Polverino E, et al. Microbial aetiology of community-acquired pneumonia and its relation to severity. Thorax. 2011 Apr;66(4):340-6. http://thorax.bmj.com/content/66/4/340.long http://www.ncbi.nlm.nih.gov/pubmed/21257985?tool=bestpractice.com 肺炎衣原体引起的 CAP 占总病例的 5%-15%。然而,荷兰的一项研究通过痰液聚合酶链反应(polymerase chain reaction,PCR,若条件允许)发现,有 4.8% 的 CAP 病例是鹦鹉热衣原体所致。[23]Spoorenberg SM, Bos WJ, van Hannen EJ, et al. Chlamydia psittaci: a relevant cause of community-acquired pneumonia in two Dutch hospitals. Neth J Med. 2016 Feb;74(2):75-81. http://www.ncbi.nlm.nih.gov/pubmed/26951352?tool=bestpractice.com 一项德国研究通过 PCR 和/或抗体检测发现,CAP 患者中有 3.5% 是由贝纳柯克斯体引起。[24]Schack M, Sachse S, Rödel J, et al. Coxiella burnetii (Q fever) as a cause of community-acquired pneumonia during the warm season in Germany. Epidemiol Infect. 2014 Sep;142(9):1905-10. https://www.cambridge.org/core/journals/epidemiology-and-infection/article/coxiella-burnetii-q-fever-as-a-cause-of-communityacquired-pneumonia-during-the-warm-season-in-germany/479C3CA472D5CF8C19C3D8CED134DC6D http://www.ncbi.nlm.nih.gov/pubmed/24252152?tool=bestpractice.com
铜绿假单胞菌也可能在肺炎患者中普遍存在,取决于地区因素;但是,与社区获得性肺炎 (CAP) 相比,该菌种在医院获得性肺炎和呼吸器相关性肺炎中更为常见。在中国的一项系统评价中,该菌种占 CAP 患者所有分离株数量的 7.7%。[25]Ding C, Yang Z, Wang J, et al. Prevalence of Pseudomonas aeruginosa and antimicrobial-resistant Pseudomonas aeruginosa in patients with pneumonia in mainland China: a systematic review and meta-analysis. Int J Infect Dis. 2016 Aug;49:119-28. http://www.sciencedirect.com/science/article/pii/S1201971216310992 http://www.ncbi.nlm.nih.gov/pubmed/27329135?tool=bestpractice.com
据报道,在接受住院治疗的免疫功能正常的成人 CAP 患者中,约有 10% 至 30% 的患者报告有呼吸道病毒感染。[14]Cillóniz C, Ewig S, Polverino E, et al. Microbial aetiology of community-acquired pneumonia and its relation to severity. Thorax. 2011 Apr;66(4):340-6. http://thorax.bmj.com/content/66/4/340.long http://www.ncbi.nlm.nih.gov/pubmed/21257985?tool=bestpractice.com [26]Jokinen C, Heiskanen L, Juvonen H, et al. Microbial etiology of community-acquired pneumonia in the adult population of 4 municipalities in eastern Finland. Clin Infect Dis. 2001 Apr 15;32(8):1141-54. http://cid.oxfordjournals.org/content/32/8/1141.long http://www.ncbi.nlm.nih.gov/pubmed/11283803?tool=bestpractice.com [27]Jennings LC, Anderson TP, Beynon KA, et al. Incidence and characteristics of viral community-acquired pneumonia in adults. Thorax. 2008 Jan;63(1):42-8. http://thorax.bmj.com/content/63/1/42.long http://www.ncbi.nlm.nih.gov/pubmed/17573440?tool=bestpractice.com [28]Burk M, El-Kersh K, Saad M, et al. Viral infection in community-acquired pneumonia: a systematic review and meta-analysis. Eur Respir Rev. 2016 Jun;25(140):178-88. http://err.ersjournals.com/content/25/140/178.long http://www.ncbi.nlm.nih.gov/pubmed/27246595?tool=bestpractice.com A/B 型流感病毒、呼吸道合胞病毒、腺病毒、鼻病毒和副流感病毒是导致免疫功能正常成人罹患 CAP 的最常见病毒。据报道,引起 CAP 的新型病原体包括偏肺病毒和冠状病毒。[29]Wunderink RG, Waterer G. Advances in the causes and management of community acquired pneumonia in adults. BMJ. 2017 Jul 10;358:j2471. http://www.ncbi.nlm.nih.gov/pubmed/28694251?tool=bestpractice.com 由于 PCR 的使用,对病毒性病因的检出也逐渐增加。
CAP 中多重微生物病因的发生比例介于 5.7% 至 13% ,取决于不同的人群和所用的微生物诊断性检查。[14]Cillóniz C, Ewig S, Polverino E, et al. Microbial aetiology of community-acquired pneumonia and its relation to severity. Thorax. 2011 Apr;66(4):340-6. http://thorax.bmj.com/content/66/4/340.long http://www.ncbi.nlm.nih.gov/pubmed/21257985?tool=bestpractice.com [27]Jennings LC, Anderson TP, Beynon KA, et al. Incidence and characteristics of viral community-acquired pneumonia in adults. Thorax. 2008 Jan;63(1):42-8. http://thorax.bmj.com/content/63/1/42.long http://www.ncbi.nlm.nih.gov/pubmed/17573440?tool=bestpractice.com [30]Johansson N, Kalin M, Tiveljung-Lindell A, et al. Etiology of community-acquired pneumonia: increased microbiological yield with new diagnostic methods. Clin Infect Dis. 2010 Jan 15;50(2):202-9. http://cid.oxfordjournals.org/content/50/2/202.long http://www.ncbi.nlm.nih.gov/pubmed/20014950?tool=bestpractice.com
病理生理学
罹患肺炎是因为病原体入侵肺实质并在肺实质中过度生长,这会超出宿主的防御极限并导致肺泡腔内出现渗出物。[31]Alcón A, Fàbregas N, Torres A. Pathophysiology of pneumonia. Clin Chest Med. 2005 Mar;26(1):39-46. http://www.ncbi.nlm.nih.gov/pubmed/15802164?tool=bestpractice.com
肺炎的发生和严重程度是由病原体因素(毒力、接种量)和宿主因素之间的平衡决定的。可能导致 CAP 的微生物病因会因多种因素而有所不同,这些因素包括地方流行病学、治疗环境(门诊治疗、住院治疗或重症监护病房)、疾病严重程度以及患者特征(例如性别、年龄和共病情况)。[14]Cillóniz C, Ewig S, Polverino E, et al. Microbial aetiology of community-acquired pneumonia and its relation to severity. Thorax. 2011 Apr;66(4):340-6. http://thorax.bmj.com/content/66/4/340.long http://www.ncbi.nlm.nih.gov/pubmed/21257985?tool=bestpractice.com
上气道中出现的微生物可能通过微量吸入进入下气道。但是,肺部防御机制(先天性和获得性)会保持下气道无菌。罹患肺炎则表明宿主防御功能出现缺陷、接触到毒性非常大的微生物或接种量较大。
免疫应答受损(例如因为 HIV 感染或高龄)或防御机制出现功能障碍(例如因为目前吸烟或被动吸烟、慢性阻塞性肺疾病或误吸)会导致患者对呼吸道感染的易感性大大提高。[6]Torres A, Peetermans WE, Viegi G, et al. Risk factors for community-acquired pneumonia in adults in Europe: a literature review. Thorax. 2013 Nov;68(11):1057-65. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812874 http://www.ncbi.nlm.nih.gov/pubmed/24130229?tool=bestpractice.com
病原体可能会通过 4 个机制到达下呼吸道:
吸入是年轻健康患者患病毒性肺炎和非典型肺炎的常见途径。易感人群吸入传染性气溶胶会引发感染。
口咽分泌物误吸到气管内,是病原体通过气管进入下气道的主要途径
局部受感染部位的血源传播(例如右侧心内膜炎)[32]Rumbak MJ. The pathogenesis of ventilator-associated pneumonia. Semin Respir Crit Care Med. 2002 Oct;23(5):427-34. http://www.ncbi.nlm.nih.gov/pubmed/16088636?tool=bestpractice.com
附近受感染病灶的直接蔓延(例如,尽管很少见,但结核病可能从附近淋巴结蔓延,累及心包或肺部)。
一种新理论认为,CAP 可能是由于正常肺部菌群失调导致的,而不是因为致病微生物侵入无菌环境所致;但这种模式仍需进一步的研究。[33]Dickson RP, Erb-Downward JR, Huffnagle GB. Towards an ecology of the lung: new conceptual models of pulmonary microbiology and pneumonia pathogenesis. Lancet Respir Med. 2014 Mar;2(3):238-46. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4004084 http://www.ncbi.nlm.nih.gov/pubmed/24621685?tool=bestpractice.com
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