The demanding attention of tuberculosis in allogeneic hematopoietic stem cell transplantation recipients: High incidence compared with general population

Abstract

Background

The risk of developing tuberculosis (TB) in allogeneic hematopoietic stem cell transplantation (HSCT) recipients is expected to be relatively high in an intermediate TB burden country. This single-center retrospective study was conducted to investigate risk factors and the incidence of TB after allogeneic HSCT.

Methods

From January 2004 to March 2011, 845 adult patients were enrolled. Starting April 2009, patients were given isoniazid (INH) prophylaxis based on interferon-γ release assay results. The incidence of TB was analyzed before and after April 2009, and compared it with that of the general population in Korea.

Results

TB was diagnosed in 21 (2.49%) of the 845 allogeneic HSCT patients. The median time to the development of TB was 386 days after transplantation (range, 49–886). Compared with the general population, the standardized incidence ratio of TB was 9.10 (95% CI; 5.59–14.79). Extensive chronic graft-versus-host disease (GVHD) was associated with the development of TB (P = 0.003). Acute GVHD, conditioning regimen with total body irradiation and conditioning intensity were not significantly related. INH prophylaxis did not reduce the incidence of TB (P = 0.548). Among 21 TB patients, one patient had INH prophylaxis.

Conclusion

Allogeneic HSCT recipients especially those who suffer from extensive chronic GVHD are at a high risk of developing TB. INH prophylaxis did not statistically change the incidence of TB, however, further well-designed prospective studies are needed.

About the Authors:

Hyo-Jin Lee

Affiliations Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea, Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Dong-Gun Lee

* E-mail: [email protected]

Affiliations Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea, Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea, The Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Su-Mi Choi

Affiliations Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea, Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Sun Hee Park

Affiliations Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea, Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Sung-Yeon Cho

Affiliations Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea, Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Jae-Ki Choi

Affiliations Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea, Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Si-Hyun Kim

Affiliations Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea, Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Jung-Hyun Choi

Affiliations Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea, Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Jin-Hong Yoo

Affiliations Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea, Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Byung-Sik Cho

Affiliation: The Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Ki-Seong Eom

Affiliation: The Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Seok Lee

Affiliation: The Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Yoo-Jin Kim

Affiliation: The Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Hee-Je Kim

Affiliation: The Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Chang-Ki Min

Affiliation: The Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Dong-Wook Kim

Affiliation: The Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Jong-Wook Lee

Affiliation: The Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Woo-Sung Min

Affiliation: The Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Jung Im Jung

Affiliation: Department of Radiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Introduction

Mycobacterium tuberculosis is an acid-fast, aerobic bacillus, which is one of the leading infectious diseases around the world [1, 2]. Tuberculosis (TB) is also well known for a significant opportunistic infection among hematopoietic stem cell transplantation (HSCT) recipients, although it is 10 times less frequent than in solid organ transplant patients [2, 3]. The immune system of HSCT recipients are suppressed as a result of their hematologic diseases, chemotherapy, radiation, immunosuppressive therapy, and graft-versus-host disease (GVHD) [1]. Thus, the incidence of TB among allogeneic HSCT recipients is reportedly 2–40 times higher than that of the general population [1, 4–6]. In particular, diagnosis of TB is frequent in Korea, with an estimated TB incidence rate of 97 cases per 100 000 persons in the general population in 2013 according to World Health Organization report [7].

Isoniazid (INH) prophylaxis in patients with latent TB infection (LTBI) is recommended for the prevention of active TB disease [2]. However, INH prophylaxis guidelines have not yet been adopted by many centers in Korea. There are a few studies on TB and INH prophylaxis in HSCT recipients.

The purpose of this study was to examine the incidence of TB disease after allogeneic HSCT as compared with the general population, identify risk factors for TB disease, and analyze the efficacy of INH prophylaxis.

Materials and methods

Study design and subjects

We retrospectively reviewed the medical records of all consecutive adult patients (age ≥18 years) who underwent allogeneic HSCT for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), multiple myeloma (MM), or myelodysplastic syndrome (MDS), from January 2004 to March 2011, at the Catholic Blood and Marrow Transplantation Center, Seoul, Korea. Patients undergoing a second transplantation, or with human immunodeficiency virus infection were excluded from the study. Those who were taking anti-TB medication before or during the HSCT were excluded as well. The demographic features, laboratory and radiologic data of study participants were carefully examined (For details see S1 Data). The end of this study was set at December 2014 or time of death or the date of loss to follow-up.

As of April 2009, patients who planned to undergo allogeneic HSCT were given INH prophylaxis (300 mg/day) based on interferon-γ release assay (IGRA) results. Korea Centers for Disease Control and Prevention has recommended INH prophylaxis for latent TB since 2008 [8, 9]. In accordance with the national policy for latent TB, the Catholic Blood and Marrow Transplantation Center in Korea changed guidelines for TB prevention in April 2009. INH prophylaxis was started on the day that the IGRA results were made available, and continued for 9 months after HSCT. The IGRA results were evaluated using QuantiFERON®-TB Gold In-Tube (QFT-GIT; Cellestis Ltd., Victoria, Australia). The incidence of TB in each study group was analyzed (group A, allogeneic HSCT between January 2004 and March 2009, n = 550; group B, allogeneic HSCT between April 2009 and March 2011, n = 295).

This study obtained approval from the Institutional Review Board of Seoul and Yeouido St. Mary’s Hospital with a waiver of informed consent. (No. KC15RIMI0162, SC10RISI0023)

Definitions

Definitions of TB and assessment of treatment outcome.

The diagnosis of TB was considered proven if M.tuberculosis was cultured from any of the clinical specimens. The diagnosis of a probable case of active TB required at least one of the following criteria in patients with clinical symptoms and signs suggestive of TB disease: 1) acid-fast bacilli from clinical specimen (sputum, body fluid, etc.) present; 2) tissue histology suggestive of TB such as caseous necrosis with or without granuloma or positive Ziehl-Neelsen staining; or 3) fluid cytology (pleural or pericardial effusion or ascites or cerebrospinal fluid [CSF]) showing exudates with lymphocyte predominance and high adenosine deaminase (>40 IU/L in the body fluid, or >10 IU/L in case of CSF), when the case had no evidence of malignancy. A possible case was defined when a patient with clinical symptoms and signs, had radiological findings suggestive of TB at the time of diagnosis without definite evidence of another infectious cause, and the patient’s condition improved with anti-TB treatment when other antibacterial and antifungal agents were ineffective [6, 10–16]. Miliary TB was defined as described in a previous study [17]. The radiological findings were confirmed by two highly-experienced radiologists. Polymerase chain reaction for TB was used only to distinguish TB and non-tuberculous mycobacterial infection, not for TB diagnosis. The IGRA results had no influence on the diagnosis of TB. Clinical response of TB treatment was classified as cure, improvement, or failure [16]. The definition of Immune reconstitution inflammatory syndrome was given as previously [18].

Transplantation procedure and diagnosis of GVHD.

All patients received oral ciprofloxacin (250–500 mg twice a day) as antibacterial prophylaxis. Itraconazole oral solution (2.5 mg/kg twice a day) or micafungin (50 mg daily) were used as primary antifungal prophylaxis, from the first day of conditioning until engraftment. Fluconazole (400 mg daily) prophylaxis after engraftment was administered according to GVHD status and the national guideline [19]. Trimethoprim-sulfamethoxazole (one single-strength tablet daily) was administered as prophylaxis for Pneumocystis jirovecii infection after engraftment until discontinuation of the immunosuppressants. The patients also received a herpes simplex virus prophylaxis of acyclovir (400–800 mg orally twice a day or 5 mg/kg intravenously two or three times a day) from day 7 to engraftment for transplants of matched related donors. Patients who underwent allogeneic HSCT from mismatched related donors, unrelated donors, or umbilical cord blood received a higher dose of intravenous acyclovir (10 mg/kg three times a day) until engraftment. To prevent cytomegalovirus disease after engraftment, the preemptive strategy was conducted in a CMV DNA load-guided, risk-adapted manner [13]. The myeloablative conditioning regimen was used when at least one of the following criteria was met: 1) total body irradiation ≥ 500 cGy as a single fraction or ≥ 800 cGy as fractionated; 2) busulfan 4 mg kg/day administered for 4 days, combined with cyclophosphamide 120 mg/kg; 3) total busulfan of ≥ 9 mg/kg; and 4) melphalan of ≥ 140 mg/m2. The reduced intensity conditioning regimen was used when meeting any of the following criteria: 1) total body irradiation < 500 cGy as a single fraction or < 800 cGy as fractionated; 2) total busulfan of < 9 mg/kg; 3) melphalan of < 140 mg/m2; 4) thiotepa of < 10 mg/kg; and 5) the carmustine, etoposide, cytarabine, and melphalan regimen [20]. Diagnoses and grades of acute GVHD were made based on the consensus criteria [21]. The definition of chronic GVHD was given by using the revised Seattle classification [20]. The patients concomitant treated with cyclosporine and rifampicin were frequently monitored for therapeutic drug levels of cyclosporine.

Statistical analysis

Overall survival (OS), disease-free survival (DFS), and the cumulative incidences of TB disease were considered the main end points of this study. OS and DFS results were plotted using the Kaplan-Meier method and compared using log-rank test. The cumulative incidences of TB disease under which method non-TB disease was used as a competing risk event of TB disease, were plotted and compared using the Gray’s test. To evaluate the potential factors for TB disease, categorical variables were analyzed using a χ2 or Fisher’s exact test. For multivariate analysis, variables with P-value of < 0.30, on univariate analysis were entered into the model selection procedure on the basis of Cox proportional hazard modeling.

Two-sided P values < 0.05 were considered statistically significant. The standardized incidence ratios (SIR) of TB disease were calculated to compare the incidence of TB disease in our cohort with that of the general population in Korea, whose data were collected from the annual reports of the Korea Centers for Disease Control and Prevention between 2004 to 2011 [22]. SIR with corresponding 95% confidence intervals (CI) were calculated using Poisson regression. Statistical studies were performed with the Statistical Package for the Social Sciences version 13.0 (SPSS, Inc., Chicago, IL, USA) and the cumulative incidence analyses were performed using with R (freely distributed on the web, http://cran.r-project.org/).

Results

Overall HSCT recipient characteristics and risk factors for the development of TB

From January 2004 to March 2011, a total of 861 patients with acute leukemia, CML, MDS, and MM underwent allogeneic HSCT. During the study period, there were 9 cases of second transplantation and 7 patients were taking anti-TB medication prior to the HSCT. After these patients were excluded, a total of 845 patients were enrolled in this study. None of the patients was human immunodeficiency virus-positive. Table 1 shows the general characteristics of the transplantations and the clinical information of the study population. Post-HSCT TB occurred in 21 (2.49%) of the 845 patients in the study. The median follow-up duration of the survivors was 2,044 days (range, 108–3,916). On multivariate analysis (Table 2), risk factors for post-HSCT TB revealed that extensive chronic GVHD was only associated with TB in the study population (P = 0.008). Acute GVHD, conditioning regimen with total body irradiation, and conditioning intensity were not significantly related. According to Gray’s test (Fig 1), there was a 4.89 ± 1.32% probability of having TB disease 1000 days after allogeneic HSCT for extensive chronic GVHD and 1.42 ± 0.50% for limited or without chronic GVHD (P = 0.003). There was no significant influence of chronic GVHD site on TB development by logistic regression. Chronic GVHD occurred in the skin (TB patients vs. Non-TB patients; 47.6% vs. 40.7%, P = 0.523), in the mouth (TB patients vs. Non-TB patients; 19.0% vs. 30.5%, P = 0.268), in the liver (TB patients vs. Non-TB patients; 33.3% vs. 19.8%, P = 0.134), in the eye (TB patients vs. Non-TB patients; 14.3% vs. 12.5%, P = 0.807), in the lung (TB patients vs. Non-TB patients; 19.0% vs. 9.7%, P = 0.168), in the gastro-intestinal tract (TB patients vs. Non-TB patients; 14.3% vs. 5.8%, P = 0.122) in that order. The outcome of chronic GVHD treatment showed also no association with TB development (P = 0.206). Grade of chronic GVHD was associated with TB development (P = 0.006). Severe chronic GVHD was 19.0% in TB patients and 13.8% in non-TB patients while moderate chronic GVHD was 47.6% and 18.1%, and mild chronic GVHD was 14.3% and 17.2%, respectively.

[Figure omitted. See PDF.]

Table 1. Overall characteristics of allogeneic hematopoietic stem cell transplantation recipients with or without tuberculosis.

https://doi.org/10.1371/journal.pone.0173250.t001

[Figure omitted. See PDF.]

Table 2. Risk factors for tuberculosis in patients after allogeneic hematopoietic stem cell transplantation.

https://doi.org/10.1371/journal.pone.0173250.t002

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Fig 1. Cumulative incidence of tuberculosis in allogeneic hematopoietic stem cell transplantation recipients with and without chronic graft-versus-host-disease.

Extensive chronic GVHD was associated with the development of TB (P = 0.003) There is a 4.89 ± 1.32% probability of having TB disease at 1000 days after allogeneic HSCT for extensive chronic GVHD and 1.42 ± 0.50% for limited or without chronic GVHD. cGVHD, chronic graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; TB, tuberculosis.

https://doi.org/10.1371/journal.pone.0173250.g001

Clinical characteristics of patients with TB

Of the 21 patients with TB after allogeneic HSCT, 10 patients (47.6%) had a previous history of active TB prior to allogeneic HSCT. There were 9 proven, 6 probable, and 6 possible cases in TB diagnosis. Median time from transplantation to TB diagnosis was 386 days (range, 49–886). Eleven of the 21 cases were pulmonary TB, while the other 10 were extrapulmonary TB (47.6%). There were two patients with miliary TB. Median time from onset of symptoms and signs to TB diagnosis was 23 days (range, 0–126). No differences in the outcome were observed for the cases diagnosed with tuberculosis before or after 100 days of HSCT.

17 patients (81.0%) received first-line anti-TB treatment (INH, rifampicin, ethambutol, and pyrazinamide) and 4 patients received second-line therapy. Among 9 cases of proven TB, 6 were subjected to an antimicrobial susceptibility test. Five of these cases had susceptible results to anti-TB medication, while only 1 case had INH resistance. The reasons for the administration of second-line therapy were drug resistance (patient No. 6), first line treatment failure (patient No. 18), and drug intolerance (patient No. 7 and 14). The median time of anti-TB treatment duration was 12 months (range, 1–18 months). Two patients (9.5%) showed anti-TB treatment failure. Patient No. 8 died of variceal bleeding within the esophagus due to liver cirrhosis and didn’t show any improvement despite acid-fast bacilli cultures all being susceptible to anti-TB medications. Patient No. 14 died of pneumonia. This patient was administered INH, ethambutol, pyrazinamide, and levofloxacin. Another 5 patients died for various reasons despite successful anti-TB treatment. Three patients (No 4, 8, and 15) developed immune reconstitution inflammatory syndrome. There wasn’t any case of relapse after anti-TB treatment administered during the study period. The clinical characteristics and diagnostic and treatment data of the patients with TB after HSCT are summarized in Table 3.

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Table 3. Clinical characteristics of patients with tuberculosis after allogeneic hematopoietic stem cell transplantation.

https://doi.org/10.1371/journal.pone.0173250.t003

Incidence ratio of TB in HSCT recipients compared with general population

The incidence ratio of post-HSCT TB compared with the general population is shown in Table 4. The overall incidence of TB in allogeneic HSCT recipients was significantly higher than that in the general population in Korea (SIR, 9.10, 95% CI, 5.59–14.79; P < 0.001). The incidence of TB in allogeneic HSCT recipients was 654.2 per 100 000 patients per year. There was no statistically significant difference in post-HSCT TB incidence ratio before and after applying INH prophylaxis practice. (P = 0.280).

[Figure omitted. See PDF.]

Table 4. The incidence of tuberculosis in allogeneic hematopoietic stem cell transplantation recipients compared with the general population in Korea.

https://doi.org/10.1371/journal.pone.0173250.t004

INH prophylaxis in latent TB

Fig 2 shows the rates of INH prophylaxis use and TB disease in group B (allogeneic HSCT between April 2009 and March 2011). Among the 83 IGRA positive patients, 35 patients (42%) were not administered INH prophylaxis or had to stop the prophylaxis. Twenty-seven patients did not start INH prophylaxis due to poor compliance among doctors (8 cases), GVHD (8), hepatotoxicity (8), poor compliance among recipients (2), and esophageal candidiasis (1). Eight patients had to stop INH prophylaxis due to hepatotoxicity (2 cases), GVHD (1), peripheral neuropathy (1), drug eruption (1), drug-induced diarrhea (1), relapses of underlying diseases (1), and poor compliance among recipients (1). The reasons for poor compliance among doctors were the regulation of clinical studies, missed orders, or the ignorance of results. Five patients had TB disease, and 2 patients had an IGRA negative result and underwent allogeneic HSCT without INH prophylaxis. Another 2 patients had IGRA positive results, but they did not take INH prophylaxis. One patient taking INH prophylaxis had TB; however, the INH was taken for only 3 months due to poor compliance. IGRA result (P = 0.341) and INH prophylaxis (P = 0.548) did not significantly alter the incidence of TB.

[Figure omitted. See PDF.]

Fig 2. Isoniazid prophylaxis and tuberculosis.

INH prophylaxis did not significantly reduce the incidence of TB (P = 0.548). Among 5 TB patients in group B, one patient had INH prophylaxis. IGRA negative included indeterminate results. IGRA, interferon-γ release assays; INH, isoniazid; TB, tuberculosis.

https://doi.org/10.1371/journal.pone.0173250.g002

Discussion

The objective of this study was to investigate the incidence of TB in allogeneic HSCT recipients compared with that in the general population in Korea. We also examined the risk factors for the development of TB and the efficacy of INH prophylaxis.

The TB incidence of HSCT recipients is affected by geographical prevalence. Studies on TB development after HSCT published from 1990 to January 2015 are summarized in Table 5. The annual TB incidence of the general population in Korea is about 70–100 cases per 100 000 patients [7, 13]. In our study, active TB after allogeneic HSCT occurred in 2.49% of patients, which is higher than that reported in many western countries, even though study periods and cohorts varied. Taiwan, India, and Australia showed a similar TB incidence (2.3–3.1%). However, Hong Kong and Pakistan had higher incidences than that reported here. Previous studies of TB disease after allogeneic HSCT in Korea demonstrated a diverse range of incidences of 3.3–4.5% (Table 5).

[Figure omitted. See PDF.]

Table 5. Description of studies of tuberculosis after hematopoietic stem cell transplantation published from 1990 to January 2015.

https://doi.org/10.1371/journal.pone.0173250.t005

The incidence of TB following HSCT is found to be 10–40 times higher than that of the general population [2]. The cumulative incidence of TB disease in our study was 9.1 times higher than that of the general population in Korea. In Taiwan, pulmonary TB in allogeneic HSCT was 13.1-fold higher [5]. In Spain, de la Camara et al. reported that allogeneic HSCT recipients showed 2.95 times higher relative risk of TB incidence compared with the general population [6]. It seems that geographic location and follow-up duration may influence the differences in the incidence of TB disease.

Several risk factors for the development of TB after HSCT have been reported, including AML, CML, MDS, the use of busulfan, cyclophosphamide, TBI, corticosteroid therapy, mismatched allografts, GVHD, or history of previous TB infection [2]. Our study shows that extensive chronic GVHD is associated with the development of TB. Donor type, underlying hematological disease, conditioning regimen, and acute GVHD were not risk factors according to our study. A TBI-based conditioning regimen was given to >70% of the recipients in our center, which seems to affect the result. The other center in Korea previously reported that HSCT patients with TBI-based conditioning are likely to have TB disease, while TBI-based conditioning was given to 45% of patients with HSCT [32, 38].

The extrapulmonary TB rate tends to be higher than that of the general population since decreased cell-mediated immune responses cannot restrict TB infection [10]. The rate of extrapulmonary TB is reportedly 15–20% in the Korean general population [39]. Our result was also much higher (47.6%) than that in the general population. Table 5 shows a diverse range of extrapulmonary TB rates. The reasons behind the wide range of extrapulmonary TB rates are due to various degrees of practices of close examinations, a high index of suspicion, and anti-TB treatment timing [10].

In this study, there was no association with the IGRA results and progression of active TB disease, which corresponds well with those found in the earlier studies. Sester et al. also reported that the IGRA or tuberculin skin test poorly predicted the progression of active TB in immunocompromised hosts [23]. The immunosuppression state of HSCT recipients would influence IGRA test accuracy [40].

INH prophylaxis has been used to prevent active TB in LTBI patients [2]. However, INH prophylaxis has several problems, including hepatotoxicity, drug interaction with immunosuppressants, and manifestation of resistance to INH [2, 41, 42]. Therefore, the efficacy of INH prophylaxis in HSCT recipients needs to be determined. The result of the present study is that INH prophylaxis did not significantly alter the incidence of TB disease, which is similar to the results of earlier studies [32, 41]. However, these findings differ from suggestions of other reports, which recommend INH prophylaxis for HSCT recipients [3, 30]. Despite the long follow-up period, here we reported TB disease in 21 patients in the whole group and only five patients in group B (INH prophylaxis group) due to TB being a relatively rare disease. The small number of patients may not be sufficient for detecting significant differences for evaluating the effect of INH prophylaxis. However, among the 21 TB patients, only one took INH prophylaxis for 3 months due to poor compliance. Well-designed prospective clinical trials are needed to estimate the efficacy of INH prophylaxis. Also, the ideal INH prophylaxis duration is debatable because TB disease usually occurs in the late post-HSCT period [31, 35]. In our report, patients developed TB at a median of 1 year after HSCT.

One recent study reported that Korea shows a low rate of multidrug-resistant TB (<2000 cases in 2011) [43]. In 2004, the proportion of INH resistance among the total number of notified new TB cases was 9.9% in Korea [44]. Our study population showed only one patient with INH resistance among 6 antimicrobial susceptibility test-proven TB cases, and this patient improved when underwent second-line anti-TB treatment. However, Korea is one of the countries in which multidrug-resistant TB has been increasing [45]. Therefore, when patients with TB are treated, resistance to anti-TB medications needs to be taken into consideration. Also, the value of INH prophylaxis needs to be assessed carefully.

The present study has some limitations. First, it was retrospective, which caused some problems in that specific information about the history of previous TB infection and data of therapeutic approach of chronic GVHD in patients without current TB disease were missing from the medical records. Second, it included a small number of patients with TB. Third, in group B, INH prophylaxis was not given to all IGRA positive patients. Regardless of these limitations, major strengths of our study include a long follow-up period (11 years) and the study population, a relatively homologous large number of allogeneic HSCT patients with only AML, CML, MDS, or MM. Also, the cumulative incidence calculated by Gray’s test considered the competing risks and we used a standardized incidence ratio when making comparisons with the general population.

In conclusion, our study provides a useful evaluation for allogeneic HSCT patient group who is at high risk of contracting TB disease, compared to the general population. TB should be considered when evaluating allogeneic HSCT patients, especially those with extensive chronic GVHD. INH prophylaxis did not statistically change the incidence of TB; however, there is a tendency of decreased TB incidence among the INH prophylaxis group. More research is warranted on the efficacy of INH prophylaxis in allogeneic HSCT recipients in an intermediate TB burden country.

Supporting information

[Figure omitted. See PDF.]

S1 Data. Minimal data set for tuberculosis in allogeneic hematopoietic stem cell transplantation recipients.

https://doi.org/10.1371/journal.pone.0173250.s001

(PDF)

Acknowledgments

The statistical consultation was supported by Catholic Research Coordinating Center of the Korea Health 21 R&D Project (A070001), Ministry of Health & Welfare, Republic of Korea.

Author Contributions

1. Conceptualization: HJL SMC SYC JKC SHK.

2. Formal analysis: HJL DGL.

3. Investigation: HJL.

4. Resources: SMC SHP SYC JKC SHK JHY BSC KSE SL YJK HJK CKM DWK JWL WSM.

5. Supervision: DGL.

6. Validation: JIJ.

7. Writing – original draft: HJL.

8. Writing – review & editing: SHP SMC JHC JHY.

Citation: Lee H-J, Lee D-G, Choi S-M, Park SH, Cho S-Y, Choi J-K, et al. (2017) The demanding attention of tuberculosis in allogeneic hematopoietic stem cell transplantation recipients: High incidence compared with general population. PLoS ONE 12(3): e0173250. https://doi.org/10.1371/journal.pone.0173250

References

1. Fan WC, Liu CJ, Hong YC, Feng JY, Su WJ, Chien SH, et al. Long-term risk of tuberculosis in haematopoietic stem cell transplant recipients: a 10-year nationwide study. Int J Tuberc Lung Dis. 2015;19: 58–64. pmid:25519791

2. Al-Anazi KA, Al-Jasser AM, Alsaleh K. Infections Caused by Mycobacterium tuberculosis in Recipients of Hematopoietic Stem Cell Transplantation. Front Oncol. 2014;4: 231. pmid:25207262

3. Bumbacea D, Arend SM, Eyuboglu F, Fishman JA, Goletti D, Ison MG, et al. The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement. Eur Respir J. 2012;40: 990–1013. pmid:22496318

4. Arslan O, Gurman G, Dilek I, Ozcan M, Koc H, Ilhan O, et al. Incidence of tuberculosis after bone marrow transplantation in a single center from Turkey. Haematologia (Budap). 1998;29: 59–62

5. 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: 1293–1297. pmid:11548848

6. de la Camara R, Martino R, Granados E, Rodriguez-Salvanes FJ, Rovira M, Cabrera R, 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: 291–298. pmid:10967568

7. World Health Oraganization. Estimates of TB and MDR-TB burden are produced by WHO in consultation with countries. 4 Oct 2016. https://extranet.who.int/sree/Reports?op=Replet&name=%2FWHO_HQ_Reports%2FG2%2FPROD%2FEXT%2FTBCountryProfile&ISO2=KR&LAN=EN&outtype=html. Cited 26 February 2015.

8. Shim TS, Koh WJ, Yim JJ, Lew WJ. Treatment of latent tuberculosis infection in Korea. Tuberculosis and Respiratory Diseases. 2008;65: 79–90.

9. Korea Centers for Disease Control and Prevention. Revised national tuberculosis control programme in Korea. 25 Aug 2012. http://cdc.go.kr/CDC/info/CdcKrInfo0301.jsp?menuIds=HOME001-MNU1154-MNU0005-MNU0037-MNU1380&cid=12254. Cited 3 October 2016.

10. Ip MS, Yuen KY, Woo PC, Luk WK, Tsang KW, Lam WK, et al. Risk factors for pulmonary tuberculosis in bone marrow transplant recipients. Am J Respir Crit Care Med. 1998;158: 1173–1177. pmid:9769278

11. Tuon FF, Litvoc MN, Lopes MI. Adenosine deaminase and tuberculous pericarditis—a systematic review with meta-analysis. Acta Trop. 2006;99: 67–74. pmid:16950165

12. Jung JI, Lee DG, Kim YJ, Yoon HK, Kim CC, Park SH. Pulmonary tuberculosis after hematopoietic stem cell transplantation: radiologic findings. J Thorac Imaging. 2009;24: 10–16. pmid:19242297

13. Eom KS, Lee DG, Lee HJ, Cho SY, Choi SM, Choi JK, et al. Tuberculosis before hematopoietic stem cell transplantation in patients with hematologic diseases: report of a single-center experience. Transpl Infect Dis. 2015;17: 73–79. pmid:25620389

14. Liebeschuetz S, Bamber S, Ewer K, Deeks J, Pathan AA, Lalvani A. Diagnosis of tuberculosis in South African children with a T-cell-based assay: a prospective cohort study. Lancet. 2004;364: 2196–2203. pmid:15610806

15. Kim SH, Choi SJ, Kim HB, Kim NJ, Oh MD, Choe KW. Diagnostic usefulness of a T-cell based assay for extrapulmonary tuberculosis. Arch Intern Med. 2007;167: 2255–2259. pmid:17998500

16. Kwon JC, Kim SH, Park SH, Choi SM, Lee DG, Choi JH, et al. Clinical characteristics and the usefulness of the QuantiFERON-TB Gold In-Tube test in hematologic patients with hepatic or splenic lesions. Korean J Intern Med. 2013;28: 187–196. pmid:23525889

17. American Thoracic Society. Diagnostic Standards and Classification of Tuberculosis in Adults and Children. This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This statement was endorsed by the Council of the Infectious Disease Society of America, September 1999. Am J Respir Crit Care Med. 2000;161(4 Pt 1): 1376–1395. pmid:10764337

18. Sun HY, Munoz P, Torre-Cisneros J, Aguado JM, Lattes R, Montejo M, et al. Mycobacterium tuberculosis-associated immune reconstitution syndrome in solid-organ transplant recipients. Transplantation. 2013;95: 1173–1181. pmid:23435454

19. Lee DG, Kim SH, Kim SY, Kim CJ, Park WB, Song YG, et al. Evidence-based guidelines for empirical therapy of neutropenic fever in Korea. Korean J Intern Med. 2011;26: 220–252. pmid:21716917

20. Kim SH, Kee SY, Lee DG, Choi SM, Park SH, Kwon JC, et al. Infectious complications following allogeneic stem cell transplantation: reduced-intensity vs. myeloablative conditioning regimens. Transpl Infect Dis. 2013;15: 49–59. d pmid:22998745

21. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15: 825–828 pmid:7581076

22. Korea Centers for Disease Control and Prevention. Annual report on the notified tuberculosis in Korea 2012. 6 Dec 2013. http://www.cdc.go.kr/CDC/info/CdcKrInfo0302.jsp?menuIds=HOME001-MNU1132-MNU1138-MNU0038&fid=32&q_type=&q_value=&cid=22011&pageNum=. Cited 26 February 2015.

23. Sester M, van Leth F, Bruchfeld J, Bumbacea D, Cirillo DM, Dilektasli AG, et al. Risk Assessment of Tuberculosis in Immunocompromised Patients. A TBNET Study. Am J Respir Crit Care Med. 2014;190: 1168–1176. pmid:25303140

24. Moon SM, Lee SO, Choi SH, Kim YS, Woo JH, Yoon DH, et al. 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: 104–109. pmid:22823749

25. Kumar R, Naithani R, Mishra P, Mahapatra M, Seth T, Dolai TK, et al. Allogeneic hematopoietic SCT performed in non-HEPA filter rooms: initial experience from a single center in India. Bone Marrow Transplant. 2009;43: 115–119. pmid:18794872

26. Ullah K, Ahmed P, Raza S, Satti T, Nisa Q, Mirza S, et al. Allogeneic stem cell transplantation in hematological disorders: single center experience from Pakistan. Transplant Proc. 2007;39: 3347–3357. pmid:18089384

27. 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;6: 16. pmid:18021401

28. Park SH, Choi SM, Lee DG, Choi JH, Yoo JH, Lee JW, et al. Current trends of infectious complications following hematopoietic stem cell transplantation in a single center. J Korean Med Sci. 2006;21: 199–207. pmid:16614501

29. 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: 741–743. pmid:16113670

30. Ahmed P, Anwar M, Khan B, Altaf C, Ullah K, Raza S, et al. Role of isoniazid prophylaxis for prevention of tuberculosis in haemopoietic stem cell transplant recipients. J Pak Med Assoc. 2005;55: 378–381 pmid:16302471

31. Yoo JH, Lee DG, Choi SM, Choi JH, Park YH, Kim YJ, et al. Infectious complications and outcomes after allogeneic hematopoietic stem cell transplantation in Korea. Bone Marrow Transplant. 2004;34: 497–504. pmid:15286689

32. Lee J, Lee MH, Kim WS, Kim K, Park SH, Lee SH, et al. Tuberculosis in hematopoietic stem cell transplant recipients in Korea. Int J Hematol. 2004;79: 185–188. pmid:15005349

33. George B, Mathews V, Srivastava A, Chandy M. Infections among allogeneic bone marrow transplant recipients in India. Bone Marrow Transplant. 2004;33: 311–315. pmid:14647246

34. 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: 142–146. pmid:15762931

35. Budak-Alpdogan T, Tangun Y, Kalayoglu-Besisik S, Ratip S, Akan H, Baslar Z, et al. The frequency of tuberculosis in adult allogeneic stem cell transplant recipients in Turkey. Biol Blood Marrow Transplant. 2000;6: 370–374. pmid:10917572

36. Aljurf M, Gyger M, Alrajhi A, Sahovic E, Chaudhri N, Musa M, et al. Mycobacterium tuberculosis infection in allogeneic bone marrow transplantation patients. Bone Marrow Transplant. 1999;24: 551–554. pmid:10482941

37. Roy V, Weisdorf D. Mycobacterial infections following bone marrow transplantation: a 20 year retrospective review. Bone Marrow Transplant. 1997;19: 467–470. pmid:9052913

38. Won YW, Yi SY, Jang JH, Kim K, Kim SJ, Kim WS, et al. Retrospective analysis of paranasal sinusitis in patients receiving hematopoietic stem cell transplantation. Int J Hematol. 2011;93: 383–388. pmid:21360008

39. Lee DG. Common infectious diseases in hematopoietic stem cell transplant Recipients. Korean J Med. 2013;84: 158.

40. Lee YM, Kim SM, Park SJ, Lee SO, Choi SH, Kim YS, et al. Factors associated with a strong response to the T-SPOT.TB in patients with extrapulmonary tuberculosis. Infect Chemother. 2014;46: 248–252. pmid:25566404

41. Akan H, Arslan O, Akan OA. Tuberculosis in stem cell transplant patients. J Hosp Infect. 2006;62: 421–426. pmid:16413085

42. Cobelens FG. For whom the bell tolls: isoniazid preventive therapy and tuberculosis drug resistance. Sci Transl Med. 2013;5: 180fs112.

43. Falzon D, Jaramillo E, Wares F, Zignol M, Floyd K, Raviglione MC. Universal access to care for multidrug-resistant tuberculosis: an analysis of surveillance data. Lancet Infect Dis. 2013;13: 690–697. pmid:23743044

44. Wright A, Zignol M, Van Deun A, Falzon D, Gerdes SR, Feldman K, et al. Epidemiology of antituberculosis drug resistance 2002–07: an updated analysis of the Global Project on Anti-Tuberculosis Drug Resistance Surveillance. Lancet. 2009;373: 1861–1873. pmid:19375159

45. Zignol M, van Gemert W, Falzon D, Sismanidis C, Glaziou P, Floyd K, et al. Surveillance of anti-tuberculosis drug resistance in the world: an updated analysis, 2007–2010. Bull World Health Organ. 2012;90: 111–119d. pmid:22423162