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Incidence and Risk Factors for Nontuberculous Mycobacterial Infection after Allogeneic Hematopoietic Cell Transplantation
Accepted Manuscript Title: Incidence and Risk Factors for Nontuberculous Mycobacterial Infection after Allogeneic Hematopoietic Cell Transplantation Author: Jennifer Beswick, Elizabeth Shin, Fotios Michelis, Santhosh Thyagu, Auro Viswabandya, Jeffrey H. Lipton, Hans Messner, Theodore K. Marras, Dennis Kim PII: DOI: Reference:
S1083-8791(17)30748-6 https://doi.org/doi:10.1016/j.bbmt.2017.09.015 YBBMT 54807
To appear in:
Biology of Blood and Marrow Transplantation
Received date: Accepted date:
19-7-2017 20-9-2017
Please cite this article as: Jennifer Beswick, Elizabeth Shin, Fotios Michelis, Santhosh Thyagu, Auro Viswabandya, Jeffrey H. Lipton, Hans Messner, Theodore K. Marras, Dennis Kim, Incidence and Risk Factors for Nontuberculous Mycobacterial Infection after Allogeneic Hematopoietic Cell Transplantation, Biology of Blood and Marrow Transplantation (2017), https://doi.org/doi:10.1016/j.bbmt.2017.09.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Incidence and risk factors for nontuberculous mycobacterial infection after allogeneic hematopoietic cell transplantation Short title / running head: NTM after allogeneic HCT Authors: Jennifer Beswick MD1, Elizabeth Shin MD2, Fotios Michelis MD2, Santhosh Thyagu MD2, Auro Viswabandya MD2, Jeffrey H Lipton PhD MD2, Hans Messner MD2, Theodore K. Marras MD*3 and Dennis (Dong Hwan) Kim MD*2
* Drs. Marras and Kim contributed equally to this work as senior authors. 1
Department of Medicine, University of Toronto
2
Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology &
Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada 3
Respirology, University Health Network, University of Toronto, Toronto, Canada
Corresponding author: Theodore K. Marras, 399 Bathurst Street, 7 East, Room 452, Toronto, Ontario, M5T 2S8, Canada, [email protected] Word counts: Abstract 250 / Text 3,239 None of the authors have conflicts of interest to disclose Prior presentation: An abstract of this study was presented at the American Society of Hematology Annual Meeting, December 2015, Orlando, Florida.
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Abbreviations aGVHD – acute graft versus host disease cGVHD – chronic graft versus host disease CMV – cytomegalovirus GVHD – graft versus host disease HCT - hematopoietic stem cell transplant MAC – Mycobacterium avium complex NTM – nontuberculous mycobacteria
Keywords: Hematopoietic stem cell transplantation Allogeneic hematopoietic stem cell transplantation Mycobacterium infections, nontuberculous Nontuberculous mycobacteria
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Abstract Allogenic hematopoietic stem cell transplant (HCT) recipients are at risk of many infections. Nontuberculous mycobacteria (NTM) are increasingly recognized as clinically significant pathogens in this population. We investigated the incidence and risk factors for NTM infection after allogeneic HCT. This retrospective cohort study included all patients with allogeneic HCT at our institution during 2001-2013. Patients who developed significant NTM infection (NTM disease) were identified. Multivariable modeling was used to identify risk factors for NTM disease, and a risk score model was constructed to identify high-risk patients. Of 1,097 allogeneic HCT patients, 45 (4.1%) had NTM isolated, and 30 (2.7%) had NTM disease (28 (93.3%) exclusively pulmonary, 2 (6.7%) pulmonary plus another site). Incidence of NTM infection by competing risk analysis was 2.8% at 5 years (95%CI, 1.9-4.0%). The median (range) time to diagnosis was 343 (19-1,967) days. In Fine-Gray proportional hazards modeling, only global severity of chronic graft versus host disease (cGVHD) (HR=1.99, 95%CI [1.12-3.53], p=0.019,) and CMV viremia (HR=5.77, 95%CI [1.71-19.45], p=0.004,) were significantly associated with NTM disease. Using these variables, a risk score was calculated (one point for CMV viremia or moderate cGVHD, 2 points for severe cGVHD). The score divided patients into low risk (0-1 points, n=820 (77.3%), three-year NTM risk 1.2%), intermediate risk (2 points, n=161 (15.4%), three-year NTM risk 7.1%), and high risk (3 points, n=56 (5.4%), three-year NTM risk 14.3%). NTM disease after allogeneic HCT is common. Severe cGVHD and CMV viremia are associated with increased risk, permitting risk stratification.
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Introduction Recipients of allogenic hematopoietic stem cell transplants (HCT) are inherently at risk for a variety of opportunistic infections as a result of their immunocompromised status 1. Several factors are implicated in their impaired cellular immunity, including their underlying disease, myeloablative conditioning regimens, graft versus host disease (GVHD) and its treatment. Although bacterial organisms account for the most frequently reported infectious complications following allogeneic HCT,[1] nontuberculous mycobacteria (NTM) are becoming increasingly recognized as clinically significant pathogens in this population. NTM are nearly ubiquitous environmental organisms, found in moist environments, including potable water and its distribution systems, as well as soils. Infections with NTM occur in humans predominantly as chronic lung infections, and less commonly as skin, soft tissue, or disseminated infections.[2] While the role of NTM pathogenesis is well established in other immunocompromised states such as AIDS, incidence and prevalence data pertaining to NTM infection in allogeneic HCT recipients are sparse and limited to single institutions over varying periods of time. The study of this entity is challenged by the difficulty of differentiating clinically significant NTM infection from culture contamination or transient colonization of the respiratory tract, and the nonmandatory reporting of NTM infection in most countries.[2] Although prior reports suggest that NTM disease in allogeneic HCT recipients is relatively rare, the incidence appears to be substantially higher than in the general population. Among allogeneic HCT recipients, the incidence has increased from 0.26-
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0.55%[3-5] in early studies, to 0.94-2.8%[6-8] in more recent investigations. The discrepant results between early and recent studies is unclear, and may be due to improvements in NTM detection, varying pre-transplant conditioning regimens and regional epidemiology of NTM disease. The increase in NTM among allogeneic HCT recipients mirrors international increases in NTM disease in general.[9] Despite the emerging evidence of this increased incidence, there remain few clinical reports addressing the prognostic implications of NTM infections among allogeneic HCT recipients. Therefore, we investigated the incidence and risk factors associated with NTM infection after allogeneic HCT.
Methods Study Population The study population consisted of 1,047 consecutive patients who underwent allogeneic HCT at the Princess Margaret Cancer Centre, a tertiary-care cancer centre in Toronto, Canada, from January 2001 to December 2013. This retrospective cohort study was approved by the University Health Network Research Ethics Board (study approval 148116-CE). Patients received conditioning regimens prior to HCT infusion as per institutional protocol.[10-13] Related donor transplants were not T-cell depleted. Unrelated donor transplants were T-dell depleted (TCD) in vivo using Alemtuzumab, ATG or not T-cell depleted. For related donors, HLA-A, -B, and -DR were screened and for unrelated donors HLA-C and -DQ were added. Unrelated donors of peripheral blood stem cells
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(PBSC) or bone marrow (BM) cells were identified through the One Match Stem Cell and Marrow Donor Network. All patients were routinely tested for CMV viremia at least once post engraftment. During study period (2001-2013), intravenous ganciclovir preemptive therapy was the standard for patients at risk for CMV. Potential cases of NTM disease were identified by reviewing institutional microbiology laboratory data. For those who had positive cultures, radiographic reports and clinical documentation were reviewed in detail to determine presence of pulmonary, nonpulmonary, or disseminated infection. Date of infection was defined as the day on which the clinical specimen was obtained for mycobacterial studies or a histopathologic specimen was obtained. Isolates were identified at the Public Health Ontario Laboratories, the Ontario provincial reference laboratory, using conventional methods as previously described.[14] Definitions Pulmonary NTM disease was differentiated from colonization according to ATS/IDSA guidelines (e-Table 1).[2] Infections at non-pulmonary sites were defined by NTM isolation from a normally sterile site with compatible symptoms. Disseminated infection was defined as isolation of NTM from two or more sites, including blood, pulmonary, skin/soft tissue, bone, lymphatics, or joints. Acute and chronic graft-versus-host disease (aGVHD and cGVHD) were diagnosed and graded using established and NIH consensus criteria, respectively.[15-17] The severity of cGVHD was graded at the time of its first manifestation.[17] Statistical Analyses
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The incidence of NTM disease was estimated using the cumulative incidence method considering the competing risk of death. Secondary outcomes of interest included risk factors associated with NTM disease, time to infection and overall survival. Overall survival after onset of NTM disease was calculated from the date of confirmed diagnosis of NTM disease to the date of death from any cause. Survival data were censored at the time of last follow-up alive, using the Kaplan-Meier method. Descriptive statistics were used to assess patient demographics, disease characteristics, and other covariates of interest, including immunosuppressive therapy, conditioning regimen used, the presence, location and severity of GVHD, and comorbid infection. Time dependent Cox’s analyses using proportional hazard regression model was applied in order to test if the effect of GVHD or CMV viremia on NTM risk is time dependent. Neither GVHD (p=0.303, HR 1.659) nor CMV viremia (p=0.148, HR 0.946) were found to be significant time-dependent covariates for the development of NTM. Thus, these two variables were included as non-time dependent covariates in the following analysis. Univariate and multivariate analyses were performed to assess for associations between potential risk factors and NTM incidence using a Fine-gray regression model considering competing risk. The following variables were included in the multivariate model: age, cGVHD/grade, aGVHD grade 2-4, CMV viremia, diagnosis, conditioning regimen, T-cell depletion, source of stem cell, donor type and HLA disparity as presented in Table 1. For multivariate modeling, a stepwise selection algorithm was applied for variable selection, using the criteria p<0.05 for variable entry and p>0.1 for variable removal. All P values were two sided. Cause-specific hazard ratios (HRs) and 95% confidence intervals (CIs)
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were estimated for the significant risk factors, based on a multivariable analysis with a statistical significance level of 0.05. A risk score model was constructed using the two variables identified in multivariate analysis as independent risk factors for NTM disease after allogeneic HCT. The model was generated by assigning a score of 1 to the development of CMV viremia or moderate grade cGVHD, and a score of 2 to the development of severe grade cGVHD by the NIH consensus criteria. This generated a total score of 0 (n=405, 38.7%), 1 (n=415, 39.6%), 2 (n=161, 15.4%) or 3 (n=56, 5.4%). Patients were then classified as either low risk (score 0 or 1; n=820, 77.3%), intermediate risk (score 2; n=161, 15.4%) or high risk (score 3; n=56, 5.4%). Then the incidence of NTM was compared according to these three risk groups using Gray method and hazard ratio was also calculated using FineGray regression model. The statistical analysis for cumulative incidence and survival analyses were performed using EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan).[18] EZR is a modified version of R commander (version 2.12.1) (http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html)
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Results Incidence of NTM after transplant Of the 1,097 patients who underwent allogeneic HCT at our institution between January 2000 and December 2013, NTM were isolated in 45 (4.1%) and were judged to be clinically significant (disease causing) in 30 (2.7%). The clinical characteristics of the patients reviewed are summarized in Table 1. The median (quartiles) follow-up among survivors overall was 51 (23-70) months, and among survivors with NTM, 21 (7-39) months after NTM diagnosis. Of the 30 clinically significant NTM infections, 28 (93.3%) were exclusively pulmonary and 2 (6.7%) were disseminated. With respect to disseminated infection, one patient had NTM isolated from blood in addition to bronchoalveolar lavage (BAL), whereas the second patient had presumed disseminated infection on the basis of characteristic skin findings in addition to pulmonary isolation, though a skin biopsy was not sought, and therefore a microbiologic diagnosis could not be confirmed. There were no NTM cases that were exclusively non-pulmonary. The incidence of NTM disease by competing risk analysis was 2.8% at 5 years (95% CI, 1.9-4.0%). The median (range) time to diagnosis was 343 (19-1,967) days, and in 83% of patients, was diagnosed within 2 years after allogeneic HCT (Figure 1). The most common species/groups isolated were Mycobacterium avium complex (MAC, n=14; 46.7%) followed by M. xenopi (n=8; 26.7%), M. fortuitum (n=5; 16.7%), M. abscessus (n=2; 6.7%), and M. gordonae (n=1; 3.3%). Twenty-two of 30 patients (73.3%) were on systemic immunosuppression at the time of diagnosis, with the majority of patients (N=19, 63.3%) on ≥20 mg of prednisone daily. Fifteen of 30 patients (50%)
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were on mycophenolate. A minority of patients (N=5, 16.7%) were on cyclosporine. Twenty-seven of 30 (90.5%) patients had concurrent infections (30.4% pulmonary, 17.3% extra-pulmonary, and 47.8% both), with fungal infections occurring most frequently (16/30, 53.3%). Twenty-seven of 30 (90%) had a diagnosis of GVHD, acute or chronic, with lung GVHD occurring in 19/30 (63.3%). Twenty-five of thirty patients (83%) with NTM disease received specific antimicrobial therapy. Treatment was based on international guidelines.[2] M. avium and M. xenopi were generally treated with a macrolide and ethambutol, plus often a fluoroquinolone and/or rifabutin. Univariate analysis of Risk Factors for NTM Infection In univariate analysis, cGVHD (p=0.011, HR 3.20 [1.06-9.68]), age (p<0.001, HR 1.05 [1.02-1.07]), and CMV viremia (p=0.0008, HR 4.64 [1.90-11.37], Table 2) were identified as significant risk factors for NTM disease. Among patients who developed NTM, GVHD preceded the diagnosis of NTM in every patient, and was detected a median (quartiles) of 317 (66-493) days before NTM diagnosis. Among patients who developed NTM, CMV viremia preceded the diagnosis of NTM in 21/23 patients, was detected simultaneously in 1 patient, and was detected 18 days following in the other patient. Overall, CMV viremia preceded NTM diagnosis by a median (quartiles) of 291 (106-450) days. Among patients who developed cGVHD, 3.9% developed NTM disease at 3 years (2.45.8%) compared with 1.3% (0.5-2.7%) in the group without cGVHD (p=0.011; HR 3.24 [1.32-7.93]). When we compared the incidence of NTM disease at 3 years according to the severity of cGVHD based on the global severity score by the NIH consensus criteria,
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NTM disease had occurred in 1.5% (0.4-4.0%) of patients with mild cGVHD, 3.9% (1.97.0%) of those with moderate cGVHD, and 10.7% (4.9-19.0%) of those with severe cGVHD (Figure 2A). Among patients who developed CMV viremia 4.8% also developed NTM by 3 years (3.0-7.0%) compared with 1.0% [0.4-2.1%]; HR 4.64 [1.89-11.37] among those without CMV viremia (Figure 2B). Other risk factors were also explored for the risk of NTM disease as shown in Table 2. Gender (p=0.89), diagnosis (p=0.67 between lymphoid vs myeloid; p=0.59 between acute leukemia vs others), allogeneic HCT conditioning regimen (p=0.17), T-cell depletion for GVHD prophylaxis (p=0.56), source of stem cells (p=1.0), donor type (p=0.21) or HLA disparity (n=0.61) were not found to be associated with the risk of NTM disease. Multivariate Analysis and NTM risk score model Using Fine-Gray proportional hazards modeling, two variables were confirmed as independent risk factors: 1) global severity score of cGVHD (p=0.019, HR 1.99 [1.123.53]) and 2) CMV viremia (p=0.004, HR 5.77 [1.71-19.45]).The group with moderate grade cGVHD showed 3.36 times higher incidence of NTM disease (HR 3.36 [0.94-12.05]) compared to those with mild grade, while those with severe grade showed 7.66 times higher risk of NTM disease (HR 7.66 [2.04-28.81]) compared to those with mild grade cGVHD. Using the two variables identified as independent risk factors for NTM disease a score was calculated. One point was assigned for CMV viremia or moderate grade chronic GVHD, and 2 points were assigned for severe grade chronic GVHD. The score divided
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patients as follows: 0 points (n=405, 38.7%), 1 point (n=415, 39.6%), 2 points (n=161, 15.4%) or 3 points (n=56, 5.4%). As shown in e-Figure 1, there was no significant difference of NTM rate between the groups with score 0 (0.8% [0.6-2.1]) and with score 1 (1.5% [0.6-3.2%]). But the groups with score 2 and 3 showed higher rates of NTM at 3 years (score 2; 7.1%, score 3; 14.3%). Accordingly, patients were divided into low risk (score 0 or 1; n=820, 77.3%), intermediate risk (score 2; n=161, 15.4%), and high risk (score 3; n=56, 5.4%) groups, as shown in Figure 3. This risk score model could stratify patients according to their NTM risk (p<0.001) Survival after NTM infection Total number of deaths and causes of death for the entire cohort of allogeneic HCT patients and by NTM status is presented in e-Table 2. Median survival duration after a diagnosis of NTM disease was 398 (95% CI, 105-764 days) days, with a survival rate of 40.8% at 2 years (95% CI, 20.3-60.4%). Figure 4A demonstrates cumulative survival following a diagnosis of NTM disease. We searched for prognostic factors associated with survival after the onset of NTM disease. Survival after NTM disease was not associated with acute GVHD, CMV viremia, number of organisms causing infection at NTM diagnosis, coexistence of fungal viral or bacterial infection, or age. However, patients with moderate/severe grade cGVHD at onset of NTM disease showed a shorter median survival than those with none/mild grade cGVHD (105 days vs 746 days; p=0.025; HR 3.37 [1.09-10.37]) as shown in Figure 4B.
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Discussion In our 13-year, retrospective study including 1,047 allogeneic HCT recipients, we identified NTM disease in 2.7%, the vast majority of which (93.3%) was pulmonary. By competing risk analysis, we calculated a 5-year risk of NTM disease of 2.8%, with a median onset at 343 days post transplant. Traditional risk factors for pulmonary NTM in the general population (age and female sex), were not associated with NTM in our cohort. Presumably the risk of allogeneic HCT and its complications overwhelm the effect of risk factors that are important in the general population. We generated a risk score stratifying patients into low, medium and high risk of NTM disease, based on the presence and severity of chronic GVHD and the presence of CMV viremia. Patients at high risk, who also appear to be at high risk for other pulmonary infections, should have pulmonary symptoms or signs carefully evaluated with chest CT scan and appropriate microbiological specimen analysis including mycobacterial studies. Our risk score model, developed from single-center data, requires external validation to assure validity. The 2.7% frequency of NTM that we observed post allogeneic HCT is approximately 65 fold higher than expected in the general population, given the period prevalence in Ontario of41/100,000.[14] This comparison could in part reflect intensive in microbiological surveillance of HCT patients. Unfortunately, we do not have comparison data for other groups, such as patients with hematological malignancies. Prior studies identified risks of NTM disease of 0.26-2.8% post allogeneic HCT,[3-8] a range may be explainable in at least two ways. First, the observation that more recent studies identified higher rates,[6-8] is consistent with increases in NTM disease in general
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populations[14, 19, 20],[9] possibly due to icreased risk factors (population ageing, underlying lung disease, immune suppression).[21] A second explanation for differences in rates of NTM disease between allogeneic HCT cohorts is regional variability, as described with these environmental organisms.[22] Pulmonary NTM was ubiquitous in our cohort, with two patients exhibiting nonpulmonary infection in addition to lung infection. Although most prior studies did not present adequate data to determine the precise proportion of pulmonary versus nonpulmonary infections there are some available data. A 20-year review from Minnesota identified exclusively non-pulmonary disease, along with a low incidence of NTM overall, at 0.47%[3] Among other cohorts, substantial proportions of observed cases were pulmonary.[4, 5, 7] Specifically in a series of 50 allogeneic HCT patients with NTM isolates, pulmonary disease was present in approximately one-third of patients with definite NTM disease and all of the patients with probable or possible disease.[7] The latter series underscores both that NTM may be most likely pulmonary in allogeneic HCT, and the challenges in determining whether a respiratory isolate represents true disease. In the context of other possible causes for pulmonary and systemic symptoms and chest imaging derangements, it can be difficult to assess whether any single respiratory tract organism is truly causing disease. In our series, pulmonary isolation was judged to be indicative of true disease in two-thirds of patients. The species distribution that we observed, with M. avium followed by M. xenopi, is consistent with the most frequently observed NTM in Ontario.[14] Prior studies have identified MAC as the most common cause of NTM lung disease post allogeneic HCT,[4,
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6, 7] also the most common cause of NTM lung disease worldwide.[22] In a study of allogeneic HCT patients with NTM lung disease in Korea, although 60% of patients had MAC, 20% had M. abscessus. The latter is a very common cause of NTM lung disease in Korea, while in Ontario, Canada, M. abscessus causes less than 3% of NTM lung disease.[14] The species distribution causing NTM lung disease in the allogeneic HCT population appears to vary regionally, likely mirroring the species distribution for that region in general. In the present study, two risk factors were identified: cGVHD and CMV viremia. It is not clear whether CMV viremia itself elevates the risk of NTM disease, or if the predisposing factor for CMV viremia could overlap with those for NTM disease. Perhaps prolonged immune recovery could predispose both to CMV infection as well as NTM disease. Also more severe grade of cGVHD could predispose to increasing risk of NTM disease through prolonged use of systemic immunosuppression as well as delayed immune recovery via systemic immunosuppressive therapy or via GVHD related mechanism. Accordingly immune monitoring as well as frequent surveillance (such as sputum AFB) will be helpful in the high risk group of patients for NTM disease including the case with CMV viremia or cGVHD of moderate or severe grade. Our study has important limitations. First, it is often challenging to determine whether respiratory NTM isolates indicate the presence of disease,[2] particularly so in patients with multiple potential causes of symptoms and chest imaging abnormalities. Although we attempted to restrict our analysis to patients with NTM disease by application of guidelines criteria[2] through detailed chart review, some patients may have been
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incorrectly classified as having either NTM disease or non-significant NTM isolation. Second, it is difficult to accurately estimate the mortality attributable to NTM disease, given that infected patients tend to have more post allogeneic HCT complications, which themselves would be expected to reduce survival, and that NTM is a delayed complication, thereby introducing an immortal time bias, which needs to be accounted for in survival analyses. With our small sample of NTM-infected patients, we think such an analysis would be unreliable. Third, changes in CMV surveillance could potentially have affected our results. CMV antigenemia testing (>1 infected cell of 200,000 nucleated cells in PB smear) was changed to CMV viremia (>200 IU) in early 2011. However, the incidence of CMV was quite stable over the entire study period, so it is unlikely that the change in testing affected our results, Finally, our results may not be
readily transportable to similar cohorts in other regions in that our risk model was generated at a single center, and so requires external validation, and NTM are environmental organisms with exposure rates that undoubtedly vary between regions.[22] Clinicians should consider local rates of NTM when calibrating a level of suspicion regarding NTM infection post allogeneic HCT. In summary, in our large experience we identified NTM disease in a substantial proportion of patients post allogeneic HCT. Risk stratification was possible according to the presence of cGVHD, moderate-severe aGVHD, and CMV viremia. Clinicians should recognize the possibility of NTM disease post allogeneic HCT, especially in the presence of risk factors, and ensure that appropriate specimens are tested for the presence of mycobacteria when indicated. Important future directions include external validation of
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our risk score, studying the mortality attributable to NTM disease, treatment outcomes, and early detection or prevention.
Acknowledgements JB, TM and DK made substantial contributions to conception, design, data acquisition, analysis, data interpretation, drafting and revising of the article, have provided final approval of the version to be published, and have agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. ES, FM, ST, AV, JL and HM made substantial contributions to data acquisition, revised the article critically for important intellectual content, have provided final approval of the version to be published, and have has agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. DK takes responsibility for the content of the manuscript including the data and the analysis. The authors have no conflicts of interest to disclose.
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Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective. Preface. Bone Marrow Transplant. 2009; 44(8):453-5. Griffith DE, Aksamit T, Brown-Elliott BA, et al. Diagnosis, Treatment and Prevention of Nontuberculous Mycobacterial Diseases. Am J Respir Crit Care Med. 2007; 175:367-416. Roy V, Weisdorf D. Mycobacterial infections following bone marrow transplantation: a 20 year retrospective review. Bone Marrow Transplant. 1997; 19(5):467-70. Gaviria JM, Garcia PJ, Garrido SM, Corey L, Boeckh M. Nontuberculous mycobacterial infections in hematopoietic stem cell transplant recipients: characteristics of respiratory and catheter-related infections. Biol Blood Marrow Transplant. 2000; 6(4):361-9. Cordonnier C, Martino R, Trabasso P, et al, Mycobacterial infection: a difficult and late diagnosis in stem cell transplant recipients. Clin Infect Dis. 2004; 38(9):1229-36..6. Kang JY, Ha JH, Kang HS, et al. Clinical significance of nontuberculous mycobacteria from respiratory specimens in stem cell transplantation recipients. Int J Hematol. 2015; 101(5):505-13. Weinstock DM, Feinstein MB, Sepkowitz KA, Jakubowski A. High rates of infection and colonization by nontuberculous mycobacteria after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003; 31(11):1015-21. Knoll B. Update on nontuberculous mycobacterial infections in solid organ and hematopoietic stem cell transplant recipients. Curr Infect Dis Rep. 2014; 16(9):421. Brode SK, Daley CL, Marras TK. The epidemiologic relationship between tuberculosis and non-tuberculous mycobacterial disease: a systematic review. Int J Tuberc Lung Dis. 2014; 18(11)1370-7. Moon JH, Hamad N, Sohn SK, et al. Improved prognostic stratification power of CIBMTR risk score with the addition of absolute lymphocyte and eosinophil counts at the onset of chronic GVHD. Ann Hematol. 2017; 96(5):805-15. Hamad N, Seftel M, Michelis FV, et al. Mycophenolate-based graft versus host disease prophylaxis is not inferior to methotrexate in myeloablative-related donor stem cell transplantation. Am J Hematol. 2015; 90(5):392-9. Sibai H, Falcone U, Deotare U, et al. Myeloablative versus Reduced-Intensity Conditioning in Patients with Myeloid Malignancies: A Propensity ScoreMatched Analysis. Biol Blood Marrow Transplant. 2016; 22(12):2270-2275. Uhm J, Hamad N, Shin EM, et al. Incidence, risk factors, and long-term outcomes of sclerotic graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2014. 20(11):1751-7.
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Marras TK, Mendelson D, Marchand-Austin A, May K, Jamieson FB. Pulmonary Nontuberculous Mycobacterial Disease, Ontario, Canada, 19982010. Emerg Infect Dis. 2013; 19(11):1889-1891. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995; 15(6):825-8. Pavletic SZ, Lee SJ, Socie G, Vogelsang G. Chronic graft-versus-host disease: implications of the National Institutes of Health consensus development project on criteria for clinical trials. Bone Marrow Transplant. 2006; 38(10):645-51. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graftversus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005; 11(12):945-56. Kanda, Y., Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 2013; 48(3):452-8. Adjemian J, Olivier KN, Seitz KE, Holland SM, Prevots DR., Prevalence of Nontuberculous Mycobacterial Lung Disease in U.S. Medicare Beneficiaries. Am J Respir Crit Care Med. 2012; 185(8):881-886. Winthrop KL, McNelley E, Kendall B, et al. Pulmonary Nontuberculous Mycobacterial Disease Prevalence and Clinical Features: An Emerging Public Health Disease. Am J Respir Crit Care Med. 2010; 182:977-982. AlHouqani M, Jamieson FB, Mehta M, Chedore P, May K, Marras TK. Aging, COPD and other risk factors do not explain the increased prevalence of pulmonary Mycobacterium avium complex in Ontario. Chest. 2012; 141(1):190-197. Prevots DR, Marras TK. Epidemiology of human pulmonary infection with nontuberculous mycobacteria: a review. Clin Chest Med. 2015; 36(1):13-34.
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Figure 1. Incidence of NTM disease after allogeneic hematopoietic stem cell transplantation Figure1
0.15
Post-transplant NTM incidence 2.7% at 3 years 95% CI (1.8-3.9%)
Cumulative incidence
of NTM infection IncidenceCumulative incidence post-HCT
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Figure 2. Risk factors for the development of NTM disease post-allogeneic hematopoietic stem cell transplant including chronic GVHD and its severity (National Institutes of Health consensus criteria global severity score) (A) and CMV viremia (B) Figure2A NTMrisk_cGVHD_GSS2
post-HCT of NTM infection IncidenceCumulative incidence Cumulative incidence
0.20
no GVHD mild moderate severe
cGVHD grade and NTM risk: Any vs none - HR 2.75 (1.79-4.23) Moderate/severe vs none/mild - HR 4.60 (2.09-10.1)
0.15
Severe grade cGVHD (n=98) 10.7% at 3 yrs (4.9-19.0%)
0.10
Moderate grade cGVHD (n=235) 3.9% at 3 years (1.9-7.0%)
0.05
Mild grade cGVHD (n=210) 1.5% at 3 years (0.4-4.0%) No cGVHD (n=494) 1.3% at 3 years (0.5-2.7%)
0.00 0
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3
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5
6
DayNTM3 Years after allogeneic stem cell transplantation DAYAGV1234cmprsk
Figure2B NTMrisk_CMVAGYN
0.20
post-HCT of NTM infection IncidenceCumulative incidence Cumulative incidence
0 1
P < 0.001 HR 4.64 (1.89-11.37)
0.15
0.10
CMV viremia (n=480) 4.8% at 3 yrs (3.0-7.0%)
0.05
No CMV viremia (n=565) 1.0% at 3 years (0.4-2.1%)
0.00 0
1
2
3
4
5
6
DayNTM3 Years after allogeneic stem cell transplantation DAYAGV1234cmprsk
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Figure 3. Risk score model for the development of NTM disease post-allogeneic hematopoietic stem cell transplant Figure3 NTMrisk_riskscore_final2
0.20
post-HCT NTM infection ofCumulative IncidenceCumulative incidence incidence
P < 0.001 HR 3.51 (2.35-5.24)
1 2 3
High risk (score 3; n=56) 14.3% at 3 yrs (5.5-27.0%)
0.15
Intermediate risk (n=161) 7.1% at 3 years (3.7-11.9%)
0.10
0.05
Low risk (n=820) 1.2% at 3 years (0.6-2.1%)
0.00 0
1
Years after
2
3
allogeneicDayNTM3 stem cell
4
5
6
transplantation
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Figure 4. Survival after onset of NTM disease post-transplant (A) and survival difference by chronic graft versus host disease severity - moderate/severe versus mild/none (B)
onset of NTM infection after Probability of survival incidence Cumulative Probability
Figure 4A 1.0
0.8
40.8% 3 year overall survival 95%CI (20.3-60.4%)
0.6
Median survival 398 days (105-764 days)
0.4
0.2
0.0 0
2
Years after
4
6
onset ofDayD_NTM NTM infection DAYAGV1234cmprsk
8
post-HCT
onset of NTM infection after Probability of survival incidence Cumulative Probability
Figure4B NTMrisk_cGVHD_GSS01vs23
1.0
no/mild grade HR 3.37 (1.09-10.379-10.37) moderate/severe grade
P = 0.025
0.8
No or mild grade cGVHD (n=15) Survival: median 746 days, one-year 63.6% (33.0-83.1%)
0.6
0.4
0.2
Moderate/Severe grade cGVHD (n=9) Survival: median 105 days, one-year 29.6% (5.2-60.7%) 0.0 0
2
4
6
8
Years after onset ofDayD_NTM NTM infection post-HCT DAYAGV1234cmprsk
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Table 1: Clinical characteristics among allogeneic hematopoietic cell transplantation patients according to subsequent NTM infection Overall NTM cases No NTM P N=1047 N=30 N=1017 value Baseline characteristics Female sex 447 (43) 12 (40) 435 (43) 0.925 Age at transplant (years) 49.5 53 49.5 0.565 - median (IQR) (38-57.5) (44-60) (38-57.5) Diagnosis AML 418 (39.9) 13 (43.3) 405 (39.8) 0.676 ALL 126 (12.0) 1 (3.3) 125 (12.3) MDS 104 (9.9) 4 (13.3) 100 (9.8) CML 95 (9.1) 2 (6.7) 93 (9.1) NHL 164 (15.7) 6 (20.0) 158 (15.5) AA 57 (5.4) 1 (3.3) 56 (5.5) Others 83 (7.9) 3 (10.0) 80 (7.9) PBSC Graft source 817/1032 (80) 28 (93.3) 789/1002 (78.7) 0.065 Related donor 541/1018 (54) 16/28 (57.1) 525 (53.6) 0.709 HLA disparity 56/1034 (5.4) 2/28 (7.1) 54/1,006 (5.4) 1.00 Conditioning Myeloablative 687/1,044 (66) 16/29 (55) 671/1,015 (66) 0.221 Reduced intensity 357/1,044 (34) 13/29 (45) 344/1,015 (34) GVHD prophylaxis T cell depletion 290 (28) 9 (30) 281 (28) 0.775 Outcomes CMV viremia 480/1045 (46) 23/29 (79) 457/1,016 (45) <0.001 Acute GVHD 743/1,017 (71) 22/27 (76) 721/990 (71) 0.577 Grade 2-4 603/1,017 (59) 19/27 (70) 584/990 (59) 0.235 Grade 3,4 116/1,017 (21) 6/27 (33) 110/990 (21) 0.199 Chronic GVHD 548/1,045 (52) 23/29 (79) 525/1,016 (52) 0.003 Mild 210/1,045 (39) 3/29 (13) 207/1,016 (40) 0.006 Moderate 235/1,045 (43) 11/29 (48) 224/1,016 (43) Severe 98/1,045 (18) 9/29 (39) 89/1,016 (17) Death 532/1,045 (51) 15/29 (52) 517 (50.9) 0.929 Non-relapse mortality 349/1,045 (33) 12/29 (41) 337 (33.2) 0.355 Relapse 195/1,045 (19) 4/29 (14) 191 (18.8) 0.633 Unless otherwise indicated, values reported as number (%) Denominator provided to indicate variables with missing data ALL - acute lymphoblastic leukemia; AML - acute myeloid leukemia; CML - chronic myeloid leukemia; CMV - cytomegalovirus; GVHD - graft-versus-host disease; HLA – human leukocyte antigen; MDS - myelodysplastic syndrome; NHL - non-Hodgkin’s lymphoma; NTM - nontuberculous mycobacteria; PBSC - peripheral blood stem cell; AA aplastic anemia
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Table 2: Univariate risk factor analysis for NTM disease post allogeneic hematopoietic cell transplantation Category
Risk factor (Number)
Age Gender
Not applicable Female (448) Male (599) None (494) Mild (210) Moderate (235) Severe (98) Grade 0/1 (414) Grade 2-4 (603) Absent (565) Present (480) Lymphoid (171) Myeloid (875) Acute leukemia (502) Others (544) Myeloablative (687) Reduced intensity (357) No (756) Yes (290) Marrow (215) Peripheral blood (816) Related (477) Unrelated (541) Matched pair (978) Mismatched pair (56)
Chronic GVHD
Acute GVHD CMV viremia Diagnosis
Conditioning T-cell depletion Stem cell source Donor type HLA disparity
NTM at 3 years (percent, 95%CI) Not applicable 2.7 (1.4-4.6) 2.7 (1.6-4.3) 1.3 (0.5-2.7) 1.5 (0.4-4.0) 3.9 (1.9-7.0) 10.7 (4.9-19.0) 2.2 (1.0-4.1) 2.8 (1.7-4.4) 1.0 (0.4-2.1) 4.8 (3.0-7.0) 2.4 (0.8-5.6) 2.8 (1.8-4.1) 2.7 (1.5-4.5) 2.7 (1.5-4.4) 2.3 (1.4-3.7) 3.4 (1.8-5.8) 2.6 (1.6-4.0) 2.8 (1.3-5.3) 0.9 (0.2-3.1) 3.3 (2.1-4.7) 2.5 (1.3-4.4) 2.8 (1.6-4.5) 2.6 (1.7-3.7) 3.6 (0.6-11.1)
Hazard Ratio (95%CI)
p-value
1.05 (1.02-1.07) 1.08 (0.52-2.24)
<0.001 0.89
2.75 (1.79-4.23)
<0.001
1.56 (0.68-3.54)
0.29
4.64 (1.89-11.37)
<0.001
0.81 (0.33-1.97)
0.67
0.82 (0.39-1.67)
0.59
1.67 (0.81-3.45)
0.17
1.28 (0.58-2.78)
0.56
3.93 (0.93-16.67)
1.0
1.09 (0.52-2.29)
0.21
1.36 (0.32-5.73)
0.61
Risk factor significance determined by Fine-gray competing risk regression model Age tested as a continuous variable with hazard ratio reported per year increase in age CMV - cytomegalovirus; GVHD - graft-versus-host disease; HLA – human leukocyte antigen; HR - hazard ratio; NTM - nontuberculous mycobacteria
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Table 3: Risk score model for the risk of NTM disease post-transplant Risk group Risk score* Number of NTM at 3 years patients (%) (95% CI) Low 0-1 820 1.2 (0.6-2.1) Intermediate 2 161 7.1 (3.7-11.9) High 3 56 14.3 (5.5-27.0) NTM - nontuberculous mycobacteria * Chronic graft versus host disease global severity score (non-mild = 0 points, moderate = 1 point, severe = 2 points); Cytomegalovirus viremia (absent = 0 points, present = 1 point)
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S1083-8791(17)30748-6 https://doi.org/doi:10.1016/j.bbmt.2017.09.015 YBBMT 54807
To appear in:
Biology of Blood and Marrow Transplantation
Received date: Accepted date:
19-7-2017 20-9-2017
Please cite this article as: Jennifer Beswick, Elizabeth Shin, Fotios Michelis, Santhosh Thyagu, Auro Viswabandya, Jeffrey H. Lipton, Hans Messner, Theodore K. Marras, Dennis Kim, Incidence and Risk Factors for Nontuberculous Mycobacterial Infection after Allogeneic Hematopoietic Cell Transplantation, Biology of Blood and Marrow Transplantation (2017), https://doi.org/doi:10.1016/j.bbmt.2017.09.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Incidence and risk factors for nontuberculous mycobacterial infection after allogeneic hematopoietic cell transplantation Short title / running head: NTM after allogeneic HCT Authors: Jennifer Beswick MD1, Elizabeth Shin MD2, Fotios Michelis MD2, Santhosh Thyagu MD2, Auro Viswabandya MD2, Jeffrey H Lipton PhD MD2, Hans Messner MD2, Theodore K. Marras MD*3 and Dennis (Dong Hwan) Kim MD*2
* Drs. Marras and Kim contributed equally to this work as senior authors. 1
Department of Medicine, University of Toronto
2
Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology &
Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada 3
Respirology, University Health Network, University of Toronto, Toronto, Canada
Corresponding author: Theodore K. Marras, 399 Bathurst Street, 7 East, Room 452, Toronto, Ontario, M5T 2S8, Canada, [email protected] Word counts: Abstract 250 / Text 3,239 None of the authors have conflicts of interest to disclose Prior presentation: An abstract of this study was presented at the American Society of Hematology Annual Meeting, December 2015, Orlando, Florida.
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Abbreviations aGVHD – acute graft versus host disease cGVHD – chronic graft versus host disease CMV – cytomegalovirus GVHD – graft versus host disease HCT - hematopoietic stem cell transplant MAC – Mycobacterium avium complex NTM – nontuberculous mycobacteria
Keywords: Hematopoietic stem cell transplantation Allogeneic hematopoietic stem cell transplantation Mycobacterium infections, nontuberculous Nontuberculous mycobacteria
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Abstract Allogenic hematopoietic stem cell transplant (HCT) recipients are at risk of many infections. Nontuberculous mycobacteria (NTM) are increasingly recognized as clinically significant pathogens in this population. We investigated the incidence and risk factors for NTM infection after allogeneic HCT. This retrospective cohort study included all patients with allogeneic HCT at our institution during 2001-2013. Patients who developed significant NTM infection (NTM disease) were identified. Multivariable modeling was used to identify risk factors for NTM disease, and a risk score model was constructed to identify high-risk patients. Of 1,097 allogeneic HCT patients, 45 (4.1%) had NTM isolated, and 30 (2.7%) had NTM disease (28 (93.3%) exclusively pulmonary, 2 (6.7%) pulmonary plus another site). Incidence of NTM infection by competing risk analysis was 2.8% at 5 years (95%CI, 1.9-4.0%). The median (range) time to diagnosis was 343 (19-1,967) days. In Fine-Gray proportional hazards modeling, only global severity of chronic graft versus host disease (cGVHD) (HR=1.99, 95%CI [1.12-3.53], p=0.019,) and CMV viremia (HR=5.77, 95%CI [1.71-19.45], p=0.004,) were significantly associated with NTM disease. Using these variables, a risk score was calculated (one point for CMV viremia or moderate cGVHD, 2 points for severe cGVHD). The score divided patients into low risk (0-1 points, n=820 (77.3%), three-year NTM risk 1.2%), intermediate risk (2 points, n=161 (15.4%), three-year NTM risk 7.1%), and high risk (3 points, n=56 (5.4%), three-year NTM risk 14.3%). NTM disease after allogeneic HCT is common. Severe cGVHD and CMV viremia are associated with increased risk, permitting risk stratification.
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Introduction Recipients of allogenic hematopoietic stem cell transplants (HCT) are inherently at risk for a variety of opportunistic infections as a result of their immunocompromised status 1. Several factors are implicated in their impaired cellular immunity, including their underlying disease, myeloablative conditioning regimens, graft versus host disease (GVHD) and its treatment. Although bacterial organisms account for the most frequently reported infectious complications following allogeneic HCT,[1] nontuberculous mycobacteria (NTM) are becoming increasingly recognized as clinically significant pathogens in this population. NTM are nearly ubiquitous environmental organisms, found in moist environments, including potable water and its distribution systems, as well as soils. Infections with NTM occur in humans predominantly as chronic lung infections, and less commonly as skin, soft tissue, or disseminated infections.[2] While the role of NTM pathogenesis is well established in other immunocompromised states such as AIDS, incidence and prevalence data pertaining to NTM infection in allogeneic HCT recipients are sparse and limited to single institutions over varying periods of time. The study of this entity is challenged by the difficulty of differentiating clinically significant NTM infection from culture contamination or transient colonization of the respiratory tract, and the nonmandatory reporting of NTM infection in most countries.[2] Although prior reports suggest that NTM disease in allogeneic HCT recipients is relatively rare, the incidence appears to be substantially higher than in the general population. Among allogeneic HCT recipients, the incidence has increased from 0.26-
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0.55%[3-5] in early studies, to 0.94-2.8%[6-8] in more recent investigations. The discrepant results between early and recent studies is unclear, and may be due to improvements in NTM detection, varying pre-transplant conditioning regimens and regional epidemiology of NTM disease. The increase in NTM among allogeneic HCT recipients mirrors international increases in NTM disease in general.[9] Despite the emerging evidence of this increased incidence, there remain few clinical reports addressing the prognostic implications of NTM infections among allogeneic HCT recipients. Therefore, we investigated the incidence and risk factors associated with NTM infection after allogeneic HCT.
Methods Study Population The study population consisted of 1,047 consecutive patients who underwent allogeneic HCT at the Princess Margaret Cancer Centre, a tertiary-care cancer centre in Toronto, Canada, from January 2001 to December 2013. This retrospective cohort study was approved by the University Health Network Research Ethics Board (study approval 148116-CE). Patients received conditioning regimens prior to HCT infusion as per institutional protocol.[10-13] Related donor transplants were not T-cell depleted. Unrelated donor transplants were T-dell depleted (TCD) in vivo using Alemtuzumab, ATG or not T-cell depleted. For related donors, HLA-A, -B, and -DR were screened and for unrelated donors HLA-C and -DQ were added. Unrelated donors of peripheral blood stem cells
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(PBSC) or bone marrow (BM) cells were identified through the One Match Stem Cell and Marrow Donor Network. All patients were routinely tested for CMV viremia at least once post engraftment. During study period (2001-2013), intravenous ganciclovir preemptive therapy was the standard for patients at risk for CMV. Potential cases of NTM disease were identified by reviewing institutional microbiology laboratory data. For those who had positive cultures, radiographic reports and clinical documentation were reviewed in detail to determine presence of pulmonary, nonpulmonary, or disseminated infection. Date of infection was defined as the day on which the clinical specimen was obtained for mycobacterial studies or a histopathologic specimen was obtained. Isolates were identified at the Public Health Ontario Laboratories, the Ontario provincial reference laboratory, using conventional methods as previously described.[14] Definitions Pulmonary NTM disease was differentiated from colonization according to ATS/IDSA guidelines (e-Table 1).[2] Infections at non-pulmonary sites were defined by NTM isolation from a normally sterile site with compatible symptoms. Disseminated infection was defined as isolation of NTM from two or more sites, including blood, pulmonary, skin/soft tissue, bone, lymphatics, or joints. Acute and chronic graft-versus-host disease (aGVHD and cGVHD) were diagnosed and graded using established and NIH consensus criteria, respectively.[15-17] The severity of cGVHD was graded at the time of its first manifestation.[17] Statistical Analyses
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The incidence of NTM disease was estimated using the cumulative incidence method considering the competing risk of death. Secondary outcomes of interest included risk factors associated with NTM disease, time to infection and overall survival. Overall survival after onset of NTM disease was calculated from the date of confirmed diagnosis of NTM disease to the date of death from any cause. Survival data were censored at the time of last follow-up alive, using the Kaplan-Meier method. Descriptive statistics were used to assess patient demographics, disease characteristics, and other covariates of interest, including immunosuppressive therapy, conditioning regimen used, the presence, location and severity of GVHD, and comorbid infection. Time dependent Cox’s analyses using proportional hazard regression model was applied in order to test if the effect of GVHD or CMV viremia on NTM risk is time dependent. Neither GVHD (p=0.303, HR 1.659) nor CMV viremia (p=0.148, HR 0.946) were found to be significant time-dependent covariates for the development of NTM. Thus, these two variables were included as non-time dependent covariates in the following analysis. Univariate and multivariate analyses were performed to assess for associations between potential risk factors and NTM incidence using a Fine-gray regression model considering competing risk. The following variables were included in the multivariate model: age, cGVHD/grade, aGVHD grade 2-4, CMV viremia, diagnosis, conditioning regimen, T-cell depletion, source of stem cell, donor type and HLA disparity as presented in Table 1. For multivariate modeling, a stepwise selection algorithm was applied for variable selection, using the criteria p<0.05 for variable entry and p>0.1 for variable removal. All P values were two sided. Cause-specific hazard ratios (HRs) and 95% confidence intervals (CIs)
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were estimated for the significant risk factors, based on a multivariable analysis with a statistical significance level of 0.05. A risk score model was constructed using the two variables identified in multivariate analysis as independent risk factors for NTM disease after allogeneic HCT. The model was generated by assigning a score of 1 to the development of CMV viremia or moderate grade cGVHD, and a score of 2 to the development of severe grade cGVHD by the NIH consensus criteria. This generated a total score of 0 (n=405, 38.7%), 1 (n=415, 39.6%), 2 (n=161, 15.4%) or 3 (n=56, 5.4%). Patients were then classified as either low risk (score 0 or 1; n=820, 77.3%), intermediate risk (score 2; n=161, 15.4%) or high risk (score 3; n=56, 5.4%). Then the incidence of NTM was compared according to these three risk groups using Gray method and hazard ratio was also calculated using FineGray regression model. The statistical analysis for cumulative incidence and survival analyses were performed using EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan).[18] EZR is a modified version of R commander (version 2.12.1) (http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html)
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Results Incidence of NTM after transplant Of the 1,097 patients who underwent allogeneic HCT at our institution between January 2000 and December 2013, NTM were isolated in 45 (4.1%) and were judged to be clinically significant (disease causing) in 30 (2.7%). The clinical characteristics of the patients reviewed are summarized in Table 1. The median (quartiles) follow-up among survivors overall was 51 (23-70) months, and among survivors with NTM, 21 (7-39) months after NTM diagnosis. Of the 30 clinically significant NTM infections, 28 (93.3%) were exclusively pulmonary and 2 (6.7%) were disseminated. With respect to disseminated infection, one patient had NTM isolated from blood in addition to bronchoalveolar lavage (BAL), whereas the second patient had presumed disseminated infection on the basis of characteristic skin findings in addition to pulmonary isolation, though a skin biopsy was not sought, and therefore a microbiologic diagnosis could not be confirmed. There were no NTM cases that were exclusively non-pulmonary. The incidence of NTM disease by competing risk analysis was 2.8% at 5 years (95% CI, 1.9-4.0%). The median (range) time to diagnosis was 343 (19-1,967) days, and in 83% of patients, was diagnosed within 2 years after allogeneic HCT (Figure 1). The most common species/groups isolated were Mycobacterium avium complex (MAC, n=14; 46.7%) followed by M. xenopi (n=8; 26.7%), M. fortuitum (n=5; 16.7%), M. abscessus (n=2; 6.7%), and M. gordonae (n=1; 3.3%). Twenty-two of 30 patients (73.3%) were on systemic immunosuppression at the time of diagnosis, with the majority of patients (N=19, 63.3%) on ≥20 mg of prednisone daily. Fifteen of 30 patients (50%)
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were on mycophenolate. A minority of patients (N=5, 16.7%) were on cyclosporine. Twenty-seven of 30 (90.5%) patients had concurrent infections (30.4% pulmonary, 17.3% extra-pulmonary, and 47.8% both), with fungal infections occurring most frequently (16/30, 53.3%). Twenty-seven of 30 (90%) had a diagnosis of GVHD, acute or chronic, with lung GVHD occurring in 19/30 (63.3%). Twenty-five of thirty patients (83%) with NTM disease received specific antimicrobial therapy. Treatment was based on international guidelines.[2] M. avium and M. xenopi were generally treated with a macrolide and ethambutol, plus often a fluoroquinolone and/or rifabutin. Univariate analysis of Risk Factors for NTM Infection In univariate analysis, cGVHD (p=0.011, HR 3.20 [1.06-9.68]), age (p<0.001, HR 1.05 [1.02-1.07]), and CMV viremia (p=0.0008, HR 4.64 [1.90-11.37], Table 2) were identified as significant risk factors for NTM disease. Among patients who developed NTM, GVHD preceded the diagnosis of NTM in every patient, and was detected a median (quartiles) of 317 (66-493) days before NTM diagnosis. Among patients who developed NTM, CMV viremia preceded the diagnosis of NTM in 21/23 patients, was detected simultaneously in 1 patient, and was detected 18 days following in the other patient. Overall, CMV viremia preceded NTM diagnosis by a median (quartiles) of 291 (106-450) days. Among patients who developed cGVHD, 3.9% developed NTM disease at 3 years (2.45.8%) compared with 1.3% (0.5-2.7%) in the group without cGVHD (p=0.011; HR 3.24 [1.32-7.93]). When we compared the incidence of NTM disease at 3 years according to the severity of cGVHD based on the global severity score by the NIH consensus criteria,
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NTM disease had occurred in 1.5% (0.4-4.0%) of patients with mild cGVHD, 3.9% (1.97.0%) of those with moderate cGVHD, and 10.7% (4.9-19.0%) of those with severe cGVHD (Figure 2A). Among patients who developed CMV viremia 4.8% also developed NTM by 3 years (3.0-7.0%) compared with 1.0% [0.4-2.1%]; HR 4.64 [1.89-11.37] among those without CMV viremia (Figure 2B). Other risk factors were also explored for the risk of NTM disease as shown in Table 2. Gender (p=0.89), diagnosis (p=0.67 between lymphoid vs myeloid; p=0.59 between acute leukemia vs others), allogeneic HCT conditioning regimen (p=0.17), T-cell depletion for GVHD prophylaxis (p=0.56), source of stem cells (p=1.0), donor type (p=0.21) or HLA disparity (n=0.61) were not found to be associated with the risk of NTM disease. Multivariate Analysis and NTM risk score model Using Fine-Gray proportional hazards modeling, two variables were confirmed as independent risk factors: 1) global severity score of cGVHD (p=0.019, HR 1.99 [1.123.53]) and 2) CMV viremia (p=0.004, HR 5.77 [1.71-19.45]).The group with moderate grade cGVHD showed 3.36 times higher incidence of NTM disease (HR 3.36 [0.94-12.05]) compared to those with mild grade, while those with severe grade showed 7.66 times higher risk of NTM disease (HR 7.66 [2.04-28.81]) compared to those with mild grade cGVHD. Using the two variables identified as independent risk factors for NTM disease a score was calculated. One point was assigned for CMV viremia or moderate grade chronic GVHD, and 2 points were assigned for severe grade chronic GVHD. The score divided
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patients as follows: 0 points (n=405, 38.7%), 1 point (n=415, 39.6%), 2 points (n=161, 15.4%) or 3 points (n=56, 5.4%). As shown in e-Figure 1, there was no significant difference of NTM rate between the groups with score 0 (0.8% [0.6-2.1]) and with score 1 (1.5% [0.6-3.2%]). But the groups with score 2 and 3 showed higher rates of NTM at 3 years (score 2; 7.1%, score 3; 14.3%). Accordingly, patients were divided into low risk (score 0 or 1; n=820, 77.3%), intermediate risk (score 2; n=161, 15.4%), and high risk (score 3; n=56, 5.4%) groups, as shown in Figure 3. This risk score model could stratify patients according to their NTM risk (p<0.001) Survival after NTM infection Total number of deaths and causes of death for the entire cohort of allogeneic HCT patients and by NTM status is presented in e-Table 2. Median survival duration after a diagnosis of NTM disease was 398 (95% CI, 105-764 days) days, with a survival rate of 40.8% at 2 years (95% CI, 20.3-60.4%). Figure 4A demonstrates cumulative survival following a diagnosis of NTM disease. We searched for prognostic factors associated with survival after the onset of NTM disease. Survival after NTM disease was not associated with acute GVHD, CMV viremia, number of organisms causing infection at NTM diagnosis, coexistence of fungal viral or bacterial infection, or age. However, patients with moderate/severe grade cGVHD at onset of NTM disease showed a shorter median survival than those with none/mild grade cGVHD (105 days vs 746 days; p=0.025; HR 3.37 [1.09-10.37]) as shown in Figure 4B.
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Discussion In our 13-year, retrospective study including 1,047 allogeneic HCT recipients, we identified NTM disease in 2.7%, the vast majority of which (93.3%) was pulmonary. By competing risk analysis, we calculated a 5-year risk of NTM disease of 2.8%, with a median onset at 343 days post transplant. Traditional risk factors for pulmonary NTM in the general population (age and female sex), were not associated with NTM in our cohort. Presumably the risk of allogeneic HCT and its complications overwhelm the effect of risk factors that are important in the general population. We generated a risk score stratifying patients into low, medium and high risk of NTM disease, based on the presence and severity of chronic GVHD and the presence of CMV viremia. Patients at high risk, who also appear to be at high risk for other pulmonary infections, should have pulmonary symptoms or signs carefully evaluated with chest CT scan and appropriate microbiological specimen analysis including mycobacterial studies. Our risk score model, developed from single-center data, requires external validation to assure validity. The 2.7% frequency of NTM that we observed post allogeneic HCT is approximately 65 fold higher than expected in the general population, given the period prevalence in Ontario of41/100,000.[14] This comparison could in part reflect intensive in microbiological surveillance of HCT patients. Unfortunately, we do not have comparison data for other groups, such as patients with hematological malignancies. Prior studies identified risks of NTM disease of 0.26-2.8% post allogeneic HCT,[3-8] a range may be explainable in at least two ways. First, the observation that more recent studies identified higher rates,[6-8] is consistent with increases in NTM disease in general
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populations[14, 19, 20],[9] possibly due to icreased risk factors (population ageing, underlying lung disease, immune suppression).[21] A second explanation for differences in rates of NTM disease between allogeneic HCT cohorts is regional variability, as described with these environmental organisms.[22] Pulmonary NTM was ubiquitous in our cohort, with two patients exhibiting nonpulmonary infection in addition to lung infection. Although most prior studies did not present adequate data to determine the precise proportion of pulmonary versus nonpulmonary infections there are some available data. A 20-year review from Minnesota identified exclusively non-pulmonary disease, along with a low incidence of NTM overall, at 0.47%[3] Among other cohorts, substantial proportions of observed cases were pulmonary.[4, 5, 7] Specifically in a series of 50 allogeneic HCT patients with NTM isolates, pulmonary disease was present in approximately one-third of patients with definite NTM disease and all of the patients with probable or possible disease.[7] The latter series underscores both that NTM may be most likely pulmonary in allogeneic HCT, and the challenges in determining whether a respiratory isolate represents true disease. In the context of other possible causes for pulmonary and systemic symptoms and chest imaging derangements, it can be difficult to assess whether any single respiratory tract organism is truly causing disease. In our series, pulmonary isolation was judged to be indicative of true disease in two-thirds of patients. The species distribution that we observed, with M. avium followed by M. xenopi, is consistent with the most frequently observed NTM in Ontario.[14] Prior studies have identified MAC as the most common cause of NTM lung disease post allogeneic HCT,[4,
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6, 7] also the most common cause of NTM lung disease worldwide.[22] In a study of allogeneic HCT patients with NTM lung disease in Korea, although 60% of patients had MAC, 20% had M. abscessus. The latter is a very common cause of NTM lung disease in Korea, while in Ontario, Canada, M. abscessus causes less than 3% of NTM lung disease.[14] The species distribution causing NTM lung disease in the allogeneic HCT population appears to vary regionally, likely mirroring the species distribution for that region in general. In the present study, two risk factors were identified: cGVHD and CMV viremia. It is not clear whether CMV viremia itself elevates the risk of NTM disease, or if the predisposing factor for CMV viremia could overlap with those for NTM disease. Perhaps prolonged immune recovery could predispose both to CMV infection as well as NTM disease. Also more severe grade of cGVHD could predispose to increasing risk of NTM disease through prolonged use of systemic immunosuppression as well as delayed immune recovery via systemic immunosuppressive therapy or via GVHD related mechanism. Accordingly immune monitoring as well as frequent surveillance (such as sputum AFB) will be helpful in the high risk group of patients for NTM disease including the case with CMV viremia or cGVHD of moderate or severe grade. Our study has important limitations. First, it is often challenging to determine whether respiratory NTM isolates indicate the presence of disease,[2] particularly so in patients with multiple potential causes of symptoms and chest imaging abnormalities. Although we attempted to restrict our analysis to patients with NTM disease by application of guidelines criteria[2] through detailed chart review, some patients may have been
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incorrectly classified as having either NTM disease or non-significant NTM isolation. Second, it is difficult to accurately estimate the mortality attributable to NTM disease, given that infected patients tend to have more post allogeneic HCT complications, which themselves would be expected to reduce survival, and that NTM is a delayed complication, thereby introducing an immortal time bias, which needs to be accounted for in survival analyses. With our small sample of NTM-infected patients, we think such an analysis would be unreliable. Third, changes in CMV surveillance could potentially have affected our results. CMV antigenemia testing (>1 infected cell of 200,000 nucleated cells in PB smear) was changed to CMV viremia (>200 IU) in early 2011. However, the incidence of CMV was quite stable over the entire study period, so it is unlikely that the change in testing affected our results, Finally, our results may not be
readily transportable to similar cohorts in other regions in that our risk model was generated at a single center, and so requires external validation, and NTM are environmental organisms with exposure rates that undoubtedly vary between regions.[22] Clinicians should consider local rates of NTM when calibrating a level of suspicion regarding NTM infection post allogeneic HCT. In summary, in our large experience we identified NTM disease in a substantial proportion of patients post allogeneic HCT. Risk stratification was possible according to the presence of cGVHD, moderate-severe aGVHD, and CMV viremia. Clinicians should recognize the possibility of NTM disease post allogeneic HCT, especially in the presence of risk factors, and ensure that appropriate specimens are tested for the presence of mycobacteria when indicated. Important future directions include external validation of
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our risk score, studying the mortality attributable to NTM disease, treatment outcomes, and early detection or prevention.
Acknowledgements JB, TM and DK made substantial contributions to conception, design, data acquisition, analysis, data interpretation, drafting and revising of the article, have provided final approval of the version to be published, and have agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. ES, FM, ST, AV, JL and HM made substantial contributions to data acquisition, revised the article critically for important intellectual content, have provided final approval of the version to be published, and have has agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. DK takes responsibility for the content of the manuscript including the data and the analysis. The authors have no conflicts of interest to disclose.
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References 1. 2. 3. 4.
5. 6. 7.
8. 9. 10.
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Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective. Preface. Bone Marrow Transplant. 2009; 44(8):453-5. Griffith DE, Aksamit T, Brown-Elliott BA, et al. Diagnosis, Treatment and Prevention of Nontuberculous Mycobacterial Diseases. Am J Respir Crit Care Med. 2007; 175:367-416. Roy V, Weisdorf D. Mycobacterial infections following bone marrow transplantation: a 20 year retrospective review. Bone Marrow Transplant. 1997; 19(5):467-70. Gaviria JM, Garcia PJ, Garrido SM, Corey L, Boeckh M. Nontuberculous mycobacterial infections in hematopoietic stem cell transplant recipients: characteristics of respiratory and catheter-related infections. Biol Blood Marrow Transplant. 2000; 6(4):361-9. Cordonnier C, Martino R, Trabasso P, et al, Mycobacterial infection: a difficult and late diagnosis in stem cell transplant recipients. Clin Infect Dis. 2004; 38(9):1229-36..6. Kang JY, Ha JH, Kang HS, et al. Clinical significance of nontuberculous mycobacteria from respiratory specimens in stem cell transplantation recipients. Int J Hematol. 2015; 101(5):505-13. Weinstock DM, Feinstein MB, Sepkowitz KA, Jakubowski A. High rates of infection and colonization by nontuberculous mycobacteria after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003; 31(11):1015-21. Knoll B. Update on nontuberculous mycobacterial infections in solid organ and hematopoietic stem cell transplant recipients. Curr Infect Dis Rep. 2014; 16(9):421. Brode SK, Daley CL, Marras TK. The epidemiologic relationship between tuberculosis and non-tuberculous mycobacterial disease: a systematic review. Int J Tuberc Lung Dis. 2014; 18(11)1370-7. Moon JH, Hamad N, Sohn SK, et al. Improved prognostic stratification power of CIBMTR risk score with the addition of absolute lymphocyte and eosinophil counts at the onset of chronic GVHD. Ann Hematol. 2017; 96(5):805-15. Hamad N, Seftel M, Michelis FV, et al. Mycophenolate-based graft versus host disease prophylaxis is not inferior to methotrexate in myeloablative-related donor stem cell transplantation. Am J Hematol. 2015; 90(5):392-9. Sibai H, Falcone U, Deotare U, et al. Myeloablative versus Reduced-Intensity Conditioning in Patients with Myeloid Malignancies: A Propensity ScoreMatched Analysis. Biol Blood Marrow Transplant. 2016; 22(12):2270-2275. Uhm J, Hamad N, Shin EM, et al. Incidence, risk factors, and long-term outcomes of sclerotic graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2014. 20(11):1751-7.
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Marras TK, Mendelson D, Marchand-Austin A, May K, Jamieson FB. Pulmonary Nontuberculous Mycobacterial Disease, Ontario, Canada, 19982010. Emerg Infect Dis. 2013; 19(11):1889-1891. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995; 15(6):825-8. Pavletic SZ, Lee SJ, Socie G, Vogelsang G. Chronic graft-versus-host disease: implications of the National Institutes of Health consensus development project on criteria for clinical trials. Bone Marrow Transplant. 2006; 38(10):645-51. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graftversus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005; 11(12):945-56. Kanda, Y., Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 2013; 48(3):452-8. Adjemian J, Olivier KN, Seitz KE, Holland SM, Prevots DR., Prevalence of Nontuberculous Mycobacterial Lung Disease in U.S. Medicare Beneficiaries. Am J Respir Crit Care Med. 2012; 185(8):881-886. Winthrop KL, McNelley E, Kendall B, et al. Pulmonary Nontuberculous Mycobacterial Disease Prevalence and Clinical Features: An Emerging Public Health Disease. Am J Respir Crit Care Med. 2010; 182:977-982. AlHouqani M, Jamieson FB, Mehta M, Chedore P, May K, Marras TK. Aging, COPD and other risk factors do not explain the increased prevalence of pulmonary Mycobacterium avium complex in Ontario. Chest. 2012; 141(1):190-197. Prevots DR, Marras TK. Epidemiology of human pulmonary infection with nontuberculous mycobacteria: a review. Clin Chest Med. 2015; 36(1):13-34.
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Figure 1. Incidence of NTM disease after allogeneic hematopoietic stem cell transplantation Figure1
0.15
Post-transplant NTM incidence 2.7% at 3 years 95% CI (1.8-3.9%)
Cumulative incidence
of NTM infection IncidenceCumulative incidence post-HCT
0.20
0.10
0.05
0.00 0
1
Years after
2
3
4
5
6
DayNTM3 allogeneic stem cell transplantation DAYAGV1234cmprsk
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Figure 2. Risk factors for the development of NTM disease post-allogeneic hematopoietic stem cell transplant including chronic GVHD and its severity (National Institutes of Health consensus criteria global severity score) (A) and CMV viremia (B) Figure2A NTMrisk_cGVHD_GSS2
post-HCT of NTM infection IncidenceCumulative incidence Cumulative incidence
0.20
no GVHD mild moderate severe
cGVHD grade and NTM risk: Any vs none - HR 2.75 (1.79-4.23) Moderate/severe vs none/mild - HR 4.60 (2.09-10.1)
0.15
Severe grade cGVHD (n=98) 10.7% at 3 yrs (4.9-19.0%)
0.10
Moderate grade cGVHD (n=235) 3.9% at 3 years (1.9-7.0%)
0.05
Mild grade cGVHD (n=210) 1.5% at 3 years (0.4-4.0%) No cGVHD (n=494) 1.3% at 3 years (0.5-2.7%)
0.00 0
1
2
3
4
5
6
DayNTM3 Years after allogeneic stem cell transplantation DAYAGV1234cmprsk
Figure2B NTMrisk_CMVAGYN
0.20
post-HCT of NTM infection IncidenceCumulative incidence Cumulative incidence
0 1
P < 0.001 HR 4.64 (1.89-11.37)
0.15
0.10
CMV viremia (n=480) 4.8% at 3 yrs (3.0-7.0%)
0.05
No CMV viremia (n=565) 1.0% at 3 years (0.4-2.1%)
0.00 0
1
2
3
4
5
6
DayNTM3 Years after allogeneic stem cell transplantation DAYAGV1234cmprsk
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Figure 3. Risk score model for the development of NTM disease post-allogeneic hematopoietic stem cell transplant Figure3 NTMrisk_riskscore_final2
0.20
post-HCT NTM infection ofCumulative IncidenceCumulative incidence incidence
P < 0.001 HR 3.51 (2.35-5.24)
1 2 3
High risk (score 3; n=56) 14.3% at 3 yrs (5.5-27.0%)
0.15
Intermediate risk (n=161) 7.1% at 3 years (3.7-11.9%)
0.10
0.05
Low risk (n=820) 1.2% at 3 years (0.6-2.1%)
0.00 0
1
Years after
2
3
allogeneicDayNTM3 stem cell
4
5
6
transplantation
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Figure 4. Survival after onset of NTM disease post-transplant (A) and survival difference by chronic graft versus host disease severity - moderate/severe versus mild/none (B)
onset of NTM infection after Probability of survival incidence Cumulative Probability
Figure 4A 1.0
0.8
40.8% 3 year overall survival 95%CI (20.3-60.4%)
0.6
Median survival 398 days (105-764 days)
0.4
0.2
0.0 0
2
Years after
4
6
onset ofDayD_NTM NTM infection DAYAGV1234cmprsk
8
post-HCT
onset of NTM infection after Probability of survival incidence Cumulative Probability
Figure4B NTMrisk_cGVHD_GSS01vs23
1.0
no/mild grade HR 3.37 (1.09-10.379-10.37) moderate/severe grade
P = 0.025
0.8
No or mild grade cGVHD (n=15) Survival: median 746 days, one-year 63.6% (33.0-83.1%)
0.6
0.4
0.2
Moderate/Severe grade cGVHD (n=9) Survival: median 105 days, one-year 29.6% (5.2-60.7%) 0.0 0
2
4
6
8
Years after onset ofDayD_NTM NTM infection post-HCT DAYAGV1234cmprsk
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Table 1: Clinical characteristics among allogeneic hematopoietic cell transplantation patients according to subsequent NTM infection Overall NTM cases No NTM P N=1047 N=30 N=1017 value Baseline characteristics Female sex 447 (43) 12 (40) 435 (43) 0.925 Age at transplant (years) 49.5 53 49.5 0.565 - median (IQR) (38-57.5) (44-60) (38-57.5) Diagnosis AML 418 (39.9) 13 (43.3) 405 (39.8) 0.676 ALL 126 (12.0) 1 (3.3) 125 (12.3) MDS 104 (9.9) 4 (13.3) 100 (9.8) CML 95 (9.1) 2 (6.7) 93 (9.1) NHL 164 (15.7) 6 (20.0) 158 (15.5) AA 57 (5.4) 1 (3.3) 56 (5.5) Others 83 (7.9) 3 (10.0) 80 (7.9) PBSC Graft source 817/1032 (80) 28 (93.3) 789/1002 (78.7) 0.065 Related donor 541/1018 (54) 16/28 (57.1) 525 (53.6) 0.709 HLA disparity 56/1034 (5.4) 2/28 (7.1) 54/1,006 (5.4) 1.00 Conditioning Myeloablative 687/1,044 (66) 16/29 (55) 671/1,015 (66) 0.221 Reduced intensity 357/1,044 (34) 13/29 (45) 344/1,015 (34) GVHD prophylaxis T cell depletion 290 (28) 9 (30) 281 (28) 0.775 Outcomes CMV viremia 480/1045 (46) 23/29 (79) 457/1,016 (45) <0.001 Acute GVHD 743/1,017 (71) 22/27 (76) 721/990 (71) 0.577 Grade 2-4 603/1,017 (59) 19/27 (70) 584/990 (59) 0.235 Grade 3,4 116/1,017 (21) 6/27 (33) 110/990 (21) 0.199 Chronic GVHD 548/1,045 (52) 23/29 (79) 525/1,016 (52) 0.003 Mild 210/1,045 (39) 3/29 (13) 207/1,016 (40) 0.006 Moderate 235/1,045 (43) 11/29 (48) 224/1,016 (43) Severe 98/1,045 (18) 9/29 (39) 89/1,016 (17) Death 532/1,045 (51) 15/29 (52) 517 (50.9) 0.929 Non-relapse mortality 349/1,045 (33) 12/29 (41) 337 (33.2) 0.355 Relapse 195/1,045 (19) 4/29 (14) 191 (18.8) 0.633 Unless otherwise indicated, values reported as number (%) Denominator provided to indicate variables with missing data ALL - acute lymphoblastic leukemia; AML - acute myeloid leukemia; CML - chronic myeloid leukemia; CMV - cytomegalovirus; GVHD - graft-versus-host disease; HLA – human leukocyte antigen; MDS - myelodysplastic syndrome; NHL - non-Hodgkin’s lymphoma; NTM - nontuberculous mycobacteria; PBSC - peripheral blood stem cell; AA aplastic anemia
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Table 2: Univariate risk factor analysis for NTM disease post allogeneic hematopoietic cell transplantation Category
Risk factor (Number)
Age Gender
Not applicable Female (448) Male (599) None (494) Mild (210) Moderate (235) Severe (98) Grade 0/1 (414) Grade 2-4 (603) Absent (565) Present (480) Lymphoid (171) Myeloid (875) Acute leukemia (502) Others (544) Myeloablative (687) Reduced intensity (357) No (756) Yes (290) Marrow (215) Peripheral blood (816) Related (477) Unrelated (541) Matched pair (978) Mismatched pair (56)
Chronic GVHD
Acute GVHD CMV viremia Diagnosis
Conditioning T-cell depletion Stem cell source Donor type HLA disparity
NTM at 3 years (percent, 95%CI) Not applicable 2.7 (1.4-4.6) 2.7 (1.6-4.3) 1.3 (0.5-2.7) 1.5 (0.4-4.0) 3.9 (1.9-7.0) 10.7 (4.9-19.0) 2.2 (1.0-4.1) 2.8 (1.7-4.4) 1.0 (0.4-2.1) 4.8 (3.0-7.0) 2.4 (0.8-5.6) 2.8 (1.8-4.1) 2.7 (1.5-4.5) 2.7 (1.5-4.4) 2.3 (1.4-3.7) 3.4 (1.8-5.8) 2.6 (1.6-4.0) 2.8 (1.3-5.3) 0.9 (0.2-3.1) 3.3 (2.1-4.7) 2.5 (1.3-4.4) 2.8 (1.6-4.5) 2.6 (1.7-3.7) 3.6 (0.6-11.1)
Hazard Ratio (95%CI)
p-value
1.05 (1.02-1.07) 1.08 (0.52-2.24)
<0.001 0.89
2.75 (1.79-4.23)
<0.001
1.56 (0.68-3.54)
0.29
4.64 (1.89-11.37)
<0.001
0.81 (0.33-1.97)
0.67
0.82 (0.39-1.67)
0.59
1.67 (0.81-3.45)
0.17
1.28 (0.58-2.78)
0.56
3.93 (0.93-16.67)
1.0
1.09 (0.52-2.29)
0.21
1.36 (0.32-5.73)
0.61
Risk factor significance determined by Fine-gray competing risk regression model Age tested as a continuous variable with hazard ratio reported per year increase in age CMV - cytomegalovirus; GVHD - graft-versus-host disease; HLA – human leukocyte antigen; HR - hazard ratio; NTM - nontuberculous mycobacteria
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Table 3: Risk score model for the risk of NTM disease post-transplant Risk group Risk score* Number of NTM at 3 years patients (%) (95% CI) Low 0-1 820 1.2 (0.6-2.1) Intermediate 2 161 7.1 (3.7-11.9) High 3 56 14.3 (5.5-27.0) NTM - nontuberculous mycobacteria * Chronic graft versus host disease global severity score (non-mild = 0 points, moderate = 1 point, severe = 2 points); Cytomegalovirus viremia (absent = 0 points, present = 1 point)
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