益气养阴法治疗特发性肺纤维化的临床研究
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摘要
目的观察中药益气养阴法治疗特发性肺纤维化(IPF)的疗效。
方法收集2007年1月～2011年9月新加坡MINO Chinese Medical Clinic诊所(日文网站：www.minomedical.com)收治IPF气阴两虚证病例44例,使用益气养阴法中药治疗,采用治疗前后自身对照设计。按疗程分成A、B两个亚组,其中A组(疗程≤6月)21例,B组(疗程>6月)23例,治疗6月、12月、24月,36月,分别观察KL-6、6分钟步行试验6分钟步行距离(6MWD)、经皮血氧饱和度最低值(SPO2)、Borg呼吸困难评分、高分辨CT (HRCT:磨玻璃阴影积分GGO、纤维化积分FS)的变化并评价中药治疗效果。结果①6月、12月、24月、36月总有效率分别为84.09%、79.55%、43.18%、31.82%,各时点疗效差异显著,P=0.000,6月和12月疗效均显著优于24月、36月疗效,P=0.000,6月与12月、24月与36月疗效均无差异,P>0.05。A组、B组两亚组在6月时疗效无差异,12月时两组有效率分别为66.67%、91.30%,P=0.045,提示两组疗效有显著差异。②KL-6、Borg评分、HRCT积分(GGO和FS)不同程度降低,且6MWD、SPO2最低值有不同程度升高。A组6月时Borg指数及GGO低于治疗前有统计学意义,P值分别为0.024、0.022；12月时以上指标与治疗前均无统计学差异,P>0.05。B组6月时GGO低于治疗前有统计学意义,P=0.026；12月时KL-6、最低SPO2、Borg指数、GGO、FS均低于治疗前水平,P值分别为0.013、0.022、0.001、0.000、0.032；24月时KL-6、最低SPO2、Borg指数、GGO、FS均低于治疗前水平,P值分别为0.012、0.011、0.002、0.000、0.003；36月时最低SPO2、Borg指数、HRCT磨玻璃阴影积分、HRCT纤维化积分均低于治疗前水平,P值分别为0.014、0.013、0.000、0.005。6MWD各时点两两比较均无统计学差异。③两组共10例在治疗及随访过程中出现KL-6正常现象,所需时间7.20±2.53月(6月-12月),中位数6.00月。其中A组4例(19.05%)、B组6例(26.09%),经秩和检验,两组发生KL-6正常情况无统计学差异,P=0.582。A组停用中药后均呈不同程度升高。B组停药后升高、停药后无升高、未停药而升高各有2例。单因素分析显示KL-6能否正常仅与基线KL-6有关,KL-6能达到正常者805.8 0±478.22 U/mL,中位数622.00 U/mL,不能达到正常者1424.79±1000.14U/mL,中位数1095.00 U/mL,f=-2.707,P=0.011。进行多因素Logistic回归分析显示KL-6能否正常仅与性别(男／女)相关,P=-0.028。KL-6恢复正常组,男性9例,女性1例,KL-6未恢复正常组,男性18例,女性16例。因此低水平KL-6及男性病例中药治疗6～12月后KL-6正常成为可能。④中药治疗期间Borg评分降低、SP02最低值升高,B组12月、24月、36月时Borg评分、SP02最低值与治疗前相比均有显著性统计学意义,P<0.05。两组各时点6MWT均较治疗前增加,但无统计学差异。⑤两组6月时磨玻璃影积分较治疗前均明显下降,P<0.05,纤维化积分均无显著性下降,P>0.05。A组12月HRCT积分与治疗前相比较均无统计学差异,P>0.05。B组12月、24月、36月时HRCT积分与治疗前相比较均有显著统计学差异,P<0.05。⑥A组有6例死亡,B组有2例死亡。单因素分析显示：12月疗效、病程、KL-6、6MWD、FS、IPF急性加重(是/否)均与死亡(是/否)相关,R<0.05。⑦发生IPF急性加重A组累计15例次,其中发生1次者7例,2次者4例；B组累计24例次,其中1次者7例,2次者4例,3次者3例,两组相比较无统计学差异,χ2=2.679,P=0.262。单因素分析：与年龄、12月疗效有关,而与性别、疾病分期、病程、中药疗程及基线KL-6、6MWD、SPO2最低值、Borg积分、GG0、FS均无关。
结论益气养阴法中药治疗气阴两虚型IPF有助改善呼吸困难症状、降低KL-6、HRCT积分,未发现中药降低死亡率及IPF急性加重发生率的作用。中药治疗有效的病例建议延长治疗时间到12月以上,有必要进一步扩大样本量、延长随访时间评估中药治疗改善IPF预后的价值。
Objective To observe the clinical effects of TCM therapy of supplementing qi and nourishing yin in treating idiopathic pulmonary fibrosis (IPF).
Method 44 IPF patients with qi and yin deficiency syndrome were retrospectively collected from MINO Chinese Medical Clinic in Singapore from January 2007 to September 2011. All patients were treated with TCM therapy of supplementing qi and nourishing yin. According to the course of treatment, they were divided into group A (21 patients, the course of treatment≤6 months) and group B (23 patients, the course of treatment> 6 months). After treated for 6 months, 12 months,24 month and 36 months, changes in KL-6,6 minute walk test (6 minute walk distance, (6MWD), the minimum value of arterial oxygen saturation (SPO2), Borg dyspnea score), high resolution CT (HRCT, ground glass score (GGO) and fibrosis score (FS)) were compared between the two groups, while the clinical effects of traditional Chinese medicine were evaluated.
Result①The total effective rates of TCM therapy were respectively 84.09% in the 6th month, 79.55% in the 12th month,43.18% in the 24th month and 31.82% in the 36th month, with significant difference among the four time points, P=0.000; the clinical effects in the 6th month and 12th month were superior to those in the 24th month and 36th month, P=0.000, while there was no significant difference between the clinical effects in the 6th month and those in the 12th month, as well as between those in the 24th month and in the 36th month, P>0.05. There was no significant difference in the clinical effects in the 6th month between group A and group B. The effective rate was 66.67% in group A and 91.30% in group B while in the 12th month, with significant difference between the two groups, Z=-2.001, P=0.045.②After receiving TCM treatment, KL-6, Borg scores and HRCT scores were decreased to varying degrees, and 6MWD and the minimum value of SPO2 were increased in 6-minute walk test. In group A, Borg scores and GGO of HRCT in the 6th month were lower than their baseline values, with significant difference, P=0.024 and P=0.022, while there was no significant difference in k1-6,6MWD, Borg scores, the minimum value of SPO2 and HRCT scores in the 12th month as compared to their baseline values, P>0.05. In group B, GGO of HRCT in the 6th month were lower than the baseline value, with significant difference, P=0.026; At the 12th month,24th month and 36th month, KL-6,6MWD, Borg scores, the lowest SPO2 and HRCT scores were lower than their baseline values, with significant difference, P<0.05. There was no significant difference in 6MWD between any two of the four time points, P>0.05.③KL-6 levels returned to normal in a total of 10 patients (4 patients in group A and 6 patients in group B) during the treatment and in the follow-up visit, with no significant difference between the two groups, P=0.582. After the treatment, KL-6 levels of the 4 patients in group A were increased in various degree, while in group B,2 patients showed an increase in KL-6 levels after treatment and 2 patients showed an increase in KL-6 levels during the treatment, while 2 patients showed no increase in KL-6 levels after treatment. Univariate analysis demonstrated that whether KL-6 levels can return to normal or not after TCM treatment is associated with the baseline value:KL-6 levels of 805.80±478.22 U/mL with a median of 622.00 U/mL could return to normal, while KL-6 levels of 1424.79±1000.14 U/mL with a median of 1095.00 U/mL could not return to normal, t=-2.707, P=0.011. A multivariate logistic regression analysis demonstrated whether KL-6 levels can return to normal or not after TCM treatment is only associated with gender (man or female),P=0.028.④During the treatment, Borg scores were decreased and the minimum value of SPO2 was increased. In group B, there were significant difference in Borg scores and the minimum value of SPO2 in the 12th month,24th month and 36th month, as compared to their baseline values, P<0.05.⑤At the 6th month, GGO was decreased significantly in both two groups, P<0.05, but FS showed no significant decrease, P>0.05. There were significant difference in HRCT scores (GGO and FS) in the 12th month,24th month and 36th month in group B, as compared to the baseline values, P<0.05, while HRCT scores in group A showed no significant difference between the 12th month and the baseline value, P>0.05.⑥The cause of death were respiratory failure, lung infections and heart and lung failure while four deaths occurred in group A and two deaths occurred in group B, with no significant difference, c2=0.313, P=0.576. Univariate analysis showed that the clinical effects of 12-months, the duration of treatment, KL-6 levels,6MWD, FS and acute exacerbation of IPF (yes/no) were associated with death (yes/no), P<0.05.⑦A total of 15 cases of acute exacerbation of IPF occurred in group A while 24 occurred in group B, with no significant difference between the two groups, c2=2.679, P=0.262. Univariate analysis showed that age and the the clinical effects of 12-months were associated with acute exacerbation of IPF (yes/no), P<0.05.
Conclusion TCM therapy of supplementing qi and nourishing yin can relieve dyspnea and decrease KL-6 level and HRCT scores in IPF patients with qi and yin deficiency syndrome, but it has not showed effects in reducing the mortality and the incidence of acute exacerbation of IPF. We suggest extending the course of the TCM treatment to more than 12 months in patients who have showed improvement after treated with TCM therapy. It is necessary to further expand the sample size and to extend the follow-up time to evaluate the value of TCM therapy in improving the prognosis of IPF.
方法收集2007年1月～2011年9月新加坡MINO Chinese Medical Clinic诊所(日文网站：www.minomedical.com)收治IPF气阴两虚证病例44例,使用益气养阴法中药治疗,采用治疗前后自身对照设计。按疗程分成A、B两个亚组,其中A组(疗程≤6月)21例,B组(疗程>6月)23例,治疗6月、12月、24月,36月,分别观察KL-6、6分钟步行试验6分钟步行距离(6MWD)、经皮血氧饱和度最低值(SPO2)、Borg呼吸困难评分、高分辨CT (HRCT:磨玻璃阴影积分GGO、纤维化积分FS)的变化并评价中药治疗效果。结果①6月、12月、24月、36月总有效率分别为84.09%、79.55%、43.18%、31.82%,各时点疗效差异显著,P=0.000,6月和12月疗效均显著优于24月、36月疗效,P=0.000,6月与12月、24月与36月疗效均无差异,P>0.05。A组、B组两亚组在6月时疗效无差异,12月时两组有效率分别为66.67%、91.30%,P=0.045,提示两组疗效有显著差异。②KL-6、Borg评分、HRCT积分(GGO和FS)不同程度降低,且6MWD、SPO2最低值有不同程度升高。A组6月时Borg指数及GGO低于治疗前有统计学意义,P值分别为0.024、0.022；12月时以上指标与治疗前均无统计学差异,P>0.05。B组6月时GGO低于治疗前有统计学意义,P=0.026；12月时KL-6、最低SPO2、Borg指数、GGO、FS均低于治疗前水平,P值分别为0.013、0.022、0.001、0.000、0.032；24月时KL-6、最低SPO2、Borg指数、GGO、FS均低于治疗前水平,P值分别为0.012、0.011、0.002、0.000、0.003；36月时最低SPO2、Borg指数、HRCT磨玻璃阴影积分、HRCT纤维化积分均低于治疗前水平,P值分别为0.014、0.013、0.000、0.005。6MWD各时点两两比较均无统计学差异。③两组共10例在治疗及随访过程中出现KL-6正常现象,所需时间7.20±2.53月(6月-12月),中位数6.00月。其中A组4例(19.05%)、B组6例(26.09%),经秩和检验,两组发生KL-6正常情况无统计学差异,P=0.582。A组停用中药后均呈不同程度升高。B组停药后升高、停药后无升高、未停药而升高各有2例。单因素分析显示KL-6能否正常仅与基线KL-6有关,KL-6能达到正常者805.8 0±478.22 U/mL,中位数622.00 U/mL,不能达到正常者1424.79±1000.14U/mL,中位数1095.00 U/mL,f=-2.707,P=0.011。进行多因素Logistic回归分析显示KL-6能否正常仅与性别(男／女)相关,P=-0.028。KL-6恢复正常组,男性9例,女性1例,KL-6未恢复正常组,男性18例,女性16例。因此低水平KL-6及男性病例中药治疗6～12月后KL-6正常成为可能。④中药治疗期间Borg评分降低、SP02最低值升高,B组12月、24月、36月时Borg评分、SP02最低值与治疗前相比均有显著性统计学意义,P<0.05。两组各时点6MWT均较治疗前增加,但无统计学差异。⑤两组6月时磨玻璃影积分较治疗前均明显下降,P<0.05,纤维化积分均无显著性下降,P>0.05。A组12月HRCT积分与治疗前相比较均无统计学差异,P>0.05。B组12月、24月、36月时HRCT积分与治疗前相比较均有显著统计学差异,P<0.05。⑥A组有6例死亡,B组有2例死亡。单因素分析显示：12月疗效、病程、KL-6、6MWD、FS、IPF急性加重(是/否)均与死亡(是/否)相关,R<0.05。⑦发生IPF急性加重A组累计15例次,其中发生1次者7例,2次者4例；B组累计24例次,其中1次者7例,2次者4例,3次者3例,两组相比较无统计学差异,χ2=2.679,P=0.262。单因素分析：与年龄、12月疗效有关,而与性别、疾病分期、病程、中药疗程及基线KL-6、6MWD、SPO2最低值、Borg积分、GG0、FS均无关。
结论益气养阴法中药治疗气阴两虚型IPF有助改善呼吸困难症状、降低KL-6、HRCT积分,未发现中药降低死亡率及IPF急性加重发生率的作用。中药治疗有效的病例建议延长治疗时间到12月以上,有必要进一步扩大样本量、延长随访时间评估中药治疗改善IPF预后的价值。
Objective To observe the clinical effects of TCM therapy of supplementing qi and nourishing yin in treating idiopathic pulmonary fibrosis (IPF).
Method 44 IPF patients with qi and yin deficiency syndrome were retrospectively collected from MINO Chinese Medical Clinic in Singapore from January 2007 to September 2011. All patients were treated with TCM therapy of supplementing qi and nourishing yin. According to the course of treatment, they were divided into group A (21 patients, the course of treatment≤6 months) and group B (23 patients, the course of treatment> 6 months). After treated for 6 months, 12 months,24 month and 36 months, changes in KL-6,6 minute walk test (6 minute walk distance, (6MWD), the minimum value of arterial oxygen saturation (SPO2), Borg dyspnea score), high resolution CT (HRCT, ground glass score (GGO) and fibrosis score (FS)) were compared between the two groups, while the clinical effects of traditional Chinese medicine were evaluated.
Result①The total effective rates of TCM therapy were respectively 84.09% in the 6th month, 79.55% in the 12th month,43.18% in the 24th month and 31.82% in the 36th month, with significant difference among the four time points, P=0.000; the clinical effects in the 6th month and 12th month were superior to those in the 24th month and 36th month, P=0.000, while there was no significant difference between the clinical effects in the 6th month and those in the 12th month, as well as between those in the 24th month and in the 36th month, P>0.05. There was no significant difference in the clinical effects in the 6th month between group A and group B. The effective rate was 66.67% in group A and 91.30% in group B while in the 12th month, with significant difference between the two groups, Z=-2.001, P=0.045.②After receiving TCM treatment, KL-6, Borg scores and HRCT scores were decreased to varying degrees, and 6MWD and the minimum value of SPO2 were increased in 6-minute walk test. In group A, Borg scores and GGO of HRCT in the 6th month were lower than their baseline values, with significant difference, P=0.024 and P=0.022, while there was no significant difference in k1-6,6MWD, Borg scores, the minimum value of SPO2 and HRCT scores in the 12th month as compared to their baseline values, P>0.05. In group B, GGO of HRCT in the 6th month were lower than the baseline value, with significant difference, P=0.026; At the 12th month,24th month and 36th month, KL-6,6MWD, Borg scores, the lowest SPO2 and HRCT scores were lower than their baseline values, with significant difference, P<0.05. There was no significant difference in 6MWD between any two of the four time points, P>0.05.③KL-6 levels returned to normal in a total of 10 patients (4 patients in group A and 6 patients in group B) during the treatment and in the follow-up visit, with no significant difference between the two groups, P=0.582. After the treatment, KL-6 levels of the 4 patients in group A were increased in various degree, while in group B,2 patients showed an increase in KL-6 levels after treatment and 2 patients showed an increase in KL-6 levels during the treatment, while 2 patients showed no increase in KL-6 levels after treatment. Univariate analysis demonstrated that whether KL-6 levels can return to normal or not after TCM treatment is associated with the baseline value:KL-6 levels of 805.80±478.22 U/mL with a median of 622.00 U/mL could return to normal, while KL-6 levels of 1424.79±1000.14 U/mL with a median of 1095.00 U/mL could not return to normal, t=-2.707, P=0.011. A multivariate logistic regression analysis demonstrated whether KL-6 levels can return to normal or not after TCM treatment is only associated with gender (man or female),P=0.028.④During the treatment, Borg scores were decreased and the minimum value of SPO2 was increased. In group B, there were significant difference in Borg scores and the minimum value of SPO2 in the 12th month,24th month and 36th month, as compared to their baseline values, P<0.05.⑤At the 6th month, GGO was decreased significantly in both two groups, P<0.05, but FS showed no significant decrease, P>0.05. There were significant difference in HRCT scores (GGO and FS) in the 12th month,24th month and 36th month in group B, as compared to the baseline values, P<0.05, while HRCT scores in group A showed no significant difference between the 12th month and the baseline value, P>0.05.⑥The cause of death were respiratory failure, lung infections and heart and lung failure while four deaths occurred in group A and two deaths occurred in group B, with no significant difference, c2=0.313, P=0.576. Univariate analysis showed that the clinical effects of 12-months, the duration of treatment, KL-6 levels,6MWD, FS and acute exacerbation of IPF (yes/no) were associated with death (yes/no), P<0.05.⑦A total of 15 cases of acute exacerbation of IPF occurred in group A while 24 occurred in group B, with no significant difference between the two groups, c2=2.679, P=0.262. Univariate analysis showed that age and the the clinical effects of 12-months were associated with acute exacerbation of IPF (yes/no), P<0.05.
Conclusion TCM therapy of supplementing qi and nourishing yin can relieve dyspnea and decrease KL-6 level and HRCT scores in IPF patients with qi and yin deficiency syndrome, but it has not showed effects in reducing the mortality and the incidence of acute exacerbation of IPF. We suggest extending the course of the TCM treatment to more than 12 months in patients who have showed improvement after treated with TCM therapy. It is necessary to further expand the sample size and to extend the follow-up time to evaluate the value of TCM therapy in improving the prognosis of IPF.
引文
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