Inhaled Corticosteroid Is Associated With an Increased Risk of TB in Patients With COPD

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1 CHEST Originl Reserch Inhled Corticosteroid Is Associted With n Incresed Risk of TB in Ptients With COPD Jung-Hyun Kim, MD ; Ji-Soo Prk, MD ; Kyung-Ho Kim, MD ; Hye-Cheol Jeong, MD ; Eun-Kyung Kim, MD ; nd Ji-Hyun Lee, MD COPD Bckground: It is well known tht orl corticosteroid nd nti-tumor necrosis fctor- gents increse the risk of TB. However, little is known bout whether inhled corticosteroid (ICS) increses the risk of TB. We performed this study to ssess the risk of pulmonry TB mong ICS users, bsed on the presence of the rdiologic sequele of pulmonry TB. Methods: A retrospective cohort study ws performed. Between Jnury 1, 2000, nd December 31, 2005, totl of 778 ptients who hd COPD were recruited. Among them, 162 ptients were excluded ccording to the exclusion criteri. In totl, 616 ptients were followed until December 31, They were divided into four groups ccording to whether they used ICS nd whether they hd rdiologic sequele of prior pulmonry TB. Results: A totl of 20 ptients developed pulmonry TB. Kpln-Meier estimtes showed n incresed risk of pulmonry TB mong the ICS users who hd rdiologic sequele of prior pulmonry TB ( P,.001). Multivrite Cox regression showed tht ICS use ws n independent risk fctor for the occurrence of pulmonry TB in ptients who hd norml chest rdiogrph (hzrd rtio, 9.079; 95% CI, ; P 5.049) nd in ptients who hd rdiologic sequele of prior pulmonry TB (hzrd rtio, ; 95% CI, ; P 5.003). Conclusion: ICS use increses the risk of pulmonry TB in ptients with COPD nd the risk is greter in ptients who hve rdiologic sequele of prior pulmonry TB. CHEST 2013; 143(4): Abbrevitions: CRRS 5 chest rdiogrph reding nd recording system; ICS 5 inhled corticosteroid; OCS 5 orl corticosteroid; PCR 5 polymerse chin rection; RR 5 reltive risk In 2000, joint sttement of the Americn Thorcic Society nd the Centers for Disese Control nd Prevention cknowledged tht. 15 mg/d of prednisone, for month or longer, is risk fctor for TB. 1 Since tht study, 7.5 mg of prednisone or its equivlent Mnuscript received My 15, 2012; revision ccepted September 15, Affilitions: From the Division of Respirtory nd Criticl Cre Medicine, Deprtment of Internl Medicine, CHA Bundng Medicl Center, CHA University, Seongnm, South Kore. Funding/Support: The uthors hve reported to CHEST tht no funding ws received for this study. Correspondence to: Ji-Hyun Lee, MD, Division of Respirtory nd Criticl Cre Medicine, Deprtment of Internl Medicine, CHA Bundng Medicl Center, CHA University, 59 Ytp-ro, Bundng-gu, Seongnm, , South Kore; e-mil: plmjhlee@ ch.c.kr 2013 Americn College of Chest Physicins. Reproduction of this rticle is prohibited without written permission from the Americn College of Chest Physicins. See online for more detils. DOI: /chest ws found to be ssocited with n incresed risk of TB.2 Also, it is well known tht immunosuppressive therpy, such s nti-tumor necrosis fctor- gents, increses the risk of TB rectivtion. 3 Inhled corticosteroid (ICS) is frequently used by ptients with sthm or COPD. Although ICS hs fewer systemic effects thn does orl corticosteroid (OCS), it hs vrious systemic side effects. 4 Trils showed tht ICS increses the risk of pneumoni in ptients with COPD. 5,6 However, it is still uncler s to whether or not ICS increses the risk of TB. Kore is one of the endemic res of TB, nd, thus, physicins frequently see in their ptients rdiologic scrs of pulmonry TB. Becuse we use incresingly more ICS to mnge bronchil sthm nd COPD, it is very importnt to know whether ICS use increses the risk of pulmonry TB. However, no studies hve been conducted concerning the risk of TB in such Originl Reserch

2 ptient groups. Therefore, we performed this study with the hypothesis tht ICS potentites the risk of the development of ctive TB in ptients who hve rdiologic sequele of prior pulmonry TB, becuse rdiologic lesion is one of the risk fctors for the development of ctive TB. 7,8 Mterils nd Methods Study Design nd Study Groups We performed retrospective cohort study in university hospitl in Seongnm, South Kore. The institutionl review bord of the hospitl pproved this study (BD D). We retrospectively included ptients with COPD from Jnury 1, 2000, to December 31, 2005, nd then reviewed their medicl records to December 31, All ptients hd chest rdiogrph nd pulmonry function test t their first visit. If the chest rdiogrph showed ny suspicious lesions, we determined whether further dignostic tests, including sputum study, comprison with previous chest rdiogrph, or following of the chest rdiogrph t lest for 6 months to rule out n ctive TB, hd been performed. All ptients with TB scr on their initil chest rdiogrph underwent these procedures, nd only ptients without ctive TB were included. In ddition, we excluded those who hd received systemic steroid mount of. 7.5 mg of prednisone, or for durtion of. 1 month. Ptients who received chemotherpy gents for mlignnt neoplsm nd single-visit ptients were lso excluded. The remining ptients were divided into four groups ccording to whether or not they used ICS, nd ccording to whether or not they hd rdiologic sequele of prior pulmonry TB (designted s ICS with TB scr, no ICS with TB scr, ICS without TB scr, nd no ICS without TB scr ). Rdiologic Sequele of TB Using chest rdiogrph reding nd recording system (CRRS), two pulmonologists independently red the chest rdiogrphs t the time of enrollment for no evidence of TB, ctive TB, or sequele of TB. 9 They were unwre of the ptients exposure to ICS throughout the reding process. The sequele of TB were clssified into the five groups Al-Hjjj nd Johrjy 10 identified in their study: clss 1, completely cler or only liner streks; clss 2, significnt pleurl thickening; clss 3, fibronodulr densities without cvittion; clss 4, persistent cvittion; nd clss 5, lung destruction with or without bullous formtion. Following the initil independent reding of the films, the two reders rered the chest rdiogrphs for which they hd given discordnt clssifictions to mke consensus clssifictions. Dignosis of TB Using the chrt review, two pulmonologists independently identified ptients who developed TB when they met ny of the following criteri: positive culture for Mycobcterium tuberculosis; positive cid-fst bcilli smers, TB-polymerse chin rection (TB-PCR), or interferon g relese ssy with rdiologic chnge suggesting pulmonry TB; newly developed lymphocyte-dominnt pleurl effusion with n denosine deminse level. 40 IU/L; improvement of rdiologic findings fter tking nti-tb medictions under clinicordiologic dignosis; or biopsy-proven grnulom with cseous necrosis with/without TB-PCR. Ptients with nontuberculous Mycobcterium disese nd extrpulmonry TB other thn TB pleurisy were excluded. Inhled Corticosteroids The ICS included ll the forms of inhled budesonide, fluticsone, ciclesonide, nd beclomethsone, whether used lone or in combintion with n inhled b -gonist. We converted the dily dose of the ICS into n equivlent fluticsone, ccording to Figure 1. Study popultion nd study groups. ICS 5 inhled corticosteroid; PCR 5 polymerse chin rection. journl.publictions.chestnet.org CHEST / 143 / 4 / APRIL

3 the Globl Inititive for Asthm (GINA) 2010 guidelines. 11 We ctegorized them into low dose (, 500 m g/d), moderte dose ( m g/d), nd high dose ( 1,000 mg/d). Sttistics Anlysis of vrince nd Kruskl-Wllis tests were used to compre the continuous vribles. Ctegoricl vribles were compred, using x 2 test or Fisher exct test. The Kpln-Meier model ws used for TB occurrence during the study period. Discontinution of ICS, following loss, nd no TB occurrence were treted s censored. The Cox proportionl hzrd model ws used to control for possible confounding vribles such s ge, sex, BMI, smoking history, nd dibetes mellitus. We used Wld forwrd process to enter the vribles, with n entry P vlue of.05 nd n exit P vlue of.10. All dt re expressed s men SD. P vlues,.05 were considered sttisticlly significnt. Sttisticl nlyses were conducted with SPSS Sttistics, version 19 (IBM). Results Among totl of 778 ptients with COPD, we excluded 77 single-visit ptients, 45 systemic steroid users, 15 ptients who hd received chemotherpy gents for cncers, nd 21 ptients with ctive TB t enrollment. An dditionl four ptients were excluded fter chrt review becuse of the uncertinty in dignosing TB: smer-positive, culture-negtive, nd TB-PCRnegtive. Finlly, 616 ptients were entered into the study ( Fig 1 ). The men ge t the time of entry ws y. The medin durtion of the follow-up ws 1,126 dys (rnge, 5-4,017 dys). A totl of 20 ptients with TB were identified during the study period: 12 in the ICS with TB scr group, two in the no ICS with TB scr group, five in the ICS without TB scr group, nd one in the no ICS without TB scr group. Dignoses of TB were mde by positive culture for 13 ptients; by cid-fst bcilli stin with proper rdiologic findings for two ptients; nd by clinicordiologic dignosis, without bcteriologic evidence, for four ptients (including two ptients with positive TB-PCR). Only one ptient hd TB pleurisy. All four ptients who hd clinicordiologic dignosis showed clinicordiologic improvement fter nti-tb medictions. The medin time period from entry to the dignosis of TB ws 1,003 dys (rnge, 101-3,531 dys). Tble 1 shows the bseline chrcteristics of ech study group. The bseline lung function, judged by, ws more preserved in ptients who hd no rdiologic scr thn in ptients who hd rdiologic scr. In ddition, lung function ws more preserved Tble 1 Bseline Chrcteristics Chrcteristics Totl (N 5 616) ICS With TB Scr (n 5 139) ICS Without TB Scr (n 5 170) No ICS With TB Scr (n 5 114) No ICS Without TB Scr (n 5 193) P Vlue Age, y ,.001 Mle sex Height, cm Weight, kg b ,b.04 BMI, kg/m b b,.001 Follow-up durtion, medin, d 1, ,327 b 1,452 b.009, L ,.001, % predicted ,.001 Rdiologic sequele Clss Clss Clss Clss Clss Tretment history for TB b b,.001 Dibetes mellitus ICS dose Low Moderte High Current or ex-smoker GOLD stge GOLD I ,.001 GOLD II GOLD III ,.001 GOLD IV ,.001 Occurrence of TB, No ,.001 Dt re expressed s men SD or percentge, unless indicted otherwise. GOLD 5 Globl Inititive for Chronic Obstructive Lung Disese; ICS 5 inhled corticosteroid. Vribles in this group re not sttisticlly different but re not the sme s the vribles in footnote b. b Vribles in this group re not sttisticlly different, but re not the sme s the vribles in footnote Originl Reserch

4 in ptients who did not use ICS thn in ptients who used ICS. A totl of 41.1% of the ptients showed rdiologic sequele of prior TB. However, only bout 65% of ptients from the ICS with TB scr nd no ICS with TB scr groups hd tretment history for TB. In contrst, 3.5% of ptients from the ICS without TB scr group nd 1.6% of ptients from the no ICS without TB scr group hd tretment history for TB, even though they did not hve rdiologic seque le. The Kpln-Meier estimtes showed incresed TB occurrence in the ICS with TB scr group ( P,.001) ( Fig 2 ). Univrite Cox regression nlysis reveled tht the ICS with TB scr group, ICS without TB scr group, moderte- or highdose ICS use, clss 3 sequele of TB, nd bseline, 25% of the predicted vlue (GOLD [Globl Inititive for Chronic Obstructive Lung Disese] stge IV) were ssocited with n incresed risk of TB. Bseline (% predicted) ws inversely sso- cited with the risk of TB ( Tble 2 ). Multivrite Cox regression nlysis reveled tht the ICS with TB scr group nd the ICS without TB scr group were independent risk fctors for TB occurrence ( Tbles 3, 4 ). Among the 20 ptients who developed TB, nine hd tretment history for TB nd one hd repeted tretment history for pulmonry TB. A history of nti-tb medictions did not lter the risk of TB occurrence posed by ICS use. Discussion In Kore in 2010, the cse notifiction rte of pulmonry TB per 100,000 ws According to the ntionwide TB surveillnce done in 1995, 3.2% of people in Kore hd TB scr on chest rdiogrph. 13 Thus, physicins frequently meet ptients who hve history of TB, or who hve rdiologic sequele of prior TB, when they prescribe ICS. In this study, 41.1% of Figure 2. The Kpln-Meier estimtes showed tht the occurrence of pulmonry TB ws significntly incresed in the ICS with TB scr group compred with the other groups. See Figure 1 legend for expnsion of bbrevitions. journl.publictions.chestnet.org CHEST / 143 / 4 / APRIL

5 Tble 2 Univrite Cox Regression Anlysis for the Occurrence of TB Vribles Hzrd Rtio 95% CI P Vlue Age Mle sex BMI, kg/m Study group ICS with TB scr ICS without TB scr No ICS with TB scr No ICS without TB scr Reference Bseline, L Bseline, % predicted GOLD stge GOLD I Reference GOLD II GOLD III GOLD IV Dibetes mellitus Current or ex-smoker History of TB tretment ICS dose Low, Moderte ,.001 High Rdiologic sequele Clss Clss Clss Clss Clss , See Tble 1 legend for expnsion of bbrevitions. the study ptients hd rdiologic sequele. Therefore, it is of gret concern s to whether ICS use increses the risk of TB in these popultions. Although ICS is ssocited with less systemic effect compred with OCS, met-nlysis showed tht ICS use, especilly. 0.8 mg/d of fluticsone, resulted in significnt drenl suppression, 14 which suggests tht ICS use my lso increse pulmonry infections. The Towrds Revolution in COPD Helth (TORCH) study found n increse in physicin-reported pneumoni ssocited with ICS in ptients with COPD. 5 The Investigting New Stndrds for Prophylxis in Reducing Excerbtions (INSPIRE) tril lso showed incresed pneumoni in ptients with COPD who used ICS compred with those who used tiotropium. 6 Tble 3 Mutivrite Cox Regression Anlysis for the Occurrence of TB Vribles Hzrd Rtio 95% CI P Vlue ICS with TB scr ICS without TB scr No ICS with TB scr No ICS without TB scr Reference See Tble 1 legend for expnsion of bbrevition. Tble 4 Vribles Tht Did Not Enter the Eqution for Mutivrite Cox Regression Anlysis Vribles Wld Score P Vlue Bseline, % predicted Moderte-dose ICS High-dose ICS GOLD stge IV Sequele clss We used the Wld forwrd process to enter vribles with n entry P vlue of.05 nd n exit P vlue of.10. See Tble 1 legend for expnsion of bbrevitions. Although there hve been severl cse reports regrding the occurrence of TB while using ICS, 15,16 previous study, in which 32 children with sthm nd who tested positive for tuberculin were followed for 9.8 months, did not show n incresed TB risk in ICS users. 17 However, the popultion of this study my hve been smll nd the study period too short to see significnt sttisticl power. A study performed in Tiwn found n incresed risk of TB in ptients who used ICS. 18 In this study, 16 out of 554 ptients with COPD developed TB. The medin intervl to the development of TB ws 20.4 months. In popultion-bsed retrospective cse-control study using Quebec dtbses, 564 TB cses were identified from 427,648 cohort subjects over 15 yers. 19 According to the study, ny ICS use (reltive risk [RR], 1.26; 95% CI, ), current ICS use (RR, 1.48; 95% CI, ), nd current high-dose ICS use of 1,000 m g/d of fluticsone (RR, 1.97; 95% CI, ) were ssocited with n incresed risk of TB mong the subjects without OCS exposure. We hypothesized tht prior tretment of TB would diminish the risk of TB. In this study, bout 65% of ptients who hd rdiologic scr hd mediction history. However, tretment history did not ffect the risk of TB occurrence. The previous two studies showed reltionship between the dose of ICS nd the risk of TB. In the Tiwn study, ICS use of. 500 m g/d of fluticsone ws ssocited with n incresed risk of TB (hzrd rtio, 4.74; 95% CI, ; P 5.014). 18 In the Cndin study, high-dose ICS (. 1,000 m g/d of fluticsone) incresed the risk of TB mong the non- OCS users (RR, 1.97; 95% CI, ). 19 In our study, the univrite nlysis showed tht ICS use of. 500 m g/d of fluticsone incresed the risk of TB; however, the multivrite nlysis filed to show such incresed risk for TB. One possible explntion for this discrepncy is tht reltively fewer ptients used high-dose ICS in our study thn in the previous studies. Identifying nd defining rdiologic sequele is quite difficult nd subjective. We dopted the CRRS, nd two pulmonologists red the rdiogrph films Originl Reserch

6 For the epidemiologic surveys of TB nd lung disese, the CRRS showed resonble k greement of 0.69 (95% CI, ) for TB. 9 We lso clssified rdiologic sequele findings into five clsses. 10 Some ptients hd mediction history for TB but were clssified into no TB scr groups, becuse they hd no visible sequele of TB on chest rdiogrphs (3.5% in the ICS without TB scr group nd 1.6% in the no ICS without TB scr group). However, this proportion ws very smll, nd the tretment history for TB ws not sttisticlly different mong the study groups. This study is strong in tht we ssessed the ICSrelted TB risk ccording to the presence of sequele of prior pulmonry TB. However, our study lso hs some limittions. We selected ptients with COPD; thus, the selected ptients were bised towrd older mle ptients. Therefore, these results cnnot be generlized to other ptients groups, such s ptients with sthm. In ddition, the destroyed lung due to pulmonry TB cnnot be ctegorized s COPD. However, these ptients lso hve obstructive lung function bnormlities nd some use bronchodiltors nd ICS, s do ptients with COPD. We tried to prove the effects of ICS especilly on the ptients with rdiologic sequele of TB, so we did not exclude these ptients from the study group. The results were not different, despite the exclusion of the clss 4 nd 5 ptients, who hd destructive sequele (dt not shown). In ddition, the burden of TB is still intermedite to high in Kore; thus, the results of this study might not be pplicble in other prts of the world, where the prevlence of TB is low. Becuse of limittions in the study design, we could not consider the totl cumultive dose of ICS, personl dherence, or complince with ICS, which re importnt fctors when we clculte the totl mount of ICS. Also, lck of detiled informtion bout previous nti-tb tretment, such s durtion, regimens, complince, nd results (cure or not), in the ptients who reclled being treted might hve ffected the results of the study. Lstly, we could not consider the possibility of ltent TB infection t the time of enrollment becuse we only checked whether the dignostic procedure to rule out ctive TB infection hd been performed in ptients with TB scr nd none of the ptients received tuberculin skin tests or interferon g relese ssy. Further prospective studies in the lrger popultion of vrious disese entities, including bronchil sthm, or study in ptients with ltent TB infection would be interesting. Conclusions In conclusion, the use of ICS incresed the risk of TB in ptients with COPD nd the risk ws greter in ptients who hd rdiologic sequele of prior pulmonry TB. This study emphsizes the fct tht we should py more ttention to the occurrence of TB when we prescribe ICS to these ptients. Acknowledgments Author contributions: Dr J-H Lee is the gurntor of the mnuscript nd tkes responsibility for the integrity of the dt nd the ccurcy of the dt nlysis. Dr J-H Kim: contributed to the study design, reding of chest rdiogrphs, sttisticl nlyses, review of ptients medicl records, nd writing of the mnuscript. Dr Prk: contributed to the review of ptients medicl records nd peer-review of this rticle. Dr K-H Kim: contributed to the study design, review of ptients medicl records, nd peer-review of this rticle. Dr Jeong: contributed to the study design, review of ptients medicl records, nd peer-review of this rticle. Dr E-K Kim: contributed to the study design, review of ptients medicl records, nd peer-review of this rticle. Dr Lee: contributed to the design nd supervision of this study s corresponding uthor, reding of chest rdiogrphs, review of ptients medicl records, nd editing the finl version of the mnuscript. Finncil/nonfinncil disclosures: The uthors hve reported to CHEST tht no potentil conflicts of interest exist with ny compnies/orgniztions whose products or services my be discussed in this rticle. References 1. 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