摘要：

目的 总结耐药结核性脑膜炎的脑脊液细胞学动态变化特点，并探讨其在结核性脑膜炎耐药和疗效评估中的价值。方法 共纳入2013年1月至2020年12月在江西省胸科医院诊断与治疗的79例结核性脑膜炎患者，行脑脊液药敏检测和至少每周一次的脑脊液细胞学检查，计数有核细胞和各类细胞百分比；药敏检测结果回报前采取H （S） REZ （V）方案，结果回报后根据耐药情况制定个体化抗结核方案。结果 根据脑脊液药敏检测结果，37例为耐药结核性脑膜炎，其中29例（78.38%）为多药耐药，耐药谱依次为异烟肼+利福平+链霉素[35.14%（13/37）]，异烟肼+利福平+链霉素+氟喹诺酮[18.92%（7/37）]，异烟肼+利福平+乙胺丁醇+链霉素[16.22%（6/37）]，异烟肼和利福平[各10.81%（4/37）]，异烟肼+利福平、异烟肼+利福平+乙胺丁醇+链霉素+氟喹诺酮、异烟肼+利福平+乙胺丁醇+链霉素+阿米卡星/卷曲霉素[各2.70%（1/37）]。抗结核治疗2和4周后，非耐药组脑脊液有核细胞计数（t=5.050，P=0.000；t=11.100，P=0.000）和中性粒细胞比例（t=15.268，P=0.000；t=17.048，P=0.000）均低于耐药组。脑脊液细胞学显示，耐药组呈现持续>4周的混合细胞炎症迁延反应，非耐药组向显著淋巴细胞反应转化。随访6个月时，耐药组总有效率低于非耐药组[45.71%（16/35）对90%（36/40）；χ²=17.218，P=0.000]。结论 结核性脑膜炎早期脑脊液细胞学以混合细胞炎症反应为主，治疗过程中持续> 4周的混合细胞炎症迁延反应是耐药结核性脑膜炎的特点，可能是提示治疗方案无效的依据。临床受限于药敏检测时限和条件限制时，监测脑脊液细胞学动态变化可能成为耐药结核性脑膜炎的辅助判断方法，可为临床疗效评价和抗结核治疗方案调整提供参考。

关键词: 结核, 脑膜, 药物耐受性, 微生物敏感性试验, 脑脊髓液, 细胞学

Abstract:

Objective To summarize the dynamic changes of cerebrospinal fluid (CSF) cytology in drug resistant tuberculous meningitis (TBM), and to explore its value in drug resistance and efficacy evaluation of TBM. Methods Seventy-nine patients with TBM who were diagnosed and treated in Jiangxi Chest Hospital from January 2013 to December 2020 were included in this study. H(S)REZ(V) scheme[isoniazid (or streptomycin), rifampicin, ethambutol, plus pyrazinamide (or levofloxacin)] regimen was adopted before the return of drug sensitivity test results. After the return of results, individualized anti-tuberculosis regimen was formulated according to drug resistance. Results According to the drug sensitivity test results of CSF, 37 cases were drug resistant TBM, of which 29 cases (78.38%) were multidrug resistant. The drug resistance spectrum was isoniazid + rifampicin + streptomycin[35.14% (13/37)], isoniazid + rifampicin + streptomycin + fluoroquinolone[18.92% (7/37)], isoniazid + rifampicin + ethambutol + streptomycin[16.22% (6/37)], isoniazid and rifampicin[10.81% each, (4/37)], Isoniazid + rifampicin, isoniazid + rifampicin + ethambutol + streptomycin + fluoroquinolone, isoniazid + rifampicin + ethambutol + streptomycin + amikacin/capreomycin[2.70% each, (1/37)]. After 2 and 4 weeks of antituberculosis treatment, the number of nucleated cells in CSF of non drug resistant group (t=5.050, P=0.000; t=11.100, P=0.000) and neutrophil ratio (t=15.268, P=0.000; t=17.048, P=0.000) were lower than drug resistant group. CSF cytology showed that the drug resistant group showed mixed cell inflammatory reaction lasting more than 4 weeks, and the non drug resistant group transformed into significant lymphocyte reaction. After 6 months of follow-up, the total effective rate of drug resistant group was lower than that of non drug resistant group[45.71% (16/35) vs. 90% (36/40); χ²=17.218, P=0.000]. Conclusions The cytological characteristics of CSF in patients with TBM are mainly characterized by mixed cell inflammatory reaction in the early stage, the delayed mixed cell inflammatory reaction lasting more than 4 weeks during treatment is the characteristic of drug resistant TBM, which may be the basis for indicating that the treatment plan is invalid. When limited by the time limit and conditions of drug sensitivity test, monitoring the dynamic changes of CSF cytology may become an auxiliary judgment method for drug resistant TBM, which can provide reference for clinical efficacy evaluation and antituberculosis treatment plan adjustment.

Key words: Tuberculosis, meningeal, Drug tolerance, Microbial sensitivity tests, Cerebrospinal fluid, Cytological techniques