死亡率和发病率
未经治疗和诊断的隐球菌病是致死的,尤其是在免疫功能不全的患者。未治疗的隐球菌性脑膜脑炎患者均是致命的。隐球菌性脑膜炎相关的死亡率在AIDS患者中可高达25%。[47]van der Horst C, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med. 1997;337:15-21.http://www.nejm.org/doi/full/10.1056/NEJM199707033370103#t=articlehttp://www.ncbi.nlm.nih.gov/pubmed/9203426?tool=bestpractice.com其他免疫功能不全患者的结局因不同的基础疾病而不同。特发性CD4淋巴细胞减少的患者预后相对较好。[61]Zonios DI, Falloon J, Huang CY, et al. Cryptococcosis and idiopathic CD4 lymphocytopenia. Medicine (Baltimore). 2007;86:78-92.http://www.ncbi.nlm.nih.gov/pubmed/17435588?tool=bestpractice.com早期适当的治疗可以减少病死率,阻止其进展成潜在致死的CNS感染。隐球菌多糖抗原(Cryptococcal polysaccharide antigen,CRAG)状态是HIV阳性患者独立的死亡预测因素。[42]Jarvis JN, Dromer F, Harrison TS, et al. Managing cryptococcosis in the immunocompromised host. Curr Opin Infect Dis. 2008;21:596-603.http://www.ncbi.nlm.nih.gov/pubmed/18978527?tool=bestpractice.com抗真菌药物的毒性不良反应很常见,约30%隐球菌性脑膜炎及HIV共感染的患者在开始或重新开始高效活性抗逆转录病毒治疗(Highly active antiretroviral treatment,HAART)后出现免疫重建炎性反应综合征(Immune reconstitution inflammatory syndrome,IRIS)。[11]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. November 2016. http://aidsinfo.nih.gov (last accessed 19 December 2016).https://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf[39]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010;50:291-322.http://cid.oxfordjournals.org/content/50/3/291.longhttp://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com[42]Jarvis JN, Dromer F, Harrison TS, et al. Managing cryptococcosis in the immunocompromised host. Curr Opin Infect Dis. 2008;21:596-603.http://www.ncbi.nlm.nih.gov/pubmed/18978527?tool=bestpractice.com
治疗失败及复发
治疗失败定义为治疗 2 周后缺乏临床改善(包括颅内压升高 [ICP] 的管理,伴有培养持续阳性)或出现初始临床应答后复发(即治疗≥4 周后症状复发且 CSF 培养阳性)。[11]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. November 2016. http://aidsinfo.nih.gov (last accessed 19 December 2016).https://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf患者需要持续抗真菌治疗1到2年也可考虑为治疗失败。[39]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010;50:291-322.http://cid.oxfordjournals.org/content/50/3/291.longhttp://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
如不进行维持治疗,治疗成功的HIV阳性隐球菌性脑膜炎患者复发风险高。治疗2周CSF培养阳性是未来复发及临床结局较差的预测因素。[1]Chayakulkeeree M, Perfect JR. Cryptococcosis. Infect Dis Clin North Am. 2006;20:507-544.http://www.ncbi.nlm.nih.gov/pubmed/16984867?tool=bestpractice.com血清CRAG滴度与临床改善并不相关,但是ART前血清CRAG滴度可以预测未来免疫重建炎性反应综合征的发生(Immune reconstitution inflammatory syndrome, IRIS)。[1]Chayakulkeeree M, Perfect JR. Cryptococcosis. Infect Dis Clin North Am. 2006;20:507-544.http://www.ncbi.nlm.nih.gov/pubmed/16984867?tool=bestpractice.com[50]Boulware DR, Meya DB, Bergemann TL, et al. Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Med. 2010;7:e1000384.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014618/http://www.ncbi.nlm.nih.gov/pubmed/21253011?tool=bestpractice.com[62]Sungkanuparph S, Filler SG, Chetchotisakd P, et al. Cryptococcal immune reconstitution inflammatory syndrome after antiretroviral therapy in AIDS patients with cryptococcal meningitis: a prospective multicenter study. Clin Infect Dis. 2009;49:931-934.http://cid.oxfordjournals.org/content/49/6/931.longhttp://www.ncbi.nlm.nih.gov/pubmed/19681708?tool=bestpractice.com如果出现新的临床症状,应小心行腰椎穿刺,以排除颅内压增高或 IRIS 的可能。在HIV阳性并成功完成初始疗程,无症状且强效HAART后持续(>6个月)CD4细胞计数 ≥200个细胞/微升的患者中,复发的风险较低。[1]Chayakulkeeree M, Perfect JR. Cryptococcosis. Infect Dis Clin North Am. 2006;20:507-544.http://www.ncbi.nlm.nih.gov/pubmed/16984867?tool=bestpractice.com[8]Hajjeh RA, Conn LA, Stephens DS, et al. Cryptococcosis: population-based multistate active surveillance and risk factors in human immunodeficiency virus-infected persons. J Infect Dis. 1999;179:449-454.http://jid.oxfordjournals.org/content/179/2/449.fullhttp://www.ncbi.nlm.nih.gov/pubmed/9878030?tool=bestpractice.com[9]Dromer F, Mathoulin-Pelissier S, Fontanet A, et al. Epidemiology of HIV-associate cryptococcosis in France (1985-2001): comparison of the pre-and post-HAART eras. AIDS. 2004;18:555-562.http://www.ncbi.nlm.nih.gov/pubmed/15090810?tool=bestpractice.com