Two childrenwith di¡ering outcomes after treatment for pulmonary tuberculosis diagnosed after allogeneic hematopoietic stemcell transplantation ppt

Case report Two children with di¡ering outcomes after treatment for pulmonary tuberculosis diagnosed after allogeneic hematopoietic stem cell transplantation J.W. Lee 1 , H J. Kwon 2 , P S. Jang 1 , N G. Chung 1 , B. Cho 1 , D C. Jeong 1 , J H. Kang 2 , H K. Kim 1 1 Division of Hematology and Oncology, Department of Pediatrics, 2 Division of Infectious Diseases, Department of Pediatrics, The Catholic University of Korea, Seoul, Republic of Korea J.W. Lee, H J. Kwon, P S. Jang, N G. Chung, B. Cho, D C. Jeong, J H. Kang, H K. Kim. Two children with di¡ering outcomes after treatment for pulmonary tuberculosis diagnosed after allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2011: 13: 520^523. All rights reserved. Abstrac t: Tuberculosis (TB) is a rare infec tious complication af ter hematopoietic stem cell transplantation (HSCT), but may be more signi¢cant in areas where the disease is endemic. Here, we present the clin i cal cours e o f 2 chi ld ren with ac u te lymph obl a stic leu kemi a w ho were diagnosed with pulmonary TB after allogeneic HSCT. Both patients were treated for either probabl e or possible invasive fungal infection, as well as TB. One patient, diagnosed with TB 3 months af ter HSCT, showed remittent fever and symptoms that progressed to acute respiratory distress syndrome and death, despite 3 modi¢cations to the anti-TB regimen. In contrast, another patient who was diagnosed with TB 8 months after transplantation, responded well to anti-TB medication and completed 1year of treatment with resolution of lung lesions. C o-morbid opportunistic infec tions, profound host immunosuppression early after transplantation, and p otential risk of mult i-drug resistant-TB may act as major barriers to e¡ective treat ment o f TB after HSCTdespite appropriate anti-TB medication.                                                                                       For recipients of allogeneic hematopoietic stem cell trans- plantation (HS CT), Mycobacterium tuberculosi s may act as a signi¢cant opportunistic pathogen in the early post- transplantation period, especially in areas where tubercu- los is (TB) i s en d emic . Inc ide nc e and risk fac tor s for mycobacter i al infectio n diagnosed in the post-HSCT period have been reviewed previously in large cohort s of patients (1^ 6), with factors such as matched unrelated and mismatched transplanta- tions, treatment with total body irradiation, and graft- versus-host d iseas e (GVHD) having a signi¢cant impact on TB incidence. However, studies of TB diagnosed solely in the pediatric HS CT p opulation are sc arce, and little is known of prognostic factors after initi ation of anti-TB med- ication . Most import a ntly, the severe immu nosup pressio n that characterizes the post-HSCT period may have a delete- rious e¡ect on response to anti-TB treatment. In this study, we report on 2 children who showed a di¡er- ing clinical course after treatment for pulmonaryTB diag- nosed a fter allogen eic HSCT for acute lymphoblastic leukem ia (A LL). Case reports Patient 1 The 17-year-old m al e patient had been diagnosed with Phil- adelphia chro mosome-positive ALL a nd had received matched unrelated bone marrow t ransplantation (BMT) 7 months af ter initial diagnosis. Myeloablative condition- ing regimen consisted of total body irradiation, cytarabine, cyclop hos ph a m ide (T BI-Ar a-Cy), and anti-thymoc y te r 2011 John Wiley & Sons A/S Transplant Infectious Disease . ISSN 1398-2273 Key words: tuberculosis; hematopoietic stem cell transplantation; children Correspondence to: Nak-Gyun Chung, MD, PhD, Department of Pediatrics, Seoul Saint Mary’s Hospital, Catholic University of Korea, Seocho- gu, Banpo-dong 505, Seoul 137-701, Republic of Korea Tel: 82 2 2258 6188 Fax: 82 2 588 3589 E-mail: cngped@catholic.ac.kr Received 26 November 2010, revised 9 January 2011, accepted for publication 5 February 2011 DOI: 10.1111/j.1399-3062.2011.00641.x Transpl Infect Dis 2011 520 globulin (ATG). Neu trophil recovery was not delayed, with ab s olute n e utrophi l c ou nt 40.5 Â 10 9 /L from day 13 of bone marrow infusion. He did not experience acute GVHD, and the immediate post-transplantation period was un- eventful except for cy tomegalovirus (CM V) DNAemia th at was treated preemptively with ganciclovir. Two months after t ransplantation he was readmitted for fever and dyspn e a of 1 day’s dur ation. A che st co mputed to- mography (CT) scan revealed nodular opacities consi stent with fungal pneumonia, and broad-spectrum antibiotics and intravenous amphotericin were started. Microbi ologi- cal studies were negative, and fever persisted with pro- gression of lung in¢ltrations despite changes to other antifungal agents. After a 6-day p eriod of defer vescence, fever started again on d ay 32 of admission. Sputum study done at this time stained positive for acid-fast bacilli (AFB) a nd isoniazid, rifa mpin, pyrazinamide, and ethambutol were started. A chest x-ray at this point showed signi ¢cant aggr avation of in¢ltrations i n the left l ung ¢ eld (Fig. 1). No tuberculous family or contact history was determ ined, but sputum culture showed growth of M. tuberculosis. Signs and symptoms of GVHD were not evident, and im- munosup pressive medi cation administered at the time of TB diagnosis was cyclosporine only. Peripheral blood lymphocyte study previous to the diagnosis showed 90% NK cells, with few B and T lymphocy tes. Fever continued with rapid aggravation of pneumonia despite treatment, prompting consideration of drug resistance of the TB strain to one or more of the anti-TB med ications initially given. Levo£oxacin was substituted for ethambutol, but fe- ver and pulmonary in¢ltrations failed to abate, and a sec- ond change was made to the anti-TB regimen, with cycloserine given instead of pyrazinamide. Progressive disease led to the addition of ethambutol to the 4-dr ug reg- imen. Sputum c ulture done 1 month after the initiation of anti-TB medication showed the g rowth of yeast, and lipo- so mal amphotericin was started. Throug hout the febrile period, serial serum galactomannan (GM) assays were neg- ative. Although follow-up sputum cultures for M. tuberculo- sis were negative, fever and lung i n¢ltrations failed to abate and the patient died of acute respiratory distress syndrome (AR DS) 3 9 days af ter the start of anti-TB me dication, 136 days af ter t ransplantation. S ensitivity results repor ted 37 days afte r diagnosis of TB showed the strain to be sus- ceptible to isoniazid and rifampin. Patient 2 The 14-year-old female patient had been diagnosed with T cell ALL, achieved delayed complete remi ssion and receive d granulocyte c olony-stimulating factor mobilized peripheral blood stem cell (PBSC) transplantation from her mother 4 months after initial diagnosis. Conditioning regi m en i nclude d TBI-Ara-Cy and ATG. P rompt neut rophi l engraftment occu rred, with absolute neutrophil count 40.5 Â 10 9 /L from day 11 of PB SC infusion. W|thin day 1 10 0 of transplantation, the patient had bee n treated for CMV DNAemia wi th gancicl ovir, and had been admit- ted t wice for probable invasive f ungal infec tion (IFI), according to standard criteria (7). Four months after trans- plantation, the patient had been exposedto Patient1during inpatient ca re but prophylactic isoniazid was withdrawn after 1week because of persistently elevated liver enzymes thatwerefoundconcurrentwithchronicskinandoral GVH D.The patient was subsequently diagnosed with late- o nset acute GVHD of skin, liver, and gastrointestinal tract that showed resoluti on with steroids. Eight months a fter transplantation, th e patient was re- admitted for fever. Chest CT imaging indicated in¢ltrations of the lef t upper lung ¢ eld and bronchoalveolar lavage (BAL) studies proved to be pos itive for AFB. Immunosuppressive medication administered at the time included oral cyclo spor- ine, as well as beclomethasone for previously diagnosed gut GVHD, with the latter stopped because of improved symp- toms. The patient was started on isonia zid, rifampin, pyrazinamide, and levo£oxacin. Relapse of fever and aggra- vation of chest in¢ltrations 2 weeks after starting anti-TB medication (Fig. 2), concurrent with positive tests for serum Fig. 1 . Patient 1 was a Phil adelphia chromosome-positive acute lymph- oblastic leukemia patient who was readmitted for fever and dyspnea 2 months after unrelated bone marrow transplantation. Sputum smear on day 36 of admission was acid-f ast bacilli positive, and a ch es t x-r ay at the time showed left lung in¢ ltrations (arrows). Lee et al:TB in children after allogeneic HSCT Transplant Infectious Disease 2011: 13: 520^523 521 GM, led to the initiation of amphotericin B and a switch from rifampin to cycloserine, which resulted in defervescence and improvement of chest lesions. The patient was discharged with voriconazole, as well as the 4-drug anti-TB regimen. The strain of M. tuberculosis cultured from BAL £uid proved to be sensitive to both ison iazid and rifampin, as well as other anti-TB medication admin istered. The sensitivity pro- ¢le, however, was di¡erent from that of theTB strain isolated in Patient 1, with sensitivity to aminoglyco sides to which the strain of Patie nt 1was resistant. Five months after initiation of anti-TB medica- tion, biopsy of a newly developed skin nodule showed chronic gr anu lom atous i n£ ammatio n wit h central ca seous necrosis, with positive results for M. tube rculosis PCR, and rifampinwas reinstated instead of pyrazinamide and cyclo- serine. The patient maintained this regimen for 5 months before cess ation of anti-TB m edication 1 year af ter initia- tion, with most recent imaging showing signi¢cant regres- sion of pulmonar yTB. Discussion Inc idenc e of T B a f te r alloge n e ic HS C T is sig n i ¢cantly high e r in re g ions whereTB is endemic, with re p o rte d rates ranging fro m 1.7% to 3.0% (8, 9). However, studies on the clin ic al cour s e of c hi ldre n diagnos e d with TB du r ing the post-HSCT period are few. The 2 patients presented here emphasize the major ob- stacles to e¡ective anti-TB treatment in the post-allogeneic HSCT period. One impediment, commonto bothpatients, is the presence of signi¢ca nt co-infections that may confound accurate interpretation of patient response to anti-TB treat- ment. Ou r patients were diagnosed with either probable or possible IFI, and were administered antifungal agents con- co mitant with the anti-TB re gimen. Continued fever, and persistence or aggravation of pulmonar y in¢ltrates in both children that led to modi¢cations to anti-TB treatment may have been the result of unproven fungal infections. Radio- log i c sign s more diag nost i c of fungal infection, such as air- crescent sign or cavity formation, as outlined in the revised diagnostic criteria for IFI (7 ), may have aided in di¡erenti- ation of worsening fungal in fection fromTB, but these were not evident in our patients. Despite di⁄culties, diagnostic tests including bronchoscopy should b e undertaken in order to isolate the cause of clinical aggravation in the post-HSCTsituation where multiple infections may coexi st. Second, the premature termination of isoniazid prophylaxis in Patient 2 because of elevated liver enzymes underscores the di⁄culty of administering anti-TB medication post-HSCT when hepatotoxicity may have many causes, including he- patic GVHD, veno-occlusive disease, and CMV infection. Despite treatment with an anti-TB regimen to which the M. tuberculosis strain proved t o be susceptible, Patient 1 experi enced a remittent fever course with productive co ugh, combined with gradual aggravation of pneumonia until death from AR D S. Th roughout this pe rio d, all othe r cultures and serum GM assay had been negative, with only an unidenti¢ed yeast found on sputum culture toward the end of the patient’s clinical cou rse. The patient had u nder- gone 3 changes to the anti-TB regimen with consideration of possible multi-drug resistant-TB (MDR-TB). Stu dies have con¢rmed a12^13% incidence of M. tuberculosis st rain resis- tant to any ¢rst-line anti-TB medication in Korea among newly diagnosed patients, with a 3^4% incidence of MDR- TB (10, 11). MDR-TB diagnosed after allogeneic BMT has also been reported (12). As results of TB drug sensitivit ies are delayed considerably, anti-TB modi¢cation was deemed necess a r y in our patient to counter p otential drug resistance as a cause of clinical aggravation. One major di¡erence between Patient 1 and Patient 2, wh o showed resolution of TB, is that the former’s TB was diagnosed much earlier, within day10 0 of transplantation. One study reported 9 patients withTB resolution among 11 overall a fter BMT (1); 9 of these 11 patients had TB diag- nosed within 100 days post transplantation. However, 2otherstudiesindicatethattimetodiagnosisafterHSCT was much sho r te r a mong patients who di e d f rom TB, th an Fig. 2 . Patient 2, with underlying acute lymphoblastic leukemia , was di- agnosed withtuberculosis 8 months after mismatched familial peripheral blood stem cel l transplantation. Fever restarted 2 weeks after initiation of anti-tuberculous medication, concurrent with serial positive results for seru m galactom annan, leadi n g to ampho teric in B admin i s tr ati o n . Fol- low-up imaging of Patient 2 at this time point showed persistent left up- per lobe consolidation (arrow). Lee et al:TB in children after allogeneic HSCT 522 Transplant Infectious Disease 2011: 13: 520^523 among those who survived (2, 3). A rapidly p rogress ive, fa- tal case of sepsis due to M. tuberculosis diagnosed within a few months of HS CT has also be en describe d (13). W|th regards to infectious complications, th e post-HSCT period ha s been divided into the pre -engraftment per iod , and intermediate ( day 100) and late (after day 100) recovery periods, wi th di¡erent pathogens being more predominant in each phase (14 ).Whether the T and B lymphocyte-based immune de¢ciency that characterizes the time up till the late recovery per iod renders TB slowly responsive or re- fractory to appropriate anti-TB medi cation requires fur- ther study. Such immune de¢ciency characterized by poor lymphocyte fun ction may last beyond the intermediate re- covery period, especially if the patient is diagnosed and treated for GVHD, as in the case of Patient 2. Chronic GVHD especially, which was not evident in either of the pa- tients at time of TB diagnosis, may lead to prolonged de¢- ciency of cell-mediated immunity. Adjustments to the anti- TB regimen may be done with greater caution if severely impaired host immunity, rather than microbial resistance, is more likely responsible for clinical deter ioration. One pediatric HSCT-based s tudy reported resolution of TB in all 4 patients diagnosed (8). However, co-morbid in- fections and severe host immune de¢ciency after HSCT may act as major barriers to treatment despite appropri ate medication. In summar y, we present 2 children diagnosed withTB after allogeneic HS CT, in whom the timing of TB infection, as well as ¢nal ou tc ome of treatment, were di¡er- ent. Fu rthe r studies are necess ary to con¢rm the poor prognosis of TB di agnosed early after HSCT. References 1. Roy V,Weisdorf D. Mycobacterial infections following bone marrow transplantation: a 20 year retrospective revi ew. Bone Marrow Transplant 1997; 19: 467^470. 2. Cordonnier C, Martino R,Trabasso P, et al. 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Revised de¢nitions of invasive fu ngal disease from the European Organization for Re search an d Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infec t Dis 2008; 46: 1813^1821. 8. George B, Mathews V,Viswabandya A, Srivastava A, Chandy M. Infections in children undergoing allogeneic bone ma rrow transplantation in India. PediatrTr ansplant 2006; 10: 4 8^54. 9. Yoo JH , Lee DG, Cho i SM , et al. Infectious co mplicatio ns and outco m es after allogeneic hematopoietic stem cell transplantation in Korea. Bone Marrow Transplant 2004; 34: 497^504. 10. Bai GH, Park YK, Choi YW, et al. Trend of anti-tuberculosis drug resistance in Korea, 1994^2004. Int J Tuberc Lung Dis 2007; 11: 571^576. 11. Choi JC, Lim SY, Suh GY, et al. Drug resistance rates of Mycobacterium tuberculosis at a private referral center in Korea. J Korea n Med S ci 2007; 22: 677^681. 12. Altcl as J, Lescano A, Salgueira C, et al. Multidrug-resistant tuberculosis in bone ma rrow tran splant recipient.Transpl Infect Dis 200 5; 7: 45^46. 13. Kindle rT, Schindel C, Bra ss U, Fische rT. Fatal sepsis due to Mycobacterium tubercu losis after allogeneic bone ma rrow transplantation. Bone Marrow Transplant 2001; 27: 217^218. 14. Einsele H, Ber tz H, B eyer J, et al. Infectious complications after allo geneic stem cell transplantation: epidemiology and interventional therapy strategies. Ann Hematol 2003; 82: S175^S185. Lee et al:TB in children after allogeneic HSCT Transplant Infectious Disease 2011: 13: 520^523 523 . Case report Two children with di¡ering outcomes after treatment for pulmonary tuberculosis diagnosed after allogeneic hematopoietic stem cell transplantation J.W H K. Kim. Two children with di¡ering outcomes after treatment for pulmonary tuberculosis diagnosed after allogeneic hematopoietic stem cell transplantation. Transpl