摘要
研究背景：2009年3月,甲型H1N1流感在墨西哥暴发,随后迅速蔓延全球；2009年6月11日,WHO将流感流行警告级别提升至6级,宣称全球已处于2009年流感大流行的初期；2010年8月10日,WHO宣布2009年甲型H1N1流感处于大流行后期。2009年我国甲型H1N1流感病例共报告死亡652例；2010年全年累计报告死亡147例；2011年1月,全国累计报告死亡15例。综合甲型H1N1流感的临床特点、危重症病例年龄分布、发生概率等,与普通季节性流感有所不同。中国大陆中医药广泛参与了甲型H1N1流感的治疗,对于中医药治疗2009甲型H1N1流感轻症及重症的疗效评价已有报道,认为中药治疗可有效缩短发热时间及改善患者临床症状,具有和奥司他韦接近的疗效。目前虽然已有对于中医治疗介入甲型H1N1流感危重症的情况调查及小样本中医药治疗甲型H1N1流感危重症的验案报道,但中医药对于甲型H1N1流感危重症的较大样本的疗效评估尚无人报道。
研究目的：总结甲型H1N1流感危重症、死亡病例的流行病学特点,归纳本组危重症病例的高危因素和临床特征,从“毒”的角度分析甲型H1N1流感危重症的中医证候学演变规律、病机特征及辨证论治规律,评价基于“菌毒并治”理论的中西医结合治疗对甲型H1N1流感危重症的临床疗效。
研究方法：本研究首先对2009甲型H1N1流感的病毒特征、甲型H1N1流感的研究现状进行综述,介绍了导师基于“菌毒并治”理论对2009甲型H1N1流感的认识和论治,即在用西医抗病毒及抗生素药物等治疗的同时,基于对甲型H1N1流感的病因病机认识,应用中医药辨证论治,祛除对人体有不利影响的毒邪。临床研究采取回顾性病例研究的方法,收集2009年9月12日～2010年2月5日在北京地坛医院、成都市传染病医院、新疆传染病医院及上海市公共卫生中心、海南省人民医院住院的108名连续的病原学确诊的甲型H1N1流感危重症病例。对患者的发病情况、临床表现、辅助检查及治疗方法进行分析,归纳本组危重症病例的高危因素和临床特征。根据生存结局,将病例分为生存组和死亡组,单因素比较分析死亡的高危因素,采用多因素二分类Logistic回归分析—向前逐步回归法,进一步观察疾病死亡的保护因素和危险因素。并附了2011年1例最终治愈和1例最终死亡的甲型H1N1流感危重症病例做为典型案例。
研究结果：共收集108例危重症病例,其中男性63例,女性45例,平均年龄40.99±20.63岁,年龄多集中于18-65岁之间,发病高峰集中在2009年11月,发病至首次就诊中位时间为0.5天(范围0～9天),发病至本次住院中位时间为5天(范围0～20天)。有至少一种基础疾病的病例有72例(66.7%),比较常见的为糖尿病、心脑血管疾病及慢性阻塞性肺病。药物治疗方面,所有的病例都接受了神经氨酸酶抑制剂奥司他韦治疗,从发病到开始抗病毒的中位时间为5天(范围0～15天),107(99.1%)例病例进行过抗细菌治疗,41(38.0%)例病例进行过抗真菌治疗,78(72.2%)例病例使用过激素治疗,52(48.15%)例病例使用中药治疗。67(62.0%)例病例因病情需要进入ICU治疗,ICU治疗中位持续时间为8天(范围1～33天),41(38.0%)例病例行有创呼吸机支持治疗。甲型H1N1流感危重症除了常见的发热、咳嗽、咯痰外,喘息气促、胸闷憋气和倦怠乏力发生率较高,病情加重时多数以持续高热、剧烈咳嗽、喘憋、血痰为主。最常见的并发症是肺炎(99.1%)、Ⅰ型呼吸衰竭(63.9%)、急性呼吸窘迫综合征(50%)、急性肝损害(35.2%)。最终29例病例死亡,死亡构成比为26.6%。
在生存组与死亡组单因素分析中,两组有统计学差异的症状为神昏谵语和呕血；入院首次ALT、AST、BUN、CK-MB、LDH、动脉血氧分压,住院天数及中药汤剂使用疗程,有创机械通气率、Ⅱ型呼吸衰竭、休克、急性肾功能衰竭、心肌酶异常及多脏器功能不全的发生率有统计学差异(P<0.05)。其中生存组的入院首次动脉氧分压高于死亡组,ALT、AST、BUN、CK-MB、LDH低于死亡组,有创机械通气率低于死亡组,Ⅱ型呼吸衰竭、休克、急性肾功能衰竭、心肌酶异常及多脏器功能不全发生率均低于死亡组。
在对20个因素进行多因素二分类Logistic回归分析中,甲流危重症预后的保护因素为2天内抗病毒、基于“菌毒并治”的中西医结合治疗；危险因素为：出现急性肾功能衰竭、休克、MODS,使用有创机械通气。经过分层分析,治疗组(中西医结合治疗)和对照组(西医治疗)发生休克的患者有统计学差异。去除休克混杂因素后,中西医结合治疗组死亡危险度为西医对照组的0.252倍。
研究结论：甲型H1N1流感患者可分初期、进展期、极期和恢复期进行辨证论治,初期主要以发热、咳嗽、咽痛、肌肉酸痛等毒邪袭肺症状为主,部分病例有胃肠道症状；进展期可见胸闷憋气及喘息气促等毒热壅肺、闭肺的表现,极期可见烦躁、神昏、痰中带血、粉红色泡沫痰、呕血等毒损肺络、津血外溢的表现,进一步发展,则出现毒邪内陷,内闭外脱。恢复期表现为热病后期余热未清、气阴两伤的特点。发病前的基础疾病是发展为危重症乃至死亡的重要因素,与“外感病的内伤基础”理论相符。其传变规律主要按卫气营血传变,如出现神昏谵语、呕血等热邪深入营血分的表现则预后凶险。但其毒邪以深入肺络血分为主,毒散全身血热妄行的全身性的动血耗血少见。甲型H1N1流感危重症“毒、热、浊、瘀、虚”并存,决定着病情的转归、预后。“菌毒并治”既包括清热解毒,还包括清热化痰、化瘀利水、益气扶正等治法。扶正解毒法应早期应用,以防止毒邪内陷,出现内闭外脱的危象。
甲型H1N1流感危重症以难治性低氧血症为突出表现,波及面广,程度重,可影响心、肝、肾等脏器,出现休克及多脏器功能衰竭等并发症。临床研究表明,及时的抗病毒治疗(2天内)可改善甲型H1N1流感危重症预后。基于“菌毒并治”理论的中西医结合治疗方案对甲型H1N1流感危重症患者的救治起到了积极的作用。
Research Back ground:In March 2009, A/H1N1 influenza was outbreak in Mexico, which quickly spread wordwide. On June 11,2009, WHO elevated the pandemic flu warning to level 6, declared the world was already at the begining of 2009 influenza pandemic. On August 10,2010, WHO announced the A/H1N1 flu was on the post period of 2009 influenza pandemic. There were a total of 652 patients reported dead in China during the year 2009 and accumulative total reported 147 death cases in 2010 and in January 2011, the number were 15. To conclude the clinical features, age distribution of critical cases and morbidity of A/H1N1 influenza, they were difference from seasonal flu.Traditional Chinese medicine had a broad participation in the treatment of A/H1N1 influenza cases in mainland China, for the curative effect of mild and severe flu has been reported, which shows that TCM can effectively shorten the duration of fever and improve the clinical symptoms, which have a similar effect as Oseltamivir. At present, although there were some study on the existing investigation of intervention on TCM therapy for A/H1N1 flu critical cases and report of a some sample proven cases, the curative effect of critical cases of huge sample are not yet discussed.
Research objective:To summarize the epidemiological characteristics of the A/H1N1 flu sever and death cases, conclude the risk factors and clinical characteristics of the critical cases, analyze the rule of TCM pattern development and pathogenesis characteristics, the rule of syndrome differentiation and treatment from the perspective of "toxin". Evaluate the clinical curative effect of combining traditional of Chinese and Western medicine based on the theory of "treating both germs and toxin".
Research Methods:Firstly, this research summarizes the characteristics of A/H1N1 influenza virus and the current research progress of A/H1N1 influenza, also introduced my adviser's understanding and treatment based on the "treating both germs and toxin", i.e., using antiviral drugs and antibiotics together, based on etiology and pathogenesis of A/H1N1, by using pattern identification and trearment, to eliminate the toxin factor which has an adverse effect to human body.Clinical research was a retrospective study, collected critical cases from hospitalized patients with laboratory-confirmed 2009 H1N1 infection, patients were from Beijing Ditan Hospital, Chengdu Infectious Disease Hospital, Xinjiang Infectious disease hospital, Shanghai public health center and hainan province people's hospital etc, during the period from September 12th 2009 to February 5th 2010. We analyzed the morbidity, clinical manifestation, auxiliary examination and treatment of patients, concluded the high risk factors and clinical features of those critical severe cases. According to the prognosis, we divided the cases into survival group and death group, using single factor comparative method to analysis high risk factors of death group, and using multivariable binary logistic regression-forward stepwise regression, to further observed the protection factors and risk factors associated with death group. At last, we analyzed two typical cases of 2011, one finally cured and one case finally death.
Research Results:A total of 108 confirmed critical severe cases were collected, including 63 male,45 female;the average(SD) age was 40.99±20.63 years old; age was more focused on 18～65 years, the morbidity peaked at November 2009, the median time from symptom onset to first medication was 0.5 days (in range of 0-9 days), and from symptom onset to hospitalized was 5 days (in range of 0-20 days). At least of one comorbidities present in 72 patients (66.7%), common comorbidities were diabetes, Cardiovascular and Cerebrovascular and COPD, by 21.3%,19.4% 12.0% respectively. Drug treatments included neuraminidase inhibitors oseltamivir (108 patients; 100%) for a median of 5 days range from 0 to 15 days, antibiotics (107 patients; 99.1%), antifungals(41 patients; 8.0%),corticosteroids (78 patients; 72.2%) and Traditional Chinese Medicine (52 patients; 48.15%).67 patients(62.0%) were admitted to ICU for a median of 8 days (range,1-33 days), and 41(38.0%) patients received invasive mechanical ventilation. Besides the common symptoms of fever, cough and cough up phlegm, there were higher chance to havce panting, shortness of breath, chest tightness, breath-holding and weakness, when disease become worsen,the dominant symptoms were continued high fever, rough cough, difficulty in breathing, bloody sputum. The common complications were pneumonia (99.1%), I type of respiratory failure (63.9%),acute respiratory distress syndrome (50%), acute liver damage (35.2%). Overall 29 cases finally died with fatality rate at 26.6%.
By single factor analysis between the death and the survival group, loss of consciousness and delirious speech, hematemesis,the first ALT, AST,BUN, CK-MB, LDH,oxygen partial pressure after admission to the hospital and invasive mechanical ventilation rate,Ⅱtype respiratory failure, shock, acute renal failure, cardiac enzyme anomalies and multiple organ dysfunction etc., were statistically significant (P<0.05). The first ALT、AST、BUN、CK、LDH and invasive mechanical ventilation rate,Ⅱtype respiratory failure, shock, acute renal failure, cardiac enzyme anomalies and multiple organ dysfunction in the death group is higher than the suvival group. Oxygen partial pressure in the death group is lower than the suvival group.
Analyzing 20 factors by multivariable binary logistic regression method, the protection factors of critical cases associated with death were received antiviral therapy within 2 days, combining traditional Chinese and western medicine treatment; Risk factors were with acute renal failure,shock, MODS and invasive mechanical ventilation. After layered analysis, the treatment group (combining traditional Chinese and western medicine treatment) and the control group (western medicine treatment) combined shock patients have statistically significant. By removed shock confound factors, there were significant differences between treatment and control group, the treatment group mortality risk was 0.252 times from control group.
Research conclusion:A/H1N1 influenza patients can be divided into initial, advanced, extreme and recovery period for the pattern identification and treatment.During the initial period, primarily symptoms were fever, cough, sore throat, muscle ache, which caused by toxin pathogen attacking lung, part of cases had gastrointestinal symptoms; For adveranced period, symptoms were panting shortness of breath, chest tightness and breath-holding, whicn because of lung blocked and shut by toxic heat; extremely period behave as agitated, loss of consciousness, bloody sputum, pink-tinged sputum, vomitting blood and so on, which caused by toxin damage lung vessels leading to external bleeding. If the disease further developed, toxin would inward invasion leading to internal block and external collapse. During recovery period, the characteristics of residual heat and damage of Qi and Yin syndrome can be seen. The bases disease of premorbid was important factors which casuse the disease develop to critically cases and even death, it fits the theory of "internal danaged is foundation of external contraction". Its transmutation was by Defense, Qi, Nutrient and Blood, if there are loss of consciousness and delirious speech, hematemesis caused by heat go deeply into Nutrient and Blood aspect may indicate an extremely dangerous state. But the toxin primary go deeply into blood aspect of lung, the frenetic movement of blood due to heat toxin leading to bleeding and hematozemia are rare. It is coexisted of "hot, toxin, turbidity, stasis and deficiency" in A/H1N1 flu critical cases, which determines the outcome and prognosis of illness. The treatment of "Treat both germs and toxin" includes not only clearing heat and detoxifying, but also clearing heat and resolveing phlegm, resolveing stasis and water-draining, boost and reinforce the healthy qi. Reinforce the healthy qi and clearing detoxifying should be used in the early stage to prevent the toxin inward invasion leading to internal block and external collapse.
The stand out representation of A/H1N1 influenza in critical cases was refractory hypoxemia, critical cases affect widely, serious in degree, involved heart, liver, kidney and other organs, causing shock and multiple organ failure. The clinical studies showed that, antiviral treatment in time(within 2 days) can improve the prognosis of critical cases and combining traditional Chinese and Western medicine based on "treat both germs and toxin " played a positive role in the treatment of A/H1N1 critical cases.
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