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Received: 3 February 2017 Revised: 29 May 2017 Accepted: 25 June 2017 DOI: 10.1111/tid.12794
ORIGINAL ARTICLE
Incidence and clinical profile of tuberculosis after allogeneic stem cell transplantation Narendra Agrawal1 | Mukul Aggarwal1 | Jyotsna Kapoor1
| Rayaz Ahmed1 |
Anjan Shrestha2 | Meena Kaushik1 | Dinesh Bhurani1 1 Department of Hematology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, Delhi, India 2
Abstract Background: Patients post allogeneic stem cell transplantation (alloSCT) are expected
Institute of Medicine, Hemato-Oncology Unit, Maharajgunj, Kathmandu, Nepal
to be at high risk of tuberculosis (TB) owing to underlying immunosuppression. We
Correspondence Dr. Dinesh Bhurani, Department of Hematology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, Delhi, India. Email:
[email protected]
tors associated with TB.
conducted a retrospective study in patients post alloSCT for clinical features and facMethods: Records of all patients transplanted from January 1, 2012 until December 31, 2015 were reviewed. Diagnosis of TB was considered if Mycobacterium tuberculosis was cultured from clinical samples or acid-fast bacilli (AFB) were demonstrated on histopathology/smears. A presumptive TB diagnosis was considered in the presence of signs and symptoms suggestive of TB with epithelioid cell granulomas, without AFB. Results: In 175 eligible patients, TB was detected in 5 patients (pulmonary = 4, lymph node = 1), with incidence of 2.84% at median of 258 (157-639) days after transplantation. Cumulative incidence rate of TB among the patients undergoing alloSCT was calculated to be 1.9/100 person-years. Median duration of symptoms was 20 days till diagnosis was confirmed. All patients were started on four-drug anti-tubercular therapy (ATT) with clinical/radiological response in all. Two patients developed hepatotoxicity (transaminitis, n = 1; hyperbilirubinemia, n = 1) following ATT. Presence of chronic graft-versus-host disease (GVHD) (P = .008) and steroid-refractory GVHD (P = .001) was found to be significantly associated with TB. Conclusion: TB should be suspected in patients with unexplained fever post alloSCT. Active GVHD and ongoing immunosuppression/steroids are possible risk factors. Early diagnosis and treatment can salvage most patients. Hepatotoxicity following ATT is a potential concern. KEYWORDS
allogeneic stem cell transplant, graft-versus-host disease, immunosuppression, tuberculosis
1 | INTRODUCTION
estimated that about 40% of the Indian population is infected with TB bacteria, the vast majority of whom have latent rather than active TB.
India has a very high burden of tuberculosis (TB). According to World Health Organization (WHO), in 2015 the estimated incidence of TB
Patients
with
hematological
malignancies
are
immune-
compromised because of the disease process as well as chemotherapy.
in India was 2.2 million out of a global incidence of 9.6 million cases,
The cell-mediated immunity of those undergoing allogeneic stem cell
or nearly one-fourth of world incidences from India. The estimated
transplantation (alloSCT) are further reduced because of the intense
TB prevalence in India for the year 2015 is given as 2.5 million.1 It is
conditioning regimen used, development of graft-versus-host disease
Transpl Infect Dis. 2018;20:e12794. https://doi.org/10.1111/tid.12794
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© 2017 John Wiley & Sons A/S. | 1 of 8 Published by John Wiley & Sons Ltd
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(GVHD) and its treatment with immunosuppressive drugs, and subse-
3 | RESULTS
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quently delayed immune reconstitution. Therefore, these patients are at a very high risk of activation of latent TB infection, especially in a population with high TB burden. Incidence of TB is 2-40 times higher among alloSCT patients than in the general population.2,3 Frequency of tubercular infection after alloSCT patients from areas of high incidence has been reported to be 1%-16%.2 The present study was undertaken to study the incidence, clinical presentation, and outcomes, and to find possible risk factors for tubercular infection post alloSCT for hematological disease and malignancies at our institute.
3.1 | Study population characteristics A total of 176 alloSCTs were performed during the study period; one patient with a history of tubercular lymphadenitis was excluded from further analysis. Median age of the eligible patients (n = 175) with alloSCT was 35 (1-66) years with male-to-female ratio of 2.1:1 (Table 1). Nineteen patients (10.8%) had comorbid illness. None of the patients were human immunodeficiency virus positive. Indications for alloSCT were malignant diseases (82.3%) (acute myeloid leukemia [AML] [n = 69], acute lymphoblastic leukemia [n = 35],
2 | PATIENTS AND METHODS Medical records of all consecutive patients who underwent alloSCT for hematological malignancy and non-malignant conditions from January 1, 2012 until December 31, 2015 were reviewed for demographic data, transplant-related parameters, and tubercular infection. Patients already on anti-tubercular therapy (ATT) at the time of SCT or who had a past history of tubercular infection were excluded. The study protocol was approved by the Institution Review Board of our institution. All patients were treated in HEPA-filtered rooms since the start of the conditioning regimen. GVHD prophylaxis consisted of a calcineurin inhibitor and short course of methotrexate in matched sibling donor (MSD) transplants, with the addition of anti-thymocyte globulin (ATG) in matched-unrelated donor transplants (MUD). For the haplo-identical transplants, post-transplant cyclophosphamide followed by tacrolimus and mycophenolate mofetil was used as GVHD prophylaxis. Patient with suspected GVHD were subjected to biopsy of the affected organ and were started on methylprednisone. In steroid-refractory cases, second-line agents for GVHD such as mycophenolate mofetil, etanercept, basiliximab, and methotrexate were used most often. Patients with unexplained weight loss, persistent low-grade fever, cough with expectoration/breathlessness, or palpable unexplained lymphadenopathy and sterile bacterial and fungal cultures, were suspected to be suffering from TB. The diagnosis of TB was considered if Mycobacterium tuberculosis was cultured from clinical samples or acid- fast bacilli (AFB) were demonstrated on histopathology/smears. A presumptive TB diagnosis was considered in the presence of signs and symptoms suggestive of TB with epithelioid cell granulomas, without AFB.4 ATT consisted of 2 months of isoniazid, rifampin, ethambutol, and pyrazinamide, followed by isoniazid, rifampin, and ethambutol for the rest of the treatment period to complete a total of 9 months of therapy. Treatment outcomes were defined in accordance to WHO guidelines for TB.5 Overall survival (OS) and the cumulative incidence of TB diseases were considered the primary end points of this study. The potential risk factors for TB disease were evaluated. Categorical variables were analyzed using Fisher’s exact test and continuous variables were analyzed using t test. The P-value
