Tuberculosis in Hematopoietic Stem Cell Transplant Recipients

Jéssica Fernandes Ramos1, Marjorie Vieira Batista1, Silvia Figueiredo Costa1,2

1 Group of Infection in immunocompromised patients of Hospital das Clinicas of University of São Paulo, Brazil.
2 Department of Infectious Diseases, Medical School, University of São Paulo, São Paulo, Brazil.

Correspondence to: Professor Silvia Figueiredo Costa. Department of Infectious Diseases, Medical School, University of São Paulo, Brazil. E-mail: costasilviaf@ig.com.br and silviacosta@usp.br
Published: November 4, 2013
Received: July 30, 2013
Accepted: October 16, 2013
Meditter J Hematol Infect Dis 2013, 5(1): e2013061, DOI 10.4084/MJHID.2013.061
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This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Abstract
Literature on tuberculosis (TB) occurring in recipients of Hematopoietic Stem Cell Transplant (HSCT) is scanty  even in countries where TB is common. Most reports of TB in HSCT patients were from ASIA, in fact the TB incidence ranging from 0.0014 (USA) to 16% (Pakistan). There are few reports of TB diagnosis during the first two weeks after HSCT; most of cases described in the literature occurred after 90 days of HSCT, and the lung was the organ most involved. The mortality ranged from 0 to 50% and is higher in allogeneic HSCT than in autologous. There is no consensus regarding the screening with tuberculin skin test or QuantiFERON-TB gold, primary prophylaxis for latent TB, and whether the epidemiologic query should be emphasized in developing countries with high prevalence of TB.

Introduction
Hematopoietic Stem cell transplant (HSCT) recipients have severe impairment in cell-mediated immunity as result of the conditioning regimen, immunosuppressive therapy and graft-versus-host disease (GVHD).[1,2] Accordingly, they are susceptible to bacterial, viral, and fungal infections. Mycobacterial infections can also occur in these patients, although the incidence is not high, even in countries where tuberculosis (TB) is common.[2] TB in this population of patient is mainly due to reactivation of latent infection.[2] However, in country where TB is endemic, pulmonary tuberculosis could be due to a new infection.
Data from the United States showed that the incidence of mycobacterium infection (MBI) among HSCT ranges from 0, 0014 % to 3%.[1,3-5] Countries in which the prevalence of tuberculosis in the general population is higher than it is in the United States have reported incidences varying from 1.6% in Spain[6] and Turkey,[7] 8.57% in Hong Kong and Taiwan to 16% in Pakistan.[8-11]
There are few reports of TB diagnosis during the first two weeks after HSCT (Table 1). Most of cases described in the literature occurred after 90 days of HSCT.[12-28]
The incidence of TB in HSCT ranged from 0, 0014% to 16% (Table 1). The diagnosis of TB varied from +21 to +1410 (median of 257, 2 days) after the HSCT. The lung was the organ most often involved. Most of cases were described in allogeneic HSCT, and the mortality in this type of HSCT was high, varying from to 0% to 50% (Table 1).
There is no consensus regarding the screening with tuberculin skin test or QuantiFERON-TB gold and primary prophylaxis for latent TB.[29-33]

Table 1. Clinical and radiological manifestation of tuberculosis in HSCT recipients

TB Risk Factors
The increased risk of tuberculosis in this setting could be explained by severely impaired cell-mediated immunity as a result of their underlying illness and conditioning chemotherapy. However, there is a lack of prospective studies on TB in HSCT and the clinical, radiological and epidemiological data are based on case reports and retrospective analysis with a small number of patients.[27,34,35,37] Previous study had showed the main risk factors for tuberculosis, comparing to control group, were allogeneic transplantations with  unrelated donors and total body irradiation (TBI), with a relative risk (RR) of 23.9 and 4.9 respectively (p<0.05), and chronic GVHD with RR of 3.6 (p<0.05).[34] Another retrospective study observed that the majority of allogeneic patients with post-transplant tuberculosis received corticosteroids for GVHD.[27] Patients with chronic GVHD have a marked delay of T cell subset recovery with low numbers of CD4 cells being present. As this period of impairment of T cell function may be indefinite in the presence of chronic GVHD, it might contribute to an increased predisposition to tuberculosis.[35-37]

Symptoms of TB diseases
The clinical presentation of tuberculosis in patients undergoing HSCT may have a wide range of signs, symptoms and radiological findings (Table 1). Tuberculosis following conventional HSCT usually presents indolent clinical courses. The lung is the most common site of the disease, and the usual manifestations are fever, cough, dyspnea and hypoxemia (Table 1). Although the clinical and radiographic presentation of TB in the HSCT population usually mimics that in the non-transplant population, atypical presentations have been described, such as diffuse alveolar hemorrhage.[34] In immunocompromised host patients, the radiological finding could be mitigated or absent on chest x-ray and on this panel the CT-scan provided additional information to help diagnose pulmonary TB.[38]
In regard to the radiologic features of pulmonary tuberculosis in HSCT recipients, recent studies evaluated chest X-ray[10] and CT-scan.[7] The chest X-ray abnormalities were air-space consolidation (100%) and nodules (80%). On chest CT scans, the most common parenchymal lesions were consolidation (100%), nodules (71%), tree-in-bud appearance (43%), and ground-glass opacity (43%). Cavities were present on CT scans in only 14% of the study patients and lymphadenopathies were noted in 71%.

TB Diagnosis
A suggestive clinical and radiologic finding is not enough to allow initiating specific treatment in patients submitted to HSCT, as recommended in populations of high endemic TB countries. The bacteriological diagnosis is crucial once the incidence is low and differential etiology should be excluded.
Similarly to other scenarios, the main challenge is to obtain a result as fast as possible to start appropriate treatment and establish environmental infection control measures.[2]
Thus, the recommendation is to detect the presence of acid-fast bacilli (AFB) in samples as soon as possible and that these samples should be cultured for identification and antimicrobial susceptibility testing.[39] Some authors had already reported cases of transplanted patients with disseminated non-tuberculosis mycobacteria infection and drug resistant TB, reinforcing the importance of such complimentary tests.[40]
An important obstacle to a fast invasive diagnostic test is the clinical condition characterized by bone marrow suppression (anemia, thrombocytopenia), although some studies showed that investigational procedures like lung CT guide-biopsy are efficacious and safe in this population.[41]
A recently published review of 56 cases of tuberculosis in HSCT, showed that only 55% of cases were diagnosed with culture, whereas acid-fast bacilli (26%) was the second most common approach for diagnosis and histology was responsible for 20,3%.[2]
Molecular methods are increasingly used in diagnosis since they are faster than mycobacterial cultures (3-6 weeks) and have the potential role to determine species. However,  there are still some issues in interpreting  mycobacterial DNA in respiratory samples (Table 2).[43,44,46] Lee et al.[45] studied real time PCR in CT guided BAL in 99 patients unable to produce sputum samples or with AFB negative result: PCR showed a positive predictive value in 81% out of 27 patients with confirmed TB, although with a lower sensitivity.

Table 2. Diagnostic methods characteristics and reported sensitivity and specificity for general population. AFB=Acid Fast Bacilli
In general population molecular tests are increasingly used, and  several guidelines as UK most recent recommendations (2011) from the National Institute for Health and Clinical Excellence (NICE) on the diagnosis of latent tuberculosis and of active tuberculosis even mention these methods.[47]
The common approach is to use rapid diagnostic tests for Mycobacterium tuberculosis complex (M tuberculosis, M bovis, M africanum) on bronchial specimens of patients only if rapid confirmation would alter the patient’s care or before conducting a large contact tracing initiative. Such tests are not recommended  for pleural, cerebrospinal fluid, or urine in order to exclude the diagnosis of TB as they have a high false negative rate.[48]
The Xpert MTB/RIF assay, which enables simultaneous detection of Mycobacterium tuberculosis (MTB) and rifampicin (RIF) resistance, was endorsed by World Health Organization (WHO) in December, 2010. This assay was specifically recommended for use as the initial diagnostic test for suspected drug-resistant or HIV-associated pulmonary tuberculosis. One Xpert MTB/RIF test on sputum detects 90% of pulmonary tuberculosis (99% of smear-positive disease and about 75% of smear-negative disease). Such high sensitivity of Xpert MTB/RIF for rifampicin resistance is accompanied by some false-positive results and confirmatory drug sensitivity testing is needed.[49]
A different test based on antigen detection was already studied in the general population. Rajpal and colleagues studied an India tribal population where nearly 80% suffers from malnutrition. In this group, they compared 41 patients with active TB (90% confirmed with AFB and/or culture positive) with 87 controls to three different diagnostic blood tests: ELISA based TB antigen, ADA and in house IS6110 based PCR. The positivity of PCR assay in TB patients was around 48.78%, which was found to be significant (p < 0.0001) than the control group (2.30%). Mean absorbance of Antigen 85 ELISA in TB group was significantly (p<0.05) higher than non-TB control group. There was no immunocompromised patient (HIV or immunossupressors) in their cohort.[50]
Blood TB PCR is still not standardized, but offers great promise for the rapid and specific diagnosis. Indian investigators recently evaluated a multiplex nested PCR method targeting insertion sequence 6110 and MPB64 sequence in 130 samples. The sensitivity and specificity of the assay was respectively 95.7% and 100% with a negative predictive value of 99.2%.[51]
Molecular techniques such as polymerase chain reaction (PCR) was rarely used for diagnosis in HSCT patients reported (3.7%), and are mainly used in combination with other diagnostic approach.[2]
There are few studies, however, comparing accuracy of different tests in this transplant setting, and most of the data come from general population, mainly from pulmonary TB.[46,57]

Treatment of TB
The use of drugs against TB should be in agreement with local recommendations, based on surveillance of mycobacterial resistance patterns to antimicrobial. Since the first drugs available in 1940s, the subsequent emergence of resistant species led to combination therapy.[53,54] In fact the treatment of TB in HSCT recipients are similar to the general population with two important differences: the duration of therapy, normally longer, and the drug regimen, because interaction was reported between rifamycins (rifampicin and rifabutin) and immunosuppressive drugs like cyclosporine.
The approach recommended by World Health Organization, North American and European guidelines is a 6-month chemotherapy regimen using a combination of 4 drugs (rifampicin, isoniazid, ethambutol, and pyrazinamide for 2 months, followed by rifampicin and isoniazid for 4 months) with cure rates of approximately 90% of drug-susceptible cases.[54-56] The Brazilian recommendation is in agreement with other countries (Table 3).[57]

Table 3. Recommended treatment schedule for TB for a patient with more than 110 lb.
Most of the reports with combination therapy in HSCT patients had shown good results. La Camara and colleagues treated nineteen patients with a median of three drugs. Seventeen received more than 3 months of treatment and all were cured. An interesting finding of this study was the interaction between cyclosporine with rifampicin, with three patients presenting a decrease in cyclosporine levels, two of whom with worsening in chronic GVHD. Three patients (18%) developed hepatotoxicity.[56]
In more pronounced immunosuppression state like in unrelated cord blood transplantation there is already TB cases reported[52,53] In this cases the therapy of choice, even with possible drug interaction, was the classic four drugs of therapeutic guidelines.
The treatment of tuberculosis (TB) is complicated by drug-induced hepatotoxicity, one of the leading types of drug-induced liver injury (DILI). Current recommendations are to obtain baseline biochemical testing in all patients being treated for TB, but there is a lack of evidence, these recommendations are based on observational studies and expert opinion. It is important to notice the phenomenon of adaptation (i.e., temporary stress or mild injury to the liver) that occurs in 20% or more of patients treated with anti-TB medications and often results in cessation or interruption of treatment.[62]
Some authors advocate that concerted efforts at identifying biomarkers or hepatic enzymes trending to prevent severe DILI.[63]
Another issue of therapy is the interaction between rifampicin and immunosuppressive drugs used in GVHD prophylaxis. Rifampicin reduces the serum levels of cyclosporine and sirolimus.[56] Rifabutin could be an alternative, because it is a weaker inducer of cytochrome P450, but the clinical experience is limited with just one report.[57] It is common in most of treatment descriptions tapering of cyclosporine and temporary addition of corticosteroids.
In spite of some prescribing practices and poor patient compliance had increased the risk of selection of drug-resistant (DR) strains of Mycobacterium tuberculosis, which are more difficult and more expensive to treat, reports of tuberculosis resistant in HSCT are rare. Cordonnier and colleagues reported 20 cases of tuberculosis. Susceptibility test results were available in 12 cases and none was resistant to any drug tested.[11] Nevertheless a case of MDR-TB (which is resistance to rifampicin and isoniazid) have already been published in this population and was successfully treated with cycloserine 500mg, levofloxacin 500mg, PAS 10g and kanamycin 1g three times a week during 18 months, with no relapse.[64]
Fortunately a portfolio of promising new TB drugs is on the horizon. Eleven new or repurposed tuberculosis drugs are in clinical investigation, 3 in phase 3 trials, which are evaluating the possibility to shorten treatment to 4 months, using strategies like inclusion of a third-generation fluoroquinolone or rifapentine (a semisynthetic rifamycin that has a longer half-life than rifampicin) and compounds as linezolid, probably a limited option in HSCT patients due the myelotoxicity when used for long period.[65]
Some perspectives in TB treatment with adjunct immunotherapies should require caution in HSCT recipients, since the safety regarding GVHD or bone marrow rejection is not well studied.[66]

TB Latent
In some countries the use of tests based on interferon release assays appear to be useful to determine latent TB infection, but further studies are needed to define their utility in immunocompromised host.[42,43]
TB screening using TST or QuantiFERON-TB gold (QFT-GIT) in HSCT is controversial.[29-32] T cells play an important role in protective immunity against tuberculosis. The question arises as to whether TST-specific memory T cells are transferred from the marrow donor to the recipient and persist in the long-term.[12]
The Infectious Diseases Working Party of the European Blood and Marrow Transplant Group survey showed that 51% of centers had a program of vaccination against tuberculosis in their countries, only 10% systematically screening their patient before transplant by TST, and 51% screening in case of suspicious.[11]
A study of 295 HSCT in Korea showed an incidence of TB of 3.1%.[19] Multivariate analysis revealed that only a previous history of TB infection and total Body Irradiation (TBI) increased the risk of TB infection in HSCT patients (relative risk, 4.8 and 12.5, respectively).[18]
Isoniazid prophylaxis in HSCT recipients with only radiological findings suggestive of past inactive TB infection did not significantly alter the incidence of TB infections (P = 0.236).[18] Other study evaluated the frequency of tuberculin skin test (TST) positivity among 26 patients and their donors screened by TST to investigate whether tuberculin positivity of a recipient or donor influenced the rate of tuberculosis disease, transplant-related events, and to evaluate the effectiveness of isoniazid (INAH) prophylaxis administered to those with positive TST.[32] The frequency of TST positivity was 23% (n = 6) among recipients and also 23% (n = 6) among donors. Two recipients and five donors with positive TST received INAH prophylaxis for six months. The transplantation procedure was not postponed for either recipient or donor TST positivity. Despite the high frequency of tuberculosis in their country, they have not detected any case of tuberculosis in their center, either among the TST screened (n = 26) or non-screened (n = 128).[32]
A recent study compared the simultaneous use of QFT-GIT and TST (>5 mm) and found similar frequencies of positive outcomes in the two screening test, although the overall agreement was poor (Kappa=0.08, 95% CI -0.006 to 0.24). However, the study did not have adequate power. The authors evaluated a cohort of 244 patients, 100 autologous and 144 allogeneic recipients during a 28-month period. No prophylaxis for latent tuberculosis was administrated, 201 (82%) patients had Bacillus Calmette-Guérin (BCG) scars or previous vaccination. Two patients developed tuberculosis after HSCT, the incidence of tuberculosis among those with positive QFT-GIT was 2.80 and among positive TST was 0 per 100 patients-years.[33] Thus, further studies are needed to validate the use of QFT-GIT in HSCT patients.

Conclusion
Most of reports of TB in HSCT patients were from ASIA, with TB incidence varying from 0.0014 (USA) to 16% (Pakistan), and the lung was the organ most often involved. The mortality varied from 0 to 50%, and it was higher in allogeneic HSCT than autologous HSCT. Thus, TB is more frequent and with worse outcome among allogeneic HSCT. Risk factors associated with TB in allogeneic HSCT are use of steroid and GVHD. There is no consensus regarding the screening with either TST or QFT-GIT, use of primary prophylaxis for latent TB, and, whether in a developing country with high prevalence of TB, the epidemiologic query should be emphasized.

References
  1. Navari RM, Sullivan, KM, Springmeyer SC, et al. Mycobacterial infections in marrow transplant patients. Transplantation 1983;36(5):509-13. http://dx.doi.org/10.1097/00007890-198311000-00008 PMid:6356515  
  2. Akan H, Arslan O, Akan OA. Tuberculosis in stem cell transplant patients. J Hosp Infect 2006;62(4):421-6. http://dx.doi.org/10.1016/j.jhin.2005.09.020 PMid:16413085   
  3. Roy V, Weisdorf D. Mycobacterial infections following bone marrow transplantation: a 20 year retrospective review. Bone Marrow Transplant 1997;19(5):467-0. http://dx.doi.org/10.1038/sj.bmt.1700686 PMid:9052913   
  4. Keung YK, Nugent K, Jumper C, Cobos E. Mycobacterium tuberculosis infection masquerading as diffuse alveolar hemorrhage after autologous stem cell transplant. Bone Marrow Transplant 1999;23(7):737-8. http://dx.doi.org/10.1038/sj.bmt.1701648 PMid:10218854   
  5. Kurzrock R, Zander A, Vellekoop L, Kanojia M, Luna, M, Dicke K. Mycobacterial pulmonary infections after allogeneic bone marrow transplantation. Am J Med 1984;77(1):35-40. http://dx.doi.org/10.1016/0002-9343 (84)90432-7    
  6. de la Câmara R, Martino R, Granados E, et al. Tuberculosis after hematopoietic stem cell transplantation: incidence, clinical characteristics and outcome. Spanish Group on Infectious Complications in Hematopoietic Transplantation. Bone Marrow Transplant 2000;26(3):291-8. http://dx.doi.org/10.1038/sj.bmt.1702506  PMid:10967568   
  7. Budak-Alpdogan T, Tangün Y, Kalayoglu-Besisik S, et al. The frequency of tuberculosis in adult allogeneic stem cell transplant recipients in Turkey. Biol Blood Marrow Transplant 2000;6(4):370-4. http://dx.doi.org/10.1016/S1083-8791(00)70013-9   
  8. Ip MS, Yuen KY, Woo PC, et al. Risk factors for pulmonary tuberculosis in bone marrow transplant recipients. Am J Respir Crit Care Med 1998;158(4):1173-7. http://dx.doi.org/10.1164/ajrccm.158.4.9712072 PMid:9769278   
  9. Ku SC, Tang JL, Hsueh PR, Luh KT, Yu CJ, Yang PC. Pulmonary tuberculosis in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2001;27(12):1293-7. http://dx.doi.org/10.1038/sj.bmt.1703092  
  10. Wang J, Chang Y, Lee L, et al. Diffuse Pulmonary Infiltrates After Bone Marrow Transplantation: The Role of Open Lung Biopsy. Ann Thorac Surg 2004;78:267–72 http://dx.doi.org/10.1016/j.athoracsur.2004.03.002 PMid:15223441   
  11. Cordonnier C, Martino R, Trabasso P, et al. European Blood and Marrow Transplant Group Infectious Diseases Working Party. Mycobacterial infection: a difficult and late diagnosis in stem cell transplant recipients. Clin Infect Dis 2004;38(9):1229-36. http://dx.doi.org/10.1086/383307 PMid:15127333   
  12. Aljurf M, Gyger M, Alrajhi A, et al. Mycobacterium tuberculosis infection in allogeneic bone marrow transplantation patients. Bone Marrow Transplant 1999;24(5):551-4 http://dx.doi.org/10.1038/sj.bmt.1701930 PMid:10482941
  13. Ullah, K., Ahmed, P., Raza, S., et al. (2007). Allogeneic stem cell transplantation in hematological disorders: single center experience from Pakistan. Transplant Proc;39(10):3347-57. http://dx.doi.org/10.1016/j.transproceed.2007.08.099 PMid:18089384  
  14. Altclas J, Lescano A, Salgueira C, et al. Multidrug-resistant tuberculosis in bone marrow transplant recipient. Transpl Infect Dis 2005;7(1):45-6. http://dx.doi.org/10.1111/j.1399-3062.2005.00083.x PMid:15984950  
  15. Maeda T, Kusumi E, Kami M, et al. Tokyo Stem Cell Transplant (SCT) Consortium. Disseminated tuberculosis following reduced-intensity cord blood transplantation for adult patients with hematological diseases. Bone Marrow Transplant 2005;35(1):91-7. http://dx.doi.org/10.1038/sj.bmt.1704740 PMid:15516933   
  16. Khan B, Ahmed P, Ullah K, Hussain CA, Hussain I, Raza S. Frequency of tuberculosis in haematological malignancies and stem cell transplant recipients. J Coll Physicians Surg Pak 2005;15(1):30-3. PMid:15670521   
  17. Garces Ambrossi G, Jakubowski A, Feinstein MB, Weinstock, DM. Active tuberculosis limited to foreign-born patients after allogeneic hematopoietic stem cell transplant. Bone Marrow Transplant 2005;36(8):741-3. http://dx.doi.org/10.1038/sj.bmt.1705129 PMid:16113670   
  18. George B, Mathews V, Srivastava A, Chandy M. Infections among allogeneic bone marrow transplant recipients in India. Bone Marrow Transplant 2004;33(3):311-15 http://dx.doi.org/10.1038/sj.bmt.1704347 PMid:14647246   
  19. Lee J, Lee MH, Kim WS, et al. Tuberculosis in hematopoietic stem cell transplant recipients in Korea. Int J Hematol 2004;79(2):185-8. http://dx.doi.org/10.1532/IJH97.A10219 PMid:15005349   
  20. Erdstein AA, Daas P, Bradstock KF, Robinson T, Hertzberg MS. Tuberculosis in allogeneic stem cell transplant recipients: still a problem in the 21st century.Transpl Infect Dis 2004;6(4):142-6. http://dx.doi.org/10.1111/j.1399-3062.2004.00068.x PMid:15762931   
  21. Yoo JH, Lee DG, Choi SM, et al. Infectious complications and outcomes after allogeneic hematopoietic stem cell transplantation in Korea. Bone Marrow Transplant 2004;34(6):497-504. http://dx.doi.org/10.1038/sj.bmt.1704636 PMid:15286689   
  22. Kerridge I, Ethell M, Potter M, Prentice HG. Mycobacterium tuberculosis infection following allogeneic peripheral blood stem cell transplantation. Intern Med J 2003;33(12):619-20. http://dx.doi.org/10.1111/j.1445-5994.2003.00451.x PMid:14656242   
  23. Kindler T, Schindel C, Brass U, Fischer T. Fatal sepsis due to Mycobacterium tuberculosis after allogeneic bone marrow transplantation. Bone Marrow Transplantation 2001, 27, 217–18 http://dx.doi.org/10.1038/sj.bmt.1702737 PMid:11281394   
  24. Campos A, Vaz CP, Campilho F, et al. Central nervous system (CNS) tuberculosis following allogeneic stem cell transplantation. Bone Marrow Transplant 2000;25(5):567-9. http://dx.doi.org/10.1038/sj.bmt.1702163 PMid:10713637   
  25. Ullah K, Raza S, Ahmed P, et al. Post-transplant infections: single center experience from the developing world. Int J infect Dis 2008;12:203-14. http://dx.doi.org/10.1016/j.ijid.2007.06.012 PMid:17920999   
  26. Machado CM, Martins TC, Colturato I, et al. Epidemiology of neglected tropical diseases in transplant recipients. Review of the literature and experience of a Brazilian HSCT center. Rev Inst Med Trop Sao Paulo. 2009;51(6):309-24. PMid:20209266   
  27. Russo RL, Dulley FL, Suganuma L, et al. Tuberculosis in hematopoietic stem cell transplant patients: case report and review of the literature. Int J Infect Dis. 2010;14 Suppl 3:e187-91. http://dx.doi.org/10.1016/j.ijid.2009.08.001 PMid:19819176   
  28. Kuan FC, Lin PY, Hwang CE, et al. Pancytopenia and myeloid maturation arrest in an autologous stem cell transplant recipient. Bone Marrow Transplant.2011;46(4):610-1. http://dx.doi.org/10.1038/bmt.2010.155 PMid:20622905   
  29. Rouleau M, Senik A, Leroy E, Vernant JP. Long-term persistence of transferred PPD-reactive T cells after allogeneic bone marrow transplantation. Transplantation 1993;55(1):72-6. http://dx.doi.org/10.1097/00007890-199301000-00014 PMid:8380510  
  30. Ahmed P, Anwar M, Khan B, et al. Role of isoniazid prophylaxis for prevention of tuberculosis in haemopoietic stem cell transplant recipients. J Pak Med Assoc 2005;55(9):378-81. PMid:16302471    
  31. Gauchon A, André N, Rome A, et al. Evaluation of a screening strategy after occurence of two simultaneous contaminating tuberculosis cases in a pediatric oncology department. Arch Pediatr 2008;15(3):236-44. http://dx.doi.org/10.1016/j.arcped.2008.01.005 PMid:18329257  
  32. Tavil B, Gulhan B, Ozcelik U, et al. Tuberculin skin test positivity in pediatric allogeneic BMT recipients and donors in Turkey. Pediatr Transplant 2007, (4):414-18. http://dx.doi.org/10.1111/j.1399-3046.2007.00679.x PMid:17493222   
  33. Moon SM, Lee SO, Choi SH, Kim YS, Woo JH, Yoon DH, Suh C, Kim DY, Lee JH, Lee JH, Lee KH, Kim SH. Comparison of the QuantiFERON-TB Gold In-Tube test with the tuberculin skin test for detecting latent tuberculosis infection prior to hematopoietic stem cell transplantation. Transpl Infect Dis. 2013;15(1):104-9. http://dx.doi.org/10.1111/j.1399- 3062.2012.00765.x PMid:22823749   
  34. Keung YK, Nugent K, Jumper C, et al. Mycobacterium tuberculosis infection masquerading as diffuse alveolar hemorrhage after autologous stem cell trans- plant. Bone Marrow Transplant 1999;23(7):737 – 35. http://dx.doi.org/10.1038/sj.bmt.1701648 PMid:10218854   
  35. Friedrich W, O'Reilly RJ, Koziner B, et al. T-lymphocyte reconstitution in recipients of bone marrow transplants with or without GVHD: imbalances on T-cell subpopulation having unique regulatory and cognitive function. Blood 1982; 59: 696–701. PMid:6800422
  36. Lum LG, Seigneuret MC, Orcutt-Thordarson N, et al. The regulation of immunoglobulin synthesis after HLA identical bone marrow transplantation. Blood 1985; 65: 1422–1433. PMid:2986745   
  37. Al-Anazi KA, Al-Jasser AM, Evans DA. Infections caused by mycobacterium tuberculosis in patients with hematological disorders and in recipients of hematopoietic stem cell transplant, a twelve year retrospective study. Ann Clin Microbiol Antimicrob. 2007 16;6:16.  
  38. Jung JI, Lee DG, Kim YJ et al. Pulmonary tuberculosis after hematopoietic stem cell transplantation: radiologic findings. J Thorac Imag. 2009;24(1):10-6. http://dx.doi.org/10.1097/RTI.0b013e31818c6b97 PMid:19242297   
  39. Delogu G and Herrmann J-L. Mycobacterium species. In European Manual of Clinical Microbiology. 1st edition. ISBN: 978-2-87805-026-4, pages 297-307, 2012.  
  40. Yamazaki R, Mori T, Nakazato T, Okamoto S et al. Non-Tuberculous Mycobacterial Infection Localized in Small Intestine Developing after Allogeneic Bone Marrow Transplantation. Inter Med 49: 1191-1193, 2010 http://dx.doi.org/10.2169/internalmedicine.49.3288 PMid:20558941   
  41. Shi JM, Cai Z, Huang H, Ling MF et al. Role of CT-guided percutaneous lung biopsy in diagnosis of pulmonary fungal infection in patients with hematologic diseases. Int J Hematol (2009) 89:624–627 http://dx.doi.org/10.1007/s12185-009-0351-0 PMid:19468797   
  42. Redelman-Sidi G and Sepkowitz KA. Interferon Gamma Release Assays in the Diagnosis of Latent Tuberculosis Infection Among Immunocompromised Adults. Am J Respir Crit Care Med. 2013. First published online doi: 10.1164/rccm/201209-1621CI.  
  43. Pai M, Palamountain K M. New tuberculosis technologies: challenges for retooling and scale-up. Int J Tuberc Lung Dis 16 (10): 1281-1290; 2012. 44.  
  44. MMWR. Updated Guidelines for the Use of Nucleic Acid Amplification Tests in the Diagnosis of Tuberculosis. January 16, 2009 / 58 (01); 7-10.  
  45. Lee J I, Lee BJ, Roy EY et al. The diagnostic accuracy of tuberculosis real-time polymerase chain reaction analysis of computed tomography-guided bronchial wash samples. Diagn Microb Infec Dis 2011; 71: 51-6 http://dx.doi.org/10.1016/j.diagmicrobio.2010.12.019 PMid:21795005   
  46. Min J-W, Yoon HI, Park KU et al. Real-time polymerase chain reaction in bronchial aspirate for rapid detection of sputum smear-negative tuberculosis.Int J Tuberc Lung Dis 2010; 14(7): 852-8 PMid:20550768   
  47. Abubakar I, Griffiths C and Ormerod P. Diagnosis of active and latent tuberculosis: summary of NICE guidance. BMJ 2012;345:e6828. http://dx.doi.org/10.1136/bmj.e6828  
  48. Horne DJ, Narita M, Spitters CL et al. Challenging Issues in Tuberculosis in Solid Organ Transplantation. Clin Infect Dis 2013. http://dx.doi.org/10.1093/cid/cit488  
  49. Lawn SD, Mwaba P, Bates M et al. Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test. Lancet Infect Dis 2013; 13: 349–61. http://dx.doi.org/10.1016/S1473-3099(13)70008-2  
  50. Rajpal S, Kashyap RS, Nayak AR et al. Laboratory Investigations on the Diagnosis of Tuberculosis in the Malnourished Tribal Population of Melghat, India. Plos One 2013, 8 (9): e74652 http://dx.doi.org/10.1371/journal.pone.0074652 PMid:24069327 PMCid:PMC3772098  
  51. Dubey A, Gwal R, Agrawal S. Mycobacterium tuberculosis detection in blood using multiplex nested polymerase chain reaction. Int J Tuberc Lung Dis. 2013 17 (10):1341-5. http://dx.doi.org/10.5588/ijtld.12.0536 PMid:24025388   
  52. Bento J, Silva AS, Rodrigues F, Duarte R. Métodos Diagnósticos em Tuberculose. Acta Med Port 2011; 24: 145-154 PMid:21672452   
  53. Hopewell PC, Pai M, Maher D et al. International standards for tuberculosis care. Lancet Infect Dis. 2006;6 (11):710 http://dx.doi.org/10.1016/S1473-3099 (06)70628-4
  54. Yew WW, Lange C and Leung CC. Treament of tuberculosis: update 2010. Eur Respir J 2011; 37: 441-462. http://dx.doi.org/10.1183/09031936.00033010  PMid:20847074   
  55. World Health Organization. Treatment of Tuberculosis Guidelines; 2009. Report No.: WHO/HTM/TB/2009/420. ISBN: 9789241547833.  
  56. American Thoracic Society: CDC; Council of the Infectious Disease Society of America. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med 2000;161:1376-95 http://dx.doi.org/10.1164/ajrccm.161.4.16141 PMid:10764337   
  57. Ministério da Saúde do Brasil. Available in http://portal.saude.gov.br/portal/arquivos/pdf/nota_tecnica_versao_28_de_agosto_v_5.pdf 
  58. La Camara R, Martino R, Granados E et al. Tuberculosis after hematopoietic stem cell transplantation: incidence, clinical characteristics and outcome. Bone Marrow Transplantation (2000) 26, 291–298 http://dx.doi.org/10.1038/sj.bmt.1702506 PMid:10967568   
  59. Maeda T, Kusumi E, Kami M et al. Disseminated tuberculosis following reduced-intensity cord blood transplantation for adult patients with hematological diseases. Bone Marrow Transplantation (2005) 35, 91–97. http://dx.doi.org/10.1038/sj.bmt.1704740 PMid:15516933  
  60. De Assis RA, Kerbauy FR, Rodrigues M et al. Mycobacterium tuberculosis infection: a rare late complication after cord blood hematopoietic SCT. Bone Marrow Transplantation (2009) 43, 667–668 http://dx.doi.org/10.1038/bmt.2008.379 PMid:19029968   
  61. Aguado JM, Torre-Cisneros J, Munoz P et al. Tuberculosis in Solid-Organ Transplant Recipients: Consensus Statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology. Clin Infect Dis 2009; 48:1276–84 http://dx.doi.org/10.1086/597590 PMid:19320593   
  62. Saukkonen JJ, Cohn DL, Jasmer RM et al. ATS (American Thoracic Society) Hepatotoxicity of Antituberculosis Therapy Subcommittee. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006;174:935–952. http://dx.doi.org/10.1164/rccm.200510-1666ST PMid:17021358   
  63. Devarbhavi H. Adaptation and Antituberculosis Drug–induced Liver Injury. Am J Respir Crit Car Med 2012; 186:387-388. http://dx.doi.org/10.1164/ajrccm.186.4.387 PMid:22896595   
  64. Altclas J, Lescano A, Palmero D et al. Multidrug-resistant tuberculosis in bone marrow transplant recipient. Transpl Infect Dis 2005: 7: 45-46. http://dx.doi.org/10.1111/j.1399-3062.2005.00083.x PMid:15984950  
  65. Lienhardt C, Raviglione M, Spigelman M et al. New Drugs for the Treatment of Tuberculosis: Needs, Challenges, Promise, and Prospects for the Future. J Infect Dis 2012; 205:S241–9. http://dx.doi.org/10.1093/infdis/jis034 PMid:22448022   
  66. Uhlin M, Andersson J, Zumla A and Maeurer M. Adjunct Immunotherapies for Tuberculosis. J Infec Dis 2012; 205: S325–34. http://dx.doi.org/10.1093/infdis/jis197 PMid:22457298