Originl Article A cross-sectionl nd follow-up study of leukopeni in tuberculosis ptients: prevlence, risk fctors nd impct of nti-tuberculosis tretment Fei-Shen Lin 1 *, Mei-Ying Wu 2 *, Wen-Jun Tu 3, Hong-Qiu Pn 4, Jin Zheng 5, Jun-Wei Shi 6, Zhong-Ting Fei 7, Rui-Mei Zhng 8, Wei-Guo Yn 9, Ming-Qun Shng 10, Qing Zheng 11, Meng-Jie Wng 12, Xi Zhng 1 1 Nnjing Chest Hospitl, Nnjing 210029, Chin; 2 The Fifth People s Hospitl of Suzhou, Suzhou 215000, Chin; 3 The Third People s Hospitl of Chngzhou, Chngzhou 213000, Chin; 4 The Third People s Hospitl of Zhenjing, Zhenjing 215005, Chin; 5 The Fifth People s Hospitl of Wuxi, Wuxi 214000, Chin; 6 The Sixth People s Hospitl of Nntong, Nntong 226011, Chin; 7 The Fourth People s Hospitl of Hui n, Hui n 223002, Chin; 8 Xuzhou Infectious Disese Hospitl, Xuzhou 221000, Chin; 9 The Second People s Hospitl of Chngshu, Chngshu 215500, Chin; 10 The Second People s Hospitl of Yncheng, Yncheng 224002, Chin; 11 The Third People s Hospitl of Yngzhou, Yngzhou 225000, Chin; 12 Deprtment of Epidemiology, West Chin School of Public Helth, Sichun University, Chengdu 610041, Chin Contributions: (I) Conception nd design: X Zhng; (II) Administrtive support: FS Lin, MY Wu; (III) Provision of study mterils or ptients: FS Lin, MY Wu, WJ Tu, HQ Pn, J Zheng, JW Shi, ZT Fei, RM Zhng, WG Yn, MQ Shng, Q Zheng, X Zhng; (IV) Collection nd ssembly of dt: FS Lin; (V) Dt nlysis nd interprettion: FS Lin, MJ Wng; (VI) Mnuscript writing: All uthors; (VII) Finl pprovl of mnuscript: All uthors. *These uthors contributed eqully to this work. Correspondence to: Xi Zhng. Nnjing Chest Hospitl, No. 215 Gungzhou Rod, Nnjing 210029, Chin. Emil: zhngxi365@sin.com. Bckground: To investigte the prevlence of nd risk fctors for leukopeni in tuberculosis ptients nd the impct of nti-tuberculosis regimens on the occurrence of leukopeni in newly treted tuberculosis ptients. Methods: A totl of 1,904 tuberculosis ptients were included in the study. A cross-sectionl survey of the prevlence of leukopeni ws initilly conducted, nd then fctors influencing leukopeni were identified using Logistic regression nlysis. Non-tretment fctors influencing peripherl blood leukocyte counts were nlyzed using univrite COX proportionl hzrds models. Covrite nlysis ws used to ssess the independent effect of different nti-tuberculosis regimens on peripherl blood leukocyte counts. Results: Being femle, dvnced ge nd longer durtion of previous nti-tuberculosis tretment (>6 month) were risk fctors for leukopeni in tuberculosis ptients, while secondry pulmonry tuberculosis, higher body mss index (BMI: 24 27.9 kg/m 2 ), nd higher degree of eduction (senior high school or bove) were protective fctors. Gender, vegetble consumption, drinking, pulmonry infection, other chronic diseses, nd use of ntibiotics were significntly ssocited with the development of leukopeni in ptients on ntituberculosis tretment. In tuberculosis ptients treted with nti-tuberculosis regimens not contining ntibiotics, peripherl blood leukocyte levels grdully declined with the prolongtion of tretment durtion. In tuberculosis ptients treted with nti-tuberculosis regimens contining ntibiotics, peripherl blood leukocyte levels showed declining trend. Conclusions: Femle ptients, ptients t dvnced ge nd recurrent tuberculosis ptients hving longer previous nti-tuberculosis tretment re high-risk popultions for leukopeni. Attention should be pid to the influence of vegetble consumption nd drinking, co-morbidities nd use of ntibiotics during ntituberculosis tretment. Keywords: Tuberculosis; leukopeni; nti-tuberculosis tretment; risk fctors Submitted My 27, 2015. Accepted for publiction Oct 28, 2015. doi: 10.3978/j.issn.2072-1439.2015.12.41 View this rticle t: http://dx.doi.org/10.3978/j.issn.2072-1439.2015.12.41
Journl of Thorcic Disese, Vol 7, No 12 December 2015 2235 Introduction Tuberculosis is chronic respirtory infectious disese cused by Mycobcterium tuberculosis. In 2012 there were 8.6 million new cses of tuberculosis nd 1.3 million tuberculosis ssocited deths worldwide (1), nd the corresponding figures in Chin were 1 million nd 44,000, respectively (2). The prevlence of tuberculosis is heterogeneous cross different countries nd regions; the prevlence is reltively low in developed countries, nd 95% of tuberculosis ptients re distributed in developing countries (3). Chin is one of 22 high tuberculosis burden countries round the world, second only to Indi (4). According to the ntionl fifth epidemiologicl smpling survey of tuberculosis in 2010 (5), the prevlence of ctive tuberculosis ws 459/1,015 in people 15 yers of ge nd older, nd incresed with ge, suggesting tht the burden of tuberculosis is still very high in Chin. Anti-tuberculosis drugs cn kill nd inhibit Mycobcterium tuberculosis, but they lso hve some side effects on different orgns, especilly the hemtologicl system (6). Mechnistic studies hve shown tht nti-tuberculosis drugs such s rifmpicin cn bind to plsm mcromoleculr proteins, promote ntibody genertion, nd form ntigenntibody complexes. When these complexes re bsorbed on leukocytes, they cn cuse leukocyte lysis nd trget cell dmge, leding to leukopeni (7-9). In study by Ngym et l. in Jpn, they found tht nti-tuberculosis drugs isonizid nd rifmpicin cn cuse leukopeni (10); Lee et l. in South Koren found tht the use of first-line nti-tuberculosis drugs cn led to leukopeni (11). In Chin, only some cse reports re showing tht initil tretment with isonizid, rifmpicin, pyrzinmide nd ethmbutol, rifpentine or levofloxcin could cuse leukopeni (12,13). But the reserches for the prevlence of nd risk fctors of leucopeni in tuberculosis ptients during the course of therpy re rre. Ptients with leucopeni hve potentil immunosuppression. The more severe leucopeni could led to the more bcteril infections (14). So it should be concerned. This cross-sectionl study nlyzed peripherl blood leukocyte levels in tuberculosis ptients, investigted the prevlence of nd risk fctors for leukopeni in tuberculosis ptients, nd conducted follow-up study of tuberculosis cses to explore the influencing fctors of leucopeni with n im to remind clinicins to py close ttention to those who hve high prevlence nd risk fctors when using ntituberculosis drugs. Mterils nd methods Subjects A totl of 1,904 tuberculosis outptients or inptients who were treted t 11 hospitls in Jingsu Province, Chin from Mrch 1, 2013 to My 31, 2013 were included in the study. They rnged in ge from 15 to 93 yers, with men ge of 46.6±19.5 yers. There were 1,308 (68.7%) mles nd 596 (31.3%) femles. There were 1,440 newly treted cses nd 464 previously treted cses. The cses with equl to or higher thn norml bseline white blood cell counts were followed up. Of ll the newly treted cses, 1,249 completed the follow-up nd 41 (3.18%) were lost to follow-up. Newly treted cses were defined s ptients who did not receive ny nti-tuberculosis therpy or hd received nti-tuberculosis therpy for less thn one month. Previously treted cses were defined s ptients who hd received ny nti-tuberculosis therpy for t lest 1 month, including newly dignosed cses, recurrent cses nd those filing initil tretment. This study ws pproved by the Ethicl Committee of Clinicl Reserch in Nnjing Chest Hospitl. All the ptients signed written informed consent nd then underwent fce-to-fce questionnire survey. The questionnire covers the following informtion: bsic informtion including gender, ethnicity, ge, resident re, degree of eduction, income, height, weight, medicl insurnce, nd life hbit; dignosis nd tretment informtion including dignosis, complictions, initil tretment or not, durtion of symptoms, dignosis nd tretment processes, nd medictions; lbortory findings including blood routine exmintion nd liver nd kidney function tests; nd follow-up informtion including tretment durtion, tretment regimen, blood routine exmintions, liver nd kidney function tests, nd body weights t 2, 4 nd 8 weeks of tretment. Sttisticl nlysis We first described bseline peripherl blood leukocyte levels in ll ptients nd clculte the percentge of ptients with leukopeni (leukocyte count <4.0 10 9 /L). Secondly, we used univrite Logistic regression nlysis to identify fctors influencing leukopeni in newly treted nd previously treted cses. In order to void missed fctors influencing leukopeni, we chose level of sttisticl significnce (nmely, α=0.1). Sttisticlly, our im ws to reduce the probbility of type II errors. Thus, entering vribles showing significnt difference (P 0.10) in
2236 Lin et l. A study of leukopeni in tuberculosis ptients univrite nlysis into multivrite Logistic regression model ws used to estimte the independent effect of ech fctor on leukopeni in tuberculosis ptients. Then we used univrite COX proportionl hzrds models to monitor the chnges in peripherl blood leukocyte levels of newly treted cses with norml bseline leukocyte levels or higher t 2, 4 nd 8 weeks fter nti-tuberculosis tretment, to describe the trend of chnges in peripherl blood leukocyte levels of tuberculosis ptients strtified by demogrphic chrcteristics, dietry hbits nd disese history (nontretment fctors), nd to nlyze the potentil importnt influencing fctors. Finlly, to describe the trend of chnges in peripherl blood leukocyte levels of tuberculosis ptients receiving different tretment regimens, we used covrince nlysis to ssess the impct of nti-tuberculosis drugs on peripherl blood leukocyte levels. All sttisticl nlyses were conducted using SPSS version 18.0. showed tht being femle nd dvnced ge (36 55 yers) were independent risk fctors (P<0.05), while secondry pulmonry tuberculosis, higher BMI (24 27.9 kg/m 2 ) nd higher degree of eduction (senior high school or bove) were independent protective fctors (P<0.05) (Tble 1). In previously treted tuberculosis ptients, univrite Logistic regression nlysis showed tht being femle, dvnced ge ( 56 yers) nd longer durtion of previous nti-tuberculosis tretment (>6 months) were risk fctors for leukopeni (P<0.10), while smoking nd drinking were protective fctors (P<0.10), which my be due to the fct tht there ws higher proportion of mles who hd smoking nd drinking hbits. Multivrite Logistic regression nlysis showed tht longer durtion of previous nti-tuberculosis tretment (>6 months) ws n independent risk fctor for leukopeni in previously treted tuberculosis ptients (P=0.04). Results A totl of 1,904 tuberculosis ptients were included in this study. They rnged in ge from 15 to 93 yers, with men ge of 46.6±19.5 yers. There were 1,308 (68.7%) mles nd 596 (31.3%) femles. Bsed on dignostic findings, 35 (1.8%) hd primry pulmonry tuberculosis, 23 (1.2%) hd disseminted tuberculosis, 1,325 (69.6%) hd secondry pulmonry tuberculosis, 334 (17.6%) hd pleurl tuberculosis, nd 187 (9.8%) hd other types of extrpulmonry tuberculosis. Prevlence of nd risk fctors for leukopeni in tuberculosis ptients This cross-sectionl study included 1,440 (75.6%) newly treted tuberculosis ptients nd 464 (24.4%) previously treted tuberculosis ptients. The bseline peripherl blood leukocyte levels of newly treted ptients is 6.4±2.6, tht of previously treted is 6.6±2.5. And the prevlence of leukopeni in newly treted ptients is 150 (10.4%), while tht of previously treted tuberculosis ptients is 42 (9.1%). In newly treted tuberculosis ptients, univrite Logistic regression nlysis showed tht being femle, dvnced ge (36 55 yers nd 56 yers) nd dibetes were risk fctors for leukopeni (P<0.10), while secondry pulmonry tuberculosis, higher BMI (24 27.9 kg/m 2 ), higher degree of eduction (senior high school or bove) nd longer durtion of symptoms (>6 months) were protective fctors (P<0.10). Multivrite Logistic regression nlysis Trend of chnges in peripherl blood leukocyte levels of newly treted cses with norml bseline leukocyte levels or higher This study included totl of 1,249 newly treted cses with norml bseline leukocyte levels or higher. After 2 weeks of nti-tuberculosis tretment, leukopeni developed in 129 (10.3%) cses. After 4 weeks of nti-tuberculosis tretment, 132 (10.6%) ptients were lost to follow-up, nd 104 (9.3%) ptients developed leukopeni. After 8 weeks of nti-tuberculosis tretment, 168 (15.0%) ptients were lost to follow-up, nd 188 (19.8%) ptients developed leukopeni. With the prolongtion of tretment durtion, the percentge of tuberculosis ptients with leukopeni grdully incresed, while peripherl blood leukocyte levels grdully declined (P<0.001) (Tble 2, Figure 1). Trend of chnges in peripherl blood leukocyte levels of tuberculosis ptients strtified by non-tretment fctors Using tretment durtion s time vrible (2, 4 nd 8 weeks of tretment), leukopeni (white blood cell count <4.0 10 9 /L) s n outcome vrible, nd demogrphic chrcteristics, dietry hbits, s well s disese relted fctors s independent vribles, we nlyzed 1,249 newly treted cses using univrite COX proportionl hzrds models. The results showed tht gender, vegetble consumption, drinking, pulmonry infection, other chronic diseses, nd use of ntibiotic were significntly ssocited with the development of leukopeni in tuberculosis ptients
Journl of Thorcic Disese, Vol 7, No 12 December 2015 2237 Tble 1 Multivrite Logistic regression nlysis of fctors ffecting prevlence of leukopeni in newly treted tuberculosis ptients Vrible β Wld P OR (95% CI) Gender Mle 1.00 Femle 0.65 12.49 <0.001 1.92 (1.34 2.76) Age (yers) 15 35 1.00 36 55 0.52 4.68 0.03 1.67 (1.05 2.67) 56 0.24 0.84 0.36 1.27 (0.76 2.09) Degree of eduction Below senior high school 1.00 Senior high school nd bove -0.49 5.52 0.02 0.61 (0.41 0.92) BMI (kg/m 2 ) <24 1.00 24 27.9 0.76 3.92 0.048 0.47 (0.22 0.99) 28 0.84 0.65 0.42 0.43 (0.06 3.34) Dignosis Primry pulmonry tuberculosis 1.00 Disseminted tuberculosis 0.13 0.02 0.88 0.88 (0.17 4.39) Secondry pulmonry tuberculosis 1.01 4.52 0.03 0.37 (0.15 0.92) Pleurl tuberculosis 0.51 1.06 0.30 0.60 (0.23 1.59) Other extrpulmonry tuberculosis 0.88 2.77 0.10 0.41 (0.15 1.17), djusted gender, ge, degree of eduction, BMI, dignosis. OR, odds rtio; CI, confidence intervl; BMI, body mss index. Tble 2 Trend of chnges in peripherl blood leukocyte levels of newly treted ptients on nti-tuberculosis tretment Leukocyte count, n (%) Time point Men ± SD (10 9 /L) Below norml Norml or higher Bseline 6.74±2.47 1,249 (100.0) Week 2 6.07±2.06 129 (10.3) 1,120 (89.7) Week 4 b 6.03±1.80 104 (9.3) 1,013 (90.7) Week 8 c 5.61±1.93 188 (19.8) 761 (80.2) F/χ 2 55.65 39.16 P <0.001 <0.001, LSD test, men difference = 0.67, P<0.001, compred with bseline vlue; b, LSD test, men difference = 0.71, P<0.001, compred with bseline vlue; c, LSD test, men difference = 1.13, P<0.001, compred with bseline vlue. SD, stndrd devition. Men leukocyte counts (10 9 /L) 8 7.5 7 6.5 6 5.5 5 4.5 4 0 2 4 8 Time (week) Figure 1 Trend of chnges in men peripherl blood leukocyte counts of newly treted ptients on nti-tuberculosis tretment. fter nti-tuberculosis tretment (P<0.05), suggesting tht the bove fctors should be controlled when nlyzing the impct of use of nti-tuberculosis drugs on leukopeni in tuberculosis ptients (Tble 3). Impct of nti-tuberculosis drugs on the trend of chnges in peripherl blood leukocyte levels of tuberculosis ptients Of 1,249 newly treted tuberculosis ptients, 882 (70.6%) were treted with first-line nti-tuberculosis drugs, minly
2238 Lin et l. A study of leukopeni in tuberculosis ptients Tble 3 Trend of chnges in peripherl blood leukocyte levels of newly treted tuberculosis ptients nd univrite COX proportionl hzrds nlysis of risk fctors for leukopeni Bseline leukocyte Vrible count (10 9 /L) (men ± SD) Leukocyte count (10 9 /L) (men ± SD) Week 2 Week 4 Week 8 Ptient number, n=1,249 Leukopeni b, n=129 (%) Leukocyte count (10 9 /L) (men ± SD) Ptient number, n=1,117 Leukopeni b, n=104 (%) Leukocyte count (10 9 /L) (men ± SD) Ptient number, n=949 Leukopeni b, RR (95% CI) n=188 (%) Gender Mle 6.94±2.56 6.17±2.05 845 76 (9.0) 6.17±1.79 756 59 (7.8) 5.77±1.98 637 113 (17.7) 1.00 Femle 6.33±2.20 5.85±2.07 404 53 (13.1) 5.73±1.80 361 45 (12.5) 5.28±1.79 312 75 (24.0) 1.49 (1.20 1.85) Vegetble consumption Occsionlly c 6.15±1.78 5.81±2.58 22 4 (18.2) 6.53±2.54 16 2 (12.5) 7.15±4.21 11 1 (9.1) 1.39 (1.05 1.85) 3 times/week 6.79±2.20 6.39±1.96 213 14 (6.6) 6.27±1.79 176 9 (5.1) 5.80±1.99 122 21 (17.2) Dily 6.74±2.54 5.99±2.05 1,009 111 (11.0) 5.97±1.79 921 92 (10.0) 5.56±1.88 814 166 (20.4) Drinking No 6.60±2.40 5.99±2.09 790 94 (11.9) 5.98±1.83 701 67 (9.6) 5.50±1.89 600 126 (21.0) 0.80 (0.67 0.96) Occsionlly 7.01±2.56 6.18±1.96 358 32 (8.9) 6.05±1.82 326 34 (10.4) 5.85±2.07 274 47 (17.2) Frequently 6.92±2.68 6.27±2.14 98 3 (3.1) 6.38±1.45 88 2 (2.3) 5.61±1.69 73 15 (20.5) Pulmonry infection No 6.44±2.14 6.09±2.10 891 87 (9.8) 5.89±1.79 807 87 (10.8) 5.64±1.92 667 108 (16.2) 1.00 Yes 7.49±3.02 6.01±1.97 358 42 (11.7) 6.39±1.80 310 17 (5.5) 5.54±1.96 282 80 (28.4) 1.40 (1.12 1.75) Other chronic diseses No 6.71±2.46 6.07±2.00 1,048 98 (9.4) 6.00±1.81 945 92 (9.7) 5.64±1.96 803 145 (18.1) 1.00 Yes 6.88±2.52 6.09±2.39 201 31 (15.4) 6.20±1.79 172 12 (7.0) 5.42±1.78 146 43 (29.5) 1.50 (1.16 1.94) Use of ntibiotics No 6.62±2.25 6.02±1.91 906 82 (9.1) 5.88±1.71 847 84 (9.9) 5.56±1.78 719 127 (17.7) 1.00 Yes 7.06±2.96 6.21±2.42 343 47 (13.7) 6.50±2.01 270 20 (7.4) 5.78±2.34 230 61 (26.5) 1.42 (1.13 1.78), chemotherpy drugs were not used in ll newly treted cses, not nlyzed; b, peripherl blood leukocyte count <4.0 10 9 /L; c, <3 times/week. SD, stndrd devition; RR, risk rtio; CI, confidence intervl.
Journl of Thorcic Disese, Vol 7, No 12 December 2015 2239 Tble 4 Trend of chnges in peripherl blood leukocyte levels of tuberculosis ptients treted with different nti-tuberculosis regimens not contining ntibiotics First-line regimens First-line regimens + second-line drugs Time point Men ± SD (10 9 /L) Ptient number Leukopeni (%) Men ± SD (10 9 /L) Ptient number Leukopeni (%) Bseline 6.51±2.17 6.80±2.45 Week 2 6.00±1.90 636 50 (7.9) 6.16±1.88 d 112 11 (9.8) Week 4 5.82±1.70 b 591 65 (11.0) 5.95±1.74 e 112 13 (11.6) Week 8 5.53±1.74 c 487 81 (16.6) 5.68±2.02 f 95 17 (17.9) F/χ 2 25.93 20.52 6.66 2.89 P <0.001 <0.001 <0.001 0.09, LSD test, men difference = 0.52, P<0.001, compred with bseline vlue; b, LSD test, men difference = 0.67, P<0.001, compred with bseline vlue; c, LSD test, men difference = 0.97, P<0.001, compred with bseline vlue; d, LSD test, men difference = 0.62, P=0.02, compred with bseline vlue; e, LSD test, men difference = 0.89, P=0.001, compred with bseline vlue; f, LSD test, men difference = 1.15, P<0.001, compred with bseline vlue. SD, stndrd devition. Tble 5 Trend of chnges in peripherl blood leukocyte levels of tuberculosis ptients treted with different nti-tuberculosis regimens contining ntibiotics First-line regimens First-line regimens + second-line drugs Time point Men ± SD (10 9 /L) Ptient number Leukopeni (%) Men ± SD (10 9 /L) Ptient number Leukopeni (%) Bseline 6.94±2.78 7.47±3.23 Week 2 5.98±2.19 268 41 (15.3) 6.96±2.64 d 66 5 (7.6) Week 4 6.47±1.93 b 204 15 (7.4) 6.60±2.29 e 59 4 (6.8) Week 8 5.57±2.08 c 177 53 (29.9) 6.67±3.02 f 46 5 (10.9) F/χ 2 14.86 12.31 1.27 0.32 P <0.001 <0.001 0.29 0.57, LSD test, men difference = 0.98, P<0.001, compred with bseline vlue; b, LSD test, men difference = 0.47, P=0.03, compred with bseline vlue; c, LSD test, men difference = 1.37, P<0.001, compred with bseline vlue; d, LSD test, men difference = 0.53, P=0.26, compred with bseline vlue; e, LSD test, men difference = 0.85, P=0.09, compred with bseline vlue; f, LSD test, men difference = 0.83, P=0.12, compred with bseline vlue. SD, stndrd devition. 2 3HRZE(S)/4 10HR(E) chemotherpy regimens; 200 (16.0%) were treted with first-line nti-tuberculosis drugs combined with second-line drugs, nmely, firstline tretment regimens combined with second-line drugs such s 4-minoslicylic cid, mikcin, ofloxcin or levofloxcin; only 8 (0.7%) were treted with second-line nti-tuberculosis drugs (due to the number of cses ws too smll, they were not included in the dt nlysis); nd nother 159 (12.7%) were treted with unknown drugs, who were not included in the dt nlysis. The peripherl blood leukocyte levels of tuberculosis ptients treted with different regimens t different time points fter tretment, nd the trend of leukocyte chnges re shown in Tbles 4 nd 5. [Note: 2 3HRZE(S)/4 10HR(E): isonizid, rifmpicin, pyrzinmide, ethmbutol with or without streptomycin for 2 3 months, then isonizid, rifmpicin with or without ethmbutol for 4 10 months]. As shown in Tble 3, unevenly distributed fctors such s gender, dietry hbits, nd co-morbidities hd significnt effect on peripherl blood leukocyte levels of tuberculosis ptients. After controlling the bove fctors using covrince nlysis, we ssessed the independent effect of nti-tuberculosis therpy on peripherl blood leukocyte levels of tuberculosis ptients, nd estimted the djusted men peripherl blood leukocyte counts t different time points different tretment. The ptients were divided into two groups bsed on the use of ntibiotics or not. According to the results of nlysis of covrince, fter controlling for gender, drinking, vegetble consumption, pulmonry infection, other chronic diseses, nd bseline levels of peripherl blood leukocytes, peripherl blood leukocyte counts in
2240 Lin et l. A study of leukopeni in tuberculosis ptients Men leukocyte counts (10 9 /L) Figure 2 Trend of chnges in peripherl blood leukocyte levels of ptients who received different regimens not contining ntibiotics. Men leukocyte counts (10 9 /L) 8 7.5 7 6.5 6 5.5 5 4.5 8 7.5 7 6.5 6 5.5 5 4.5 4 4 First-line regimen Combintion of first- nd second-line regimens 0 2 4 8 Time (week) First-line regimen Combintion of first- nd second-line regimens 0 2 4 8 Time (week) Figure 3 Trend of chnges in peripherl blood leukocyte levels of ptients who received different regimens contining ntibiotics. ptients receiving different tretments did not differ significntly t 2, 4 nd 8 weeks (P>0.05), suggesting tht different nti-tuberculosis regimens, nmely first-line regiments nd first-line regiments combined with secondline drugs, hd no sttisticlly significnt effect on the levels of peripherl blood leukocytes (Tble 5). On the other hnd, bsed on the djusted men peripherl blood leukocyte counts t different time points estimted by covrince regression nlysis, it ws found tht in ptients without use of ntibiotics, peripherl blood leukocyte levels showed grdully declining trend with the prolongtion of the use of nti-tuberculosis drugs (P<0.001), while in ptients with use of ntibiotics, peripherl blood leukocyte levels showed decline trend initilly, but decresed slow or slightly rebounded subsequently, lthough they were still below the bseline levels (Figures 2 nd 3). Discussion Currently, the burden of tuberculosis is high in Chin, where the disese is chrcterized by high prevlence, high rte of drug resistnce, high mortlity, nd high morbidity (15). Anti-tuberculosis drugs chieve the gol of tretment of tuberculosis by ltering the bsic biologicl process fter entering into the humn body, but they often result in some dverse rections, including those ffecting the hemtologicl system, digestive system, kidney nd liver function nd the centrl nervous system (15), with the hemtologicl system being one of the most commonly ffected systems (6). The present study nlyzed the chrcteristics of tuberculosis ptients with leukopeni by investigting the prevlence of nd risk fctors for leukopeni in tuberculosis ptients, nd explored the impct of nti-tuberculosis drugs on peripherl blood leukocyte counts of tuberculosis ptients by conducting follow-up study of newly treted tuberculosis ptients nd previously treted tuberculosis ptients, thus providing bsis finding for clinicins to be cutious when fcing the ptients with high risk of leucopeni during the therpy course. Chrcteristics of tuberculosis ptients with leukopeni This study found tht in newly treted tuberculosis ptients, the prevlence of leukopeni ws higher in women, which is consistent with the finding by Lee et l. (11). This my be becuse women s immune function is lower thn men s. In ddition, the prevlence of leukopeni ws higher in older ptients, which my be ssocited with decresed immune function in the elderly (16). These findings suggest tht specil ttention should be pid to hemtologicl system nd immune system functions of femle nd elderly tuberculosis ptients in the dignosis nd tretment of tuberculosis. We found tht the prevlence of leukopeni in ptients with higher eduction degree ws lower, which my be becuse such ptients hd good helth nd lifestyle hbits nd more exercise tht could enhnce their immunity. This suggests tht ptients with tuberculosis should cultivte good helth nd lifestyle hbits nd enhnce exercise to improve their immunity. Ptients who ccept high degree of eduction indictes more understnding nd complince of the disese. Otherwise, resonble diet structure my
Journl of Thorcic Disese, Vol 7, No 12 December 2015 2241 be fctor of voiding leucopeni. Also, the prevlence of leukopeni in ptients with higher BMI ws lower. Higher BMI is often ssocited with reltively bundnt intke of nutrients, nd studies hve found tht ptients with higher protein contents hve elevted levels of CD4 + T lymphocytes, which cn enhnce the immune function through secretion of lymphtic fctors (17), while the vegetble diet ws ssocited with n incresed risk of leukopeni. The reson might be tht the ptients prefer vegetrin diet my tke less ft nd protein, which will cuse the lck of feedstock of blood. In ddition, we found tht the prevlence of leukopeni in ptients with secondry pulmonry tuberculosis ws lower. This my be becuse T cell-medited immune memory responses to secondry tuberculosis infection were fster thn immune responses to primry tuberculosis infection (15). In ddition, this study found tht the prevlence of leukopeni in previously treted ptients with longer previous nti-tuberculosis tretment durtion (>6 months) ws higher, which is consistent with the previous finding (18). In such ptients, immune system function often grdully declines, nd the bility to defend nd remove pthogenic gents is wekened. As result, pulmonry complictions such s infection often occur, which cn led to reduced leukocyte counts. Impct of nti-tuberculosis drugs on peripherl blood leukocyte counts of tuberculosis ptients In tuberculosis ptients treted with nti-tuberculosis regimens not contining ntibiotics, the prevlence of leukopeni grdully incresed nd peripherl blood leukocyte levels grdully declined with the prolongtion of tretment durtion. After controlling for gender, drinking, vegetble consumption, pulmonry infection, other chronic diseses, nd bseline levels of peripherl blood leukocytes, peripherl blood leukocyte counts in ptients receiving different tretments did not differ significntly t different time points, suggesting tht both first-line regiments nd first-line regiments combined with second-line drugs hd no sttisticlly significnt effect on the levels of peripherl blood leukocytes t different time points. However, the levels of peripherl blood leukocytes showed grdully declining trend in ptients receiving ny of the tretment regimens. Mechnistic studies hve shown tht ntituberculosis drugs s hptens re ttched to the surfce of blood leukocytes, form complexes, nd induce the genertion of nti-complex ntibodies, whose mjor prts cn be engulfed by mcrophges. Anti-tuberculosis drugs cn lso bind to plsm mcromoleculr proteins, promote ntibody genertion, nd form ntigen-ntibody complexes. When these complexes re bsorbed on leukocytes, they cn cuse leukocyte lysis nd trget cell dmge, leding to leukopeni (7,11). The results of our study lso demonstrte tht nti-tuberculosis drugs cn cuse leukopeni in tuberculosis ptients, nd peripherl blood leukocytes show declining trend with the prolongtion of nti-tuberculosis tretment durtion. In tuberculosis ptients treted with nti-tuberculosis regimens contining ntibiotics, the prevlence of leukopeni grdully incresed nd peripherl blood leukocyte levels showed declining trend in ptients treted with first-line regimens, but the decline in peripherl blood leukocyte levels ws not obvious in ptients treted with first-line regimens combined with second-line ntituberculosis drugs. After controlling for other nontretment fctors, the impct of different tretments on peripherl blood leukocyte counts t different time points showed no significnt differences, nd with the prolongtion of tretment durtion, peripherl blood leukocyte counts decresed slow or slightly rebounded. The possible explntion is tht ntibiotic tretment initilly leds to pronounced decrese in leukocyte count. The use of ntibiotics improves the bility of mcrophges to engulf bcteri, enhnces the bctericidl effect of polymorphonucler leukocytes nd mcrophges nd thereby improves the coordinted bctericidl effects of the immune system (19). As result, peripherl blood leukocyte counts decresed slow or slightly rebounded. Conclusions To sum up, femle ptients, ptients t dvnced ge nd recurrent tuberculosis ptients hving longer previous nti-tuberculosis tretment re high-risk popultions for leukopeni, while those with higher eduction level, higher BMI, nd secondry pulmonry tuberculosis re ssocited with lower prevlence of leukopeni. Anti-tuberculosis drugs cn ffect the occurrence nd development of leukopeni, while ptients living hbits such s vegetble consumption nd drinking, co-morbidities nd the use of ntibiotics my lso ffect the development of leukopeni. These findings suggest tht clinicins should py ttention to vrious influencing fctors during nti-tuberculosis tretment so s to be ble to promptly find the chnges of the hemtologicl system nd give timely symptomtic
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