| Background:Tuberculosis is a common public health and social problem of global concern.In China,the incidence rate of tuberculosis is high,the incidence rate is increasing,the clinical diagnosis rate is low,and the resistance is strong.Tuberculous pleurisy is a late allergic reaction caused by tuberculosis infection to the pleural membrane in patients with tuberculosis.It is the most common form of extrapulmonary tuberculosis and is also the main cause of pleural effusion.In the high burden area of tuberculosis,such as China,tuberculous pleurisy accounts for 25%of all tuberculosis.It has caused great damage to human health and society.To understand the clinical and pathological characteristics of tuberculous pleurisy and how to make a clear diagnosis and clinical intervention as soon as possible is the focus of our current clinical work.Moreover,grass-roots hospitals and outpatients are also need economic,simple and safe test indicators to improve the diagnosis rate of tuberculous pleurisy and reduce the clinical misdiagnosis rate.Object:We first retrospectively analyzed the clinicopathological features of 304 cases of tuberculous pleurisy,and then evaluated the value of medical thoracoscopy in the qualitative diagnosis of tuberculous pleurisy.Then,the clinical and pathological differences of two types of tuberculous pleural effusion(TPE)dominated by neutrophils and lymphocytes were analyzed and compared.Then,we focused on the pathogenic factors and clinical characteristics of TPE dominated by neutrophils,and how to distinguish it from pleural effusion adjacent to pneumonia.Finally,the accuracy of relevant parameters obtained from routine blood and pleural effusion detection in disease diagnosis and differential diagnosis were studied and analyzed,so as to find a relevant combination of new indicators,which can distinguish TPE from other types of pleural effusion,in order to better guide clinical practice.MethodsPart ?:The clinical data of 304 patients with TPE who underwent medical thoracoscopy were analyzed retrospectively.The selected patients were negative for human immunodeficiency virus,and the cases met the diagnostic criteria of tuberculous pleurisy.All patients underwent biopsy and pathological examination.They were diagnosed as tuberculous pleurisy for the first time and none of them had received anti-tuberculosis treatment or for more than one week.The patients' medical records were retrospectively analyzed and the following data were collected:gender,age,clinical manifestations(including fever,chest tightness,chest pain,cough,expectoration,night sweat,fatigue and weight loss),complications,routine and biochemical examination of pleural effusion(including cell count and classification,protein,glucose,lactate dehydrogenase(LDH),adenosine deaminase(ADA)),anti-Mycobacterium tuberculosis(MTB)antibody in pleural effusion and serum,microbiological examination(sputum,pleural effusion,tuberculosis smear and culture in pleural biopsy tissue),thoracoscopic findings,pleural biopsy results and chest CT findings.The total number of positive tuberculosis detected in pleural effusion is the sum of acid-fast bacillus(AFB)positive pleural smear and MTB positive pleural culture.The total number of positive intrathoracic tuberculosis was the sum of positive pleural smear AFB,positive pleural culture MTB and positive pleural biopsy culture MTB.According to the general findings of medical thoracoscopy,they are classified as follows:nodule group and nonnodule group;low ADA group(pleural fluid ADA(pfADA)?40U/L)and high ADA group(pfADA>40U/L);group age<18 years,group age18-34years,group age3539years and group age?60years.The clinical,laboratory,thoracoscopic and pathological characteristics were compared and analyzed between the groups.Part ?:The clinical data of 304 patients with TPE of two types(mainly lymphocytes and neutrophils)were analyzed retrospectively.The data used were the first part.In addition,the clinical indexes related to neutrophil predominance TPE(NP-TPE)(leukocyte count and classification,LDH,ADA,glucose and protein)were collected twice.The clinical,laboratory,thoracoscopic and pathological features of TPE mainly composed of lymphocytes and neutrophils were analyzed and compared.The risk factors of TPE dominated by neutrophils were analyzed by logistic regression analysis.The two groups of patients were followed up and the prognosis were analyzed.Part ?:In this study,the clinical data of 129 patients with pleural effusion(The inclusion criteria of patients with tuberculous pleural effusion were the same as above.Patients with pneumonic pleural effusion had no antibiotic therapy or antibiotic therapy for less than 3 days)were collected retrospectively.They were divided into NP-TPE(23 cases)group and parapneumonic pleural effusion(PPE)group(106 cases).We compared the difference of each laboratory data ratio between the two groups and summarized the data with the difference p value less than 0.001 for receiver operating characteristic curve(ROC)curve analysis.Then we calculated the sensitivity and specificity of each ratio parameter in the diagnosis of TPE and calculated the area under the curve(AUC)and Youden index to explore the diagnostic value of each ratio parameter in the diagnosis of NP-TPE.Part ?:The serum and pleural fluid test data of 618 patients without anti tuberculosis or anti-tumor treatment who underwent pleural effusion examination for the first time were collected retrospectively and divided into three groups,including 412 cases of TPE,100 cases of malignant pleural effusion(MPE)and 106 cases of PPE.We compared the difference of each laboratory data ratio between the three groups and summarized the data with the difference p value less than 0.001 for ROC curve analysis.The sensitivity and specificity of each ratio parameter in the diagnosis of TPE were calculated,and the AUC and Youden index were calculated to explore the diagnostic value of each ratio parameter in TPE.ResultsPart ?:Diagnosis and treatment of tuberculous pleurisy by medical thoracoscopy:a retrospective study of 304 patients1.Baseline characteristics of the study populationThe study included 304 patients with tuberculous pleurisy.The average age of these patients was 35.08±14.55 years of which 273(89.8%)were aged between 18 and 59 years.In addition,there were 228 males and 76 females.The average onset time of tuberculous pleurisy during medical thoracoscopy was 1.76±2.1 1 months.The common clinical symptoms included fever(76.3%),cough(75.3%),chest tightness(66.4%),chest pain(60.9%),fatigue(41.1%)and night sweat(37.5%).Weight loss occurred in 40 patients(13.2%).Most patients had pleural effusion on one side(94.0%),only 6.0%had bilateral pleural effusion,and 180 patients(59.2%)had pulmonary tuberculosis.2.Tuberculosis laboratory testingThe levels of protein(PRO),glucose(GLU),LDH and ADA in pleural fluid were 48.1(44.3,51.6)g/L,4.56(2.79,5.60)mmol/L,446(278,836)U/L ? 43.1(32.5,58.1)U/L,respectively.Monocytes were found dominated in the pleural effusion of 89.1%(271/304)and multinucleated cells were found dominated in the pleural effusion of 10.9%(33/304).Anti-MTB antibody was detected in 59.6%(164/275)patients' pleural effusion and 26.8%(60/224)patients' serum.The positive rates of AFB in pleural effusion and sputum smear were 2.2%(6/270)and 2.9%(6/210),respectively;The positive rates of MTB in pleural effusion and sputum were 19.9%(53/267)and 15.3%(29/190),respectively;The positive rate of Mycobacterium tuberculosis culture in pleural biopsy and the total positive rate of intrathoracic tuberculosis were 59.9%(182/304)and 62.8%(191/304).These data show that the diagnosis rate can be significantly improved by using medical thoracoscopic biopsy.3.Results of medical thoracoscopyOne or more abnormalities on the pleural surface were observed in all patients under medical thoracoscopy(Figure1),which include 84 cases(27.6%)of loculation of pleural fluid,218 cases(71.7%)of pleural adhesions,157 cases(51.6%)of pleural thickening,127 cases(41.8%)of pleural nodules,77 cases of pleural isolation(25.3%),21 cases of purulent moss(6.9%),23 cases of caseous necrosis(7.6%),and 57 cases of with a jelly-like appearance(18.8%).The results of medical thoracoscopy showed that pleural thickening accounted for 44.7%(135/302),purulent moss or caseous necrosis accounted for 39.7%(120/302),and pleural nodules accounted for 15.6%(47/302).4.Clinical characteristics of granulomatous and non-granulomatous tuberculous pleurisyThe results of pleural biopsy showed that 70.1%(213/304)had granuloma.Compared with the non-granulomatous group,the pleural effusion in the granulomatous group was mainly monocytes(95.7%,204/213),and th e duration of onset was shorter(P<0.01).In granuloma group,the levels of PRO,GLU and ADA in pleural effusion increased significantly,while the level of LDH decreased significantly(P<0.01).Compared with the pleural biopsy culture of non-granulomatous patients(46.2%),the pleural biopsy culture from granulomatous patients was more likely to detect MTB(66.0%)(P<0.01)and the total positive rate of MTB in thoracic cavity was also higher(67.6%)(P<0.01).5.To explore the clinical characteristics of patients with tuberculous pleurisy according to the level of ADACompared with patients with tuberculous pleurisy with low pfADA level(?40U/L),patients with tuberculous pleurisy with high pfADA level(>40U/L)had significantly higher levels of pleural effusion PRO(48.7 vs 47.6 g/L,P<0.05)and LDH(555 vs 313U/L,P<0.001).The level of pleural fluid GLU in patients with high ADA level tuberculous pleurisy(4.20 vs 5.10 mmol/L,P<0.01)decreased significantly.Patients with tuberculous pleurisy with high ADA level were more likely to have granuloma in pleural biopsy specimens(75.3%vs 62.2%,P<0.05),and the culture rate of pleural effusion was relatively high(23.8%vs 14.0%,P<0.05).6.The clinical characteristics of patients with tuberculous pleurisy were analyzed according to their ageYoung patients with ADA>40U/L were more common.The percentages of patients with high pfADA level(>40U/L)in group age<18 years,group age 18-34 years,group age 35-59 years and group age?60 years were 88.9%(8/9),68.3%(110/161),48.6%(52/107)and 38.1%(8/21),respectively(P<0.001).Compared with patients over 60 years old,patients with tuberculous pleurisy aged 18-34 years were more likely to have granuloma in pleural biopsy specimens(82.3%vs 45.5%,P<0.01).Part ?:Clinical and pathological features and prognostic analysis of NP-TPEIn this study,a total of 304 patients with tuberculous pleurisy were enrolled:89.1%(271/304)of patients had pleural effusion dominated by mononuclear cells and 10.9%(33/304)had pleural effusion dominated by multinucleated cells.1.Analysis of clinical characteristicsCompared with lymphocytic tuberculous pleurisy,patients with NP-TPE had higher rates of high fever(51.5%vs 32.4%,P=0.030),lower rates of chest tightness(48.5%vs 68.6%,P=0.021)and lower rates of pulmonary tuberculosis(42.8%vs 60.8%,P=0.037).2.Microbiological and laboratory differencesBoth groups of patients have increased pfADA.The proportion of patients with pfADA>40U/L were 62.2%and 71.1%,respectively.And the NP-TPE patients has relatively higher pfADA.The positive rate of biopsy tissue culture in patients with NPTPE was significantly lower than that in patients with tuberculous pleurisy dominated by lymphocytes(36.4%vs 62.7%,P=0.01).LDH(1297 vs410 U/L,P<0.001)and ADA(54.1 vs 42.9 U/L,P=0.043)in pleural effusion were significantly higher in NP-TPE.Pleural GLU(1.92 vs 4.70 mmol/L,P<0.001)and PRO(47.4 vs 48.4 g/L,P=0.024)of NP-TPE was significantly lower than that of lymphocytic type.In addition,compared with patients with lymphocytic tuberculous pleurisy,patients with NP-TPE had lower serum albumin(ALB)levels(32.0 vs.36.1 g/L,P=0.041)and higher Creactive protein(CRP)levels(27.5 vs 12.0mg/L,P<0.001).3.Thoracoscopic findings and pathological differences of pleural biopsyIn NP-TPE,encapsulated effusion accounted for 27.3%,which is similar to lymphocyte dominated tuberculous pleurisy.Thoracoscopic pleural biopsy showed that the incidence of granuloma in patients with NP-TPE was 27.2%,which was significantly lower than that in patients with tuberculous pleurisy dominated by lymphocytes(27.2%vs 75.2%,P<0.001).In NP-TPE,the rates of pus mosses and caseous necrosis were 27.3%and 18.1%respectively,which were significantly higher than those dominated by lymphocytes(27.3%vs 4.43%,P<0.001;18.1%vs 6.27%,P<0.05).In NP-TPE,the positive rate of noninvasive detection of MTB was 19.2%.The positive rate of MTB in thoracoscopic tissue culture by the invasive method was 36.8%,and the positive rate of granuloma in pathological biopsy was 27%.Combined with thoracoscopic biopsy tissue culture,the total positive rate of MTB was 42.1%.4.Biochemical changes of continuous pleural effusion in patients with NP-TPEIn 21 patients with NP-TPE,the median duration of the second pleural effusion examination was 7 days(5-21 days).The median percentage of lymphocytes in pleural effusion increased(30%vs 10%,P<0.001),and so did the glucose level(3.49 mmol/L vs.1.92 mmol/L,P=0.005).The concentrations of LDH(1034U/L vs 1440U/.L,P=0.203)and ADA(46.3U/L vs 54.1U/L,P=0.491)showed a downward trend,but there was no significant difference.The pleural effusion of 9 cases(42.8%)progressed to be dominated by lymphocytes after repeated pleural puncture.5.Logistic regression analysis was used to analyze the risk factors of NP-TPEUnivariate analysis showed that the levels of PRO,GLU and ALB in pleural effusion,blood WBC,typical granuloma in biopsy,nodules,caseous substances and purulent moss under thoracoscopy were the risk factors of NP-TPE.The studies showed that patients with low levels of PRO,GLU or ALB were more likely to develop neutrophil dominated tuberculous pleurisy(P<0.05).Patients with higher blood WBC level are more likely to develop tuberculous pleurisy dominated by neutrophils.Patients without typical granuloma or nodules under thoracoscopy or with caseous material or pus are more likely to develop tuberculous pleurisy dominated by neutrophils.Multivariate analysis showed that without typical granuloma were the most likely risk factor to develop neutrophil dominated tuberculous pleurisy(P<0.05).6.Prognostic analysis of NP-TPEAll patients were given standard anti-tuberculosis treatment.The proportions of patients with combined systemic glucocorticoids,with combined intrathoracic injections of glucocorticoids,with intrathoracic injections of urokinase,with intrathoracic injections of anti-tuberculosis drugs and treated with pleural decortication were 68.8%(209/304),49.0%(149/304),65.1%(198/304),87.8%(267/304)and 5.3%(16/304),respectively.A total of 151 patients were followed up.The average treatment time was 10.36±4.54 months.The follow-up data showed that standard anti-tuberculosis therapy combined with systemic glucocorticoids therapy,with intrathoracic injections of glucocorticoids,with intrathoracic injections of urokinase,and with intrathoracic injections of anti-tuberculosis drugs had no significant effect on the patients' remission rate,recurrence rate,non-absorption rate of pleural effusion,pleural hypertrophy and pleural collapse,and the difference was not statistically significant.There was no significant difference in the duration of treatment and intrathoracic injection(including urokinase,glucocorticoids and anti-tuberculosis drugs)between both groups(Table 11).Follow-up analysis showed that no significant statistical difference in the remission rate and recurrence rate of tuberculosis existed between the two groups.The non-absorption rate of pleural effusion was relatively high in patients with neutrophil dominated tuberculous pleurisy,but the statistical difference had no significance between the two groups(P=0.085).There were relatively more patients with pleural exfoliation in the patient group dominated by neutrophils(P<0.05).There was no significant difference in pleural thickening and thoracic collapse between the two groups.Part ?:Clinical comparison and differentiation between NP-TPE and parapneumonic effusion1.Comparison of clinical serum and pleural effusion detection indexes between NPTPE and PPE groupsThis part of the study retrospectively collected and analyzed the clinical data of 126 patients with pleural effusion without anti-tuberculosis or anti-tumor treatment for the first time,including 23 patients with NP-TPE and 106 patients with PPE.In this study,we found that the age of patients in NP-TPE group was significantly younger than that in PPE group(P=0.009).In terms of hematological parameters,the results showed that the blood WBC,lymphocyte absolute value and CRP in NP-TPE group were lower than those in PPE patients,and the difference was statistically significant(P<0.05).At the same time,the study showed that the level of serum ALB in patients with PPE was significantly lower than that in patients with NP-TPE,which showed that inflammation could significantly increase body consumption.In addition,pfLDH in NP-TPE patients was significantly lower than that in PPE patients(564vs2557U/L,P<0.001).There was no significant difference in other parameters between the two groups.Among the eight parameter ratios,the pfLDH/pfADA(15.2vs55.62),the percentage of neutrophils/lymphocytes in pleural effusion(1.86vs13.29)and the percentage of serum LDH/lymphocytes in pleural effusion(647.5vs2130)in NP-TPE group were lower than those in PPE group(P<0.05).2.Subgroup analysis and comparison were carried out according to the age of patientsPrevious related studies have shown that age is an important factor affecting the change of pfADA level in patients with TPE.The study shows that the pfADA level of patients with age?50 years old is significantly higher than that of patients with age>50 years old.In this study,the patients are divided into two groups:Patients with age?50 years old and patients with age>50 years old for subgroup analysis.The results show that in the subgroup of patients with age?50 years old,NP-TPE patients have better blood WBC in terms of hematological parameters(6.27vs13.26×109/L,P<0.001),lymphocyte absolute value(1.11vs1.64×109/L,P=0.014),erythrocyte sedimentation rate(ESR)(40vs71mm/h,P=0.004)and CRP(45vs155mg/L,P=0.006)were lower than those in patients with PPE(P<0.05);In terms of pleural effusion parameters,the results showed that the level of LDH in NP-TPE group was significantly lower than that in PPE(689vs2471 U/L,P<0.001),In the subgroup of patients aged>50 years,the blood WBC of NP-TPE patients was lower than that of PPE patients(6.17vs 11.27)× 109/L,P=0.004);In terms of pleural effusion parameters,the results showed that the level of LDH in NP-TPE group was significantly lower than that in PPE(323vs2615 U/L,P<0.001).In addition,there was only pfLDH/pfADA in NP-TPE group(14.85vs55.44,P=0.001).3.The sensitivity and specificity of related detection indexes in the diagnosis of NPTPE and PPE patientsIn this study,we use ROC curve analysis to determine the best cut-off value of the relevant parameters.The results showed that the cut-off value of pfADA alone in the diagnosis of NP-TPE was 84U/L,whose sensitivity was 95.7%and the specificity was only 36.9%.The cut-off value of pfLDH in the diagnosis of NP-TPE was 1228.5U/L,whose sensitivity was 82.6%,and the specificity was 75.7%.Therefore,our results show that the specificity of pfADA or pfLDH alone in the diagnosis of NP-TPE is poor.In this study,we selected 8 parameters for the diagnosis and differential diagnosis of NP-TPE and PPE.The results showed that the cut-off value of pfLDH/pfADA(Rl)was 30.91,which has high sensitivity as 88.2%and high specificity as 93.5%.Part ?:Clinical significance of pfLDH/pfADA in the diagnosis of TPE1.Comparison of demographic and laboratory indexes among three groupsIn this study,we found that compared with MPE and PPE,the onset age of TPE patients(38.74±19.22)was significantly younger.The age of MPE patients was the highest with an average age of 60.99±13.04 years and the difference was statistically significant(P<0.001).The level of leukocyte in patients with TPE was the lowest,that in patients with PPE was the highest,and that in patients with MPE increased slightly(P<0.001).The median level of CRP(120.00mg/L)and ESR(74mm/h)in patients with PPE were significantly higher than those in patients with TPE and both were higher than those in patients with MPE(P<0.001).Among the three groups,the median level of serum ALB(32.6g/L)in patients with PPE was the lowest.In addition,the absolute value of blood lymphocytes in patients with TPE was the lowest,and the level in patients with PPE was the highest.The level of serum ADA in patients with TPE was significantly higher than those in PPE and MPE.There was no significant difference in serum LDH level among groups.The median ADA level in pleural fluid of TPE patients was 41 U/L,that of MPE patients was the lowest as 9U/L,and that of PPE patients was the highest as 43U/L.There was significant difference among the three groups(P<0.001).The level of LDH in pleural fluid of PPE patients was significantly increased,which was 2542U/L and higher than 449U/L of TPE patients.The difference was statistically significant(P<0.001).The median level of pleural PRO in TPE patients was 50.1g/L,which was slightly higher than that in the other two groups.The median level of pleural GLU in TPE patients was 4.62 mmol/L,which increased slightly in MPE patients.But it decreased significantly in PPE patients to 1.23 mmol/L(P<0.001).2.Comparison of laboratory parameter ratios between TPE and non-TPE patientsWe calculated the ratio of various laboratory parameters and summarized the ratio parameters with a difference of P<0.001 between TPE group and non-TPE group.PfLDH and pfADA were involved in 8(57.14%)and 7(50.00%)ratio parameters respectively.The difference p values between the two groups were p<0.001 and p=0.005 respectively.Other laboratory parameters involved were pleural GLU(P=0.038),pleural PRO(P<0.001),CRP(P<0.001),ESR(P=0.168),ALB(P<0.001),serum ADA(P=0.001)and serum LDH(P=0.074).The difference p values of ALB/pfADA,pfLDH/pfADA and pfLDH/pfGLU between TPE and PPE or MPE were less than 0.001.3.Diagnostic value of laboratory indexes and ratios in differentiating TPE from nonTPEThrough ROC analysis of laboratory indexes and ratios for distinguishing TPE and non-TPE,ROC curves of parameters whose AUC rank in the forefront were drawn,which include serum ADA,pfADA,pfLDH,pfLDH/pfADA and pfLDH/serum ADA.The results showed that among the original baseline biochemical parameters,the AUC of serum ADA in the diagnosis of TPE was the highest,which was 0.713(0.662,0.765),the best boundary value was 10.5u/l,the sensitivity was 71.9%,the specificity was only 66.5%,and the yoden index was only 0.384.In the parameter ratio,the AUC of pfLDH/pfADA in the diagnosis of TPE was the highest,which was 0.946(0.925,0.966),the best boundary value was 23.20,the sensitivity was 93.9%,the specificity was 87.0%,and the yoden index was 0.809;There were significant differences in AUC,LDH/serum ADA and serum ADA in pleural effusion(P<0.001).Therefore,pfLDH/pfADA has higher diagnostic value in differentiating TPE from non TPE.4.Diagnostic value of laboratory indexes and ratios in differentiating TPE from PPE and MPEROC analysis was performed on the laboratory indexes and ratios of TPE,PPE and MPE.The results showed that among the baseline biochemical parameters(Table 4),the AUC of TPE and PPE differentiated by pfLDH was the highest,which was 0.918(0.882,0.954),and the best boundary value was 1064.5u/l;In the parameter ratio,the AUC of pfLDH/pfADA was the highest,which was 0.964(0.939,0.989),and its best boundary value was 24.32.The difference between AUC and pfLDH and between AUC and pfADA was statistically significant(P=0.019,P<0.001).Therefore,LDH/ADA with higher diagnostic value can be recommended for the differential diagnosis of TPE and PPE.In differentiating TPE from MPE,the AUC of pfADA was 0.945(0.922,0.968)and the AUC of pfLDH/pfADA was 0.926(0.896,0.956).The difference has no significance(P=0.086).Therefore,in addition to pfADA,pfLDH/pfADA also has a certain value in the differential diagnosis of TPE and MPE.Conclusions:1.Medical thoracoscopy is an effective method for the diagnosis of TPE.Pleural biopsy and tuberculous culture can improve the positive rate of the diagnosis of TPE;The typical characteristics of TPE,such as the positive of pleural tuberculosis and pfADA>40u/L,are more common in young patients than in elderly patients.In elderly patients,when the level of pfADA?40u/L,the diagnosis of TP cannot be easily ruled out.2.Patients with NP-TPE show a stronger inflammatory response under thoracoscopy.Systemic application of hormone,local application of hormone in thoracic cavity,local anti tuberculosis treatment in thoracic cavity and intrapleural injection of urokinase had no significant effect on the long-term prognosis of patients with NP-TPE.3.Compared with the single biomarker,the ratio of LDH/ADA in pleural effusion has higher diagnostic value in identifying TPE and can identify TPE patients early,simply and economically. |
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