Analysis Of The Clinical Characteristics And Prognostic Factors Of Patients With Tuberculous Meningitis Admitted To The Intensive Care Unit

OBJECTIVETuberculous meningitis(TBM)is the most lethal form of tuberculosis.Mortality in adult patients with TBM reaches 30%-60%,and neurological sequelae were reported in more than 50%of survivors.Patients with TBM who had neurological complications frequently require admission to the intensive care unit(ICU).However,studies on patients with TBM requiring ICU admission are scarce due to the limited access of patients to intensive care in developing countries.Therefore,we conducted this retrospective study on adult patients with TBM admitted to ICU in a tuberculosis endemic area.Our objectives were to analyze the clinical characteristics of adult TBM patients admitted to the ICU and to identify prognostic factors of unfavorable outcome.METHODSThis was a single-center retrospective study on consecutive adult patients with TBM admitted to the medical ICU of Shandong Provincial Chest Hospital,Cheeloo College of Medicine,Shandong University,a 900-bed tertiary hospital located in Shandong Province,China,from January 2008 to April 2018.Participants were included if they met the diagnostic criteria for TBM established by the expert consensus definition of 2010.The primary endpoint was graded with the Glasgow Outcome Scale(GOS)28 days after ICU admission.The second endpoint was overall mortality during a 1-year follow-up period.Univariate logistic regression analysis was performed to evaluate the relationships between variables and primary outcome.Variables associated with unfavorable outcome in univariate analysis(P<0.10)were included in the multivariate model.Discriminations among the different scoring systems were tested using the area under the receiver operating characteristic(ROC)curves.The best cut-off points were that which maximized the sum of sensitivity and specificity.Survival outcomes were measured by the Kaplan-Meier survival curve,and the log-rank test was used to determine statistical difference.Univariate Cox proportional hazard regression model was performed to evaluate associations between variables and 1-year mortality.Variables associated with mortality in univariate analysis(p<0.10)were entered into the multivariate model.RESULTS1.Clinical characteristics and prognostic factors of adult patients with TBMAmong the 151 patients with suspected TBM admitted to the ICU,80 were included.The median age was 38.5(18-79)years and 45(56%)were males.All patients had MRC stage III illness on admission.The median duration before ICU admission was 20(3-365)days.Altered consciousness(87%),lethargy(85%),neck stiffness(83%),fever(77%)and headache(73%)were the most common symptoms and signs.CSF analysis revealed a typical pleocytosis of 104(2-1268)cells/μl,elevated protein levels of 1462(299-3816)mg/L,and low glucose levels of 2.32(0.33-12.60)mmol/L.CSF cultures for Mycobacterium tuberculosis were positive in 22(28%)of the 79 patients’ CSF specimens on which the test were performed,including one multidrug-resistant and three rifampicin-resistant strains.CSF polymerase chain reactions(PCR)were positive in 21(27%)of 78 patients.Among cranial images,hydrocephalus was found in 45(62%)of 73 patients while infarcts were found in 36(49%).The median scores of GCS,APACHE II and SOFA were 3(3-10),23(10-37),and 7(3-13)respectively on admission.First-line anti-tuberculosis therapy consisted of isoniazid,rifampicin,ethambutol and pyrazinamide was initiated in all cases on admission.Four patients were secondarily detected with resistance to first-line drugs and switched to other drugs during their ICU stay.Adjunctive steroids were given to reduce inflammation in all patients on admission.Overall,58(73%)patients received invasive mechanical ventilation and 11(14%)received lateral ventricular drainage during their ICU stay.At 28 days,39(49%)patients had unfavorable outcomes,including 29(36%)deaths.Variables including clinical and laboratory characteristics,and the three evaluating scores were independently analyzed in univariate logistic regression analysis.Only irritability,mechanical ventilation,APACHE Ⅱ and SOFA scores showed statistical significance.Multivariate logistic regression analysis identified three independent factors of unfavorable outcome:APACHE Ⅱ>23,SOFA>8,and the requirement of invasive mechanical ventilation.One-year outcomes were available for 69 patients.Six patients died during the follow-up period,all of whom were from the unfavorable-outcome group.The 1-year overall mortality estimated by Kaplan-Meier analysis was 46%.The univariate Cox regression analysis showed that male sex,APACHE II,SOFA score,and mechanical ventilation were associated with 1-year mortality.Multivariate Cox regression analysis identified two factors positively associated with 1-year mortality:APACHE Ⅱ>23,and the requirement of mechanical ventilation.Among 1-year survivors,functional independence(GOS of 5)was observed in 28/34(82%)cases.Of the 6 patients with functional dependence(GOS of 4),visual impairment was found in one case and reduced muscle strength was found in five cases.In the ROC analysis,the areas under the curve were:GCS 0.60,APACHE Ⅱ 0.81,and SOFA 0.67.To obtain the strongest power of prediction,the cut-off points were 4 for GCS,23 for APACHE Ⅱ,and 8 for SOFA respectively.The difference in Kaplan-Meier survival curve between patients with APACHE Ⅱ score ≤23 and>23 was statistically significant(P<0.001).Patients stratified by SOFA(≤8 and>8)yielded the similar result(P<0.001).There is no statistically significant difference between survival curves for patients stratified by GCS≤4 and>4(P=0.38).When APACHE Ⅱ.SOFA and mechanical ventilation were included in a model,the model showed good discrimination as evident by an AUC=0.878(95%CI 0.805-0.950,P<0.001)and good calibration(Hosmer and Lemeshow test P=0.904).When we performed subgroup analysis of the definite and probable TBM cases,the results changed little.2.Clinical characteristics and prognostic factors of pediatric patients with TBMDuring the study period,20 cases of pediatric TBM were reported.The median age was 5.5(1-16)years and 12(60%)were males.All patients presented with MRC stage III illness on admission.The median duration before ICU admission was 20(7-150)days.No patient had been diagnosed with TB before,while 5(25%)patients had a definite history of TB exposure.Altered consciousness(95%),lethargy(85%),nausea and vomiting(80%),fever(80%)and headache(75%)were the most common symptoms,while neck stiffness(80%)was the most common signs.CSF analysis revealed a typical pleocytosis of 124(2-578)cells/μl,elevated protein levels of 1313(217-2395)mg/L,and low glucose levels of 1.45(0.30-4.50)mmol/L.CSF cultures for Mycobacterium tuberculosis were positive in 7(35%)patients.CSF PCR were positive in 7(35%)patients too.Among cerebral images,hydrocephalus was found in 15(79%)of 19 patients while infarcts were found in 7(37%).Thirteen children showed evidence of pulmonary TB on chest CT,and 3 were miliary.The median scores of GCS,APACHE Ⅱ and SOFA on admission were 3(3-8),21(12-27),and 5(3-10)respectively.Overall,10(50%)patients received invasive mechanical ventilation and 7(35%)received EVD during their ICU stay.At 28 days,13(65%)patients had unfavorable outcomes,including 7(35%)deaths.Variables such as clinical and laboratory characteristics,and different evaluating scores were independently analyzed in univariate logistic regression analysis.Only female sex and mechanical ventilation showed statistical significance.One-year outcomes were available for 18 patients.Another three patients died during the follow-up period,all of whom were from the unfavorable-outcome group.The 1-year overall mortality estimated by Kaplan-Meier analysis was 50%.Multivariate Cox regression analysis identified two factors positively associated with 1-year mortality:female sex(aHR 17.86;95%CI 2.97-107.59;P=0.002),and the requirement of mechanical ventilation(aHR 8.99;95%CI 1.53-52.82;P=0.015).Among 1-year survivors,functional independence(GOS of 5)was observed in 5/8(62.5%)cases.Of the 3 patients with functional dependence,reduced muscle strength was found in one case(GOS of 4)and vegetative state was found in two cases(GOS of 2).In the ROC analysis,the areas under the curve were:GCS 0.72(95%CI 0.46-0.98;P=0.11),APACHE Ⅱ 0.71(95%CI 0.46-0.97;P=0.12),and SOFA 0.65(95%CI 0.40-0.91;P=0.27).To obtain the strongest power of prediction,the cut-off points were 5 for GCS(sensitivity 0.92 and specificity 0.57),19 for APACHE Ⅱ(sensitivity 0.85 and specificity 0.57),and 7 for SOFA(sensitivity 0.31 and specificity 1.00)respectively.None of the three scoring systems showed to have good specificity and sensitivity both.Kaplan-Meier survival curves for patients with GCS score ≤5 and>5 showed no statistical difference with P=0.19.Patients stratified by APACHE Ⅱ(≤19 and>19)yielded the similar result(P=0.41).CONCLUSION1.In China,most TBM patients admitted to ICU were severe cases in MRC stage Ⅲ,for whom common clinical factors were not effective enough to predict outcomes.Our study demonstrated that the widely used APACHE Ⅱ and SOFA scores on admission could be used to predict short-term outcomes,while APACHE Ⅱ could also be used to predict long-term outcomes of adult patients with TBM in ICU.2.An unfavorable outcome in pediatric TBM patients admitted to the ICU was observed in 65%of cases and independently associated with female sex and the requirement of invasive mechanical ventilation.Further prospective studies on a larger sample size of pediatric TBM patients are needed to verify this.