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Bronchiolitis Obliterans: Pleading for a Pragmatic Approach
Accepted Manuscript Bronchiolitis obliterans – pleading for a pragmatic approach D. Wolff, G. Hildebrandt PII:
S1083-8791(16)00088-4
DOI:
10.1016/j.bbmt.2016.01.022
Reference:
YBBMT 54186
To appear in:
Biology of Blood and Marrow Transplantation
Received Date: 13 January 2016 Accepted Date: 14 January 2016
Please cite this article as: Wolff D, Hildebrandt G, Bronchiolitis obliterans – pleading for a pragmatic approach, Biology of Blood and Marrow Transplantation (2016), doi: 10.1016/j.bbmt.2016.01.022. 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.
ACCEPTED MANUSCRIPT Bronchiolitis obliterans – pleading for a pragmatic approach D. Wolff1 & G. Hildebrandt2 1
Dept. of Internal Medicine III, University Hospital of Regensburg, Germany
2
RI PT
University of Kentucky, Division of Hematology & Blood and Marrow Transplantation, Lexington KY
TE D
M AN U
SC
Bronchiolitis obliterans (BO) presents one of the most challenging organ manifestations of chronic Graft-versus-Host Disease (cGvHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT) due to its associated morbidity and mortality.[1] Moreover, progress in treatment has been hampered by the fact, that with an incidence of 2 - 10% after alloHSCT BO, in the context of cGVHD is an orphan disease with literally no approved treatment after failure of steroids, and only a few clinical trials evaluating therapeutic strategies for cGVHD have focused on pulmonary manifestations.[1] A “one fits all” approach can be applied to neither underlying pathophysiology nor treatment of different cGVHD manifestations, and there is evidence demonstrating a distinct pathophysiology with extremely high levels of sBAFF and role of polymorphisms of innate immunity in the development of BOS.[2, 3] Furthermore, the clinical course of BO varies considerably with two histological forms being described with the lymphocytic bronchiolitis subtype showing higher response rates to therapeutic interventions compared to the constrictive subtype.[4]
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EP
Currently, treatment of BO often is not performed according to general guidelines - an issue frequently present in orphan diseases, but is rather done based on individual expert opinions, limited evidence and institutional policies. This motivated the German-Austrian-Swiss-GVHD Consortium to provide at least some guidance (guidelines would have required resilient evidence) for clinical routine practice [5], including a consensus, which was achieved following extensive discussions, to screen patients after alloHSCT regularly using pulmonary function tests, since mild BO is frequently asymptomatic and progression to a moderate stage is often non reversible and significantly impairs quality of life and physical functioning.[6] A similar has also been proposed now by the NIH-consensus on ancillary therapy and supportive care in cGvHD.[7] The German-Austrian-Swiss-GVHD Consortium consensus was criticized for summarizing the “don´t knows”, which is perfectly true, but patients with BO require clinical care even if evidence for treatment is sparse or literally absent and when therapeutic options suggested represent more a list of agents whose use is not completely irrational.[8] Nevertheless, it needs to be kept in mind, that some of the currently applied treatment options and recommended guidance may be discarded after systematic evaluation, as shown in the past by results of randomized trials on treatment of acute and chronic GvHD. Therefore, trials focusing on BO are urgently required.
ACCEPTED MANUSCRIPT
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SC
RI PT
Williams et al now provide an important step towards standardized care in BOpatients by combining inhaled Fluticasone, Azithromycin and Montelukast (FAM) for treatment of newly diagnosed BO.[9] While scientific purists could argue combining 3 agents with limited evidence for activity in BO bears a risk of establishing a “standard” without knowledge of the true contribution of each component to the success (if at all) and more rigorous evaluation may discard one or two components, prior work indicates at least some rationale for the drugs incorporated in the FAM regimen, including experimental work on prophylactic Azithromycin demonstrating reduced peribronchial and perivascular inflammatory cell infiltrates and diminished collagen deposition resulting in improved survival of treated animals.[10] Fluticasone [11] and Azithromycin [12, 13] have been evaluated within small randomized trials in BO, although not always with encouraging results. Evidence for Montelukast is limited to a phase II trial [14] and is probably the “weakest” partner of FAM, yet to be considered relatively safe and risk-sparing. Most of the patients dying of BO succumb to infectious complications as a result of long term immunosuppressive treatment attempts, although proof for intense immunosuppressive treatment changing outcome is sparse. Therefore, any approach showing therapeutic activity without increasing the risk for infectious complications and lacking significant other side effects is highly warranted.
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EP
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The presented evaluation on the FAM regimen meets the above proposed criteria with a relative low toxicity profile and a low failure rate, defined as a decline in FEV 1 of more than 10%, in 2/36 patients (6%) at 3 months (primary study end point) and 6/36 patients (17%) over a time span of 6 months. Including those patients, for whom lung function tests results were not sufficiently available, failures would increase at 6 months to 36%. Moreover, 7 patients received a new systemic treatment before reaching the primary endpoint and additional 4 patients before 6 months, impairing the evaluation of the activity of the FAM regimen in these patients. The latter is an issue that applies frequently to cGvHD trials evaluating organ specific interventions in patients with multiorgan-involvement as disease progression at other organ sites or toxicity of treatment may require change of treatment, yet can be accounted for by a bounteous calculation of the dropout rate and separate evaluation of patients receiving additional new treatment potentially interfering with response assessment or more conservative labeling this subgroup of patients as treatment failure.[15] Also, the follow up of 6 months precludes any direct conclusion of the effect of FAM on overall survival in newly diagnosed BO since the effect of FAM may be temporary and trials with a longer follow up are warranted. Nevertheless, the presented phase IIa trial has several strengths including standardized criteria of diagnosis of BO with centralized review [16], providing detailed toxicity-rates of FAM and most importantly documentation of the slope of FEV1 before onset of intervention. The latter approach has been proposed by the updated NIH-consensus in 2014 and is of critical relevance in a disease being associated with non-reversible lung function changes, for which stable organ function
ACCEPTED MANUSCRIPT could be either attributed to beneficial effects of the intervention or inactivity of the disease already before start of intervention.[15] What are the next potential steps:
RI PT
Since the FAM regimen clearly requires further evaluation, designing a randomized trial for newly diagnosed BO evaluating a new experimental immunosuppressive agent + FAM versus FAM alone (versus new experimental immunosuppressive agent without FAM) would be warranted. Since BO frequently presents during primary treatment of cGvHD, simply continuing prior treatment in the control arm would be unethical and impair recruitment – an issue which already was considered in the presented trial and resulted in the decision to dispense a trial design with randomization.
M AN U
SC
An additional aspect to be studied is the impact of microbiome in BO since the role genetic polymorphisms involved in innate immunity [2] and activity of an antibiotic agent in BO leads to the speculation whether microbial changes may be involved in the disease, an aspect already studied currently in acute gastrointestinal GvHD [17, 18] and the evaluation of Azithromycin prophylaxis in mice not only improved lung but also gastrointestinal disease.[10]
EP
TE D
Last but not least clinical trials may be complemented with register trials within the IBMTR or EBMT capturing patients with a longer follow up to analyze effects on overall survival and to address selection bias during recruitment of clinical trials. The presented data by Williams et al. support the idea, that novel less toxic measures, which some unknowingly call “supportive care”, may have the potential to be as effective as classic immunosuppressive intervention, and that these measures not only need to be captured as “ancillary” interventions within register studies, but should also be included in treatment guidance recommendations and future guidelines.
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ACKNOWLEDGMENTS Financial disclosure: D. Wolff received support from the German José Carreras Foundation. Conflict of interest statement: There are no conflicts of interest to report. G. Hildebrandt has nothing to disclose and no conflict of interest. Chien, J.W., et al., Bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft-versus-host disease. Biol Blood Marrow Transplant, 2010. 16(1 Suppl): p. S106-14. Hildebrandt, G.C., et al., Recipient NOD2/CARD15 variants: a novel independent risk factor for the development of bronchiolitis obliterans after allogeneic stem cell transplantation. Biol Blood Marrow Transplant, 2008. 14(1): p. 67-74. Kuzmina, Z., et al., CD19(+)CD21(low) B cells and patients at risk for NIH-defined chronic graft-versus-host disease with bronchiolitis obliterans syndrome. Blood, 2013. 121(10): p. 1886-95. Holbro, A., et al., Lung histology predicts outcome of bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant, 2013. 19(6): p. 97380.
ACCEPTED MANUSCRIPT
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Hildebrandt, G.C., et al., Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD. Bone Marrow Transplant, 2011. 46(10): p. 1283-95. Palmer, J., et al., Pulmonary symptoms measured by the national institutes of health lung score predict overall survival, nonrelapse mortality, and patient-reported outcomes in chronic graft-versus-host disease. Biol Blood Marrow Transplant, 2014. 20(3): p. 337-44. Carpenter, P.A., et al., National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant, 2015. 21(7): p. 1167-87. Martin, P.J. and J.W. Chien, What we know and mostly do not know about bronchiolitis obliterans syndrome. Bone Marrow Transplant, 2012. 47(1): p. 1-4. Williams, K.M., et al., Fluticasone, Azithromycin, and Montelukast Treatment for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant, 2015. Radhakrishnan, S.V., et al., Preventive azithromycin treatment reduces noninfectious lung injury and acute graft-versus-host disease in a murine model of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant, 2015. 21(1): p. 30-8. Bergeron, A., et al., Budesonide/Formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation. Am J Respir Crit Care Med, 2015. 191(11): p. 1242-9. Lam, D.C., et al., Effects of azithromycin in bronchiolitis obliterans syndrome after hematopoietic SCT--a randomized double-blinded placebo-controlled study. Bone Marrow Transplant, 2011. 46(12): p. 1551-6. Khalid, M., et al., Azithromycin in bronchiolitis obliterans complicating bone marrow transplantation: a preliminary study. Eur Respir J, 2005. 25(3): p. 490-3. Williams, K.M.P., S.Z.; Lee, S.J., Interim analysis of a phase II trial of montelukast for the treatment of bronchiolitis obliterans syndrome after HSCTreveal immunobiology of the disease. Biol Blood Marrow Transplant, 2013: p. S143. Lee, S.J., et al., Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report. Biol Blood Marrow Transplant, 2015. 21(6): p. 984-99. Jagasia, M.H., et al., National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant, 2015. 21(3): p. 389-401 e1. Penack, O., E. Holler, and M.R. van den Brink, Graft-versus-host disease: regulation by microbe-associated molecules and innate immune receptors. Blood, 2010. 115(10): p. 186572. Holler, E., et al., Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant, 2014. 20(5): p. 640-5.
AC C
5.
S1083-8791(16)00088-4
DOI:
10.1016/j.bbmt.2016.01.022
Reference:
YBBMT 54186
To appear in:
Biology of Blood and Marrow Transplantation
Received Date: 13 January 2016 Accepted Date: 14 January 2016
Please cite this article as: Wolff D, Hildebrandt G, Bronchiolitis obliterans – pleading for a pragmatic approach, Biology of Blood and Marrow Transplantation (2016), doi: 10.1016/j.bbmt.2016.01.022. 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.
ACCEPTED MANUSCRIPT Bronchiolitis obliterans – pleading for a pragmatic approach D. Wolff1 & G. Hildebrandt2 1
Dept. of Internal Medicine III, University Hospital of Regensburg, Germany
2
RI PT
University of Kentucky, Division of Hematology & Blood and Marrow Transplantation, Lexington KY
TE D
M AN U
SC
Bronchiolitis obliterans (BO) presents one of the most challenging organ manifestations of chronic Graft-versus-Host Disease (cGvHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT) due to its associated morbidity and mortality.[1] Moreover, progress in treatment has been hampered by the fact, that with an incidence of 2 - 10% after alloHSCT BO, in the context of cGVHD is an orphan disease with literally no approved treatment after failure of steroids, and only a few clinical trials evaluating therapeutic strategies for cGVHD have focused on pulmonary manifestations.[1] A “one fits all” approach can be applied to neither underlying pathophysiology nor treatment of different cGVHD manifestations, and there is evidence demonstrating a distinct pathophysiology with extremely high levels of sBAFF and role of polymorphisms of innate immunity in the development of BOS.[2, 3] Furthermore, the clinical course of BO varies considerably with two histological forms being described with the lymphocytic bronchiolitis subtype showing higher response rates to therapeutic interventions compared to the constrictive subtype.[4]
AC C
EP
Currently, treatment of BO often is not performed according to general guidelines - an issue frequently present in orphan diseases, but is rather done based on individual expert opinions, limited evidence and institutional policies. This motivated the German-Austrian-Swiss-GVHD Consortium to provide at least some guidance (guidelines would have required resilient evidence) for clinical routine practice [5], including a consensus, which was achieved following extensive discussions, to screen patients after alloHSCT regularly using pulmonary function tests, since mild BO is frequently asymptomatic and progression to a moderate stage is often non reversible and significantly impairs quality of life and physical functioning.[6] A similar has also been proposed now by the NIH-consensus on ancillary therapy and supportive care in cGvHD.[7] The German-Austrian-Swiss-GVHD Consortium consensus was criticized for summarizing the “don´t knows”, which is perfectly true, but patients with BO require clinical care even if evidence for treatment is sparse or literally absent and when therapeutic options suggested represent more a list of agents whose use is not completely irrational.[8] Nevertheless, it needs to be kept in mind, that some of the currently applied treatment options and recommended guidance may be discarded after systematic evaluation, as shown in the past by results of randomized trials on treatment of acute and chronic GvHD. Therefore, trials focusing on BO are urgently required.
ACCEPTED MANUSCRIPT
M AN U
SC
RI PT
Williams et al now provide an important step towards standardized care in BOpatients by combining inhaled Fluticasone, Azithromycin and Montelukast (FAM) for treatment of newly diagnosed BO.[9] While scientific purists could argue combining 3 agents with limited evidence for activity in BO bears a risk of establishing a “standard” without knowledge of the true contribution of each component to the success (if at all) and more rigorous evaluation may discard one or two components, prior work indicates at least some rationale for the drugs incorporated in the FAM regimen, including experimental work on prophylactic Azithromycin demonstrating reduced peribronchial and perivascular inflammatory cell infiltrates and diminished collagen deposition resulting in improved survival of treated animals.[10] Fluticasone [11] and Azithromycin [12, 13] have been evaluated within small randomized trials in BO, although not always with encouraging results. Evidence for Montelukast is limited to a phase II trial [14] and is probably the “weakest” partner of FAM, yet to be considered relatively safe and risk-sparing. Most of the patients dying of BO succumb to infectious complications as a result of long term immunosuppressive treatment attempts, although proof for intense immunosuppressive treatment changing outcome is sparse. Therefore, any approach showing therapeutic activity without increasing the risk for infectious complications and lacking significant other side effects is highly warranted.
AC C
EP
TE D
The presented evaluation on the FAM regimen meets the above proposed criteria with a relative low toxicity profile and a low failure rate, defined as a decline in FEV 1 of more than 10%, in 2/36 patients (6%) at 3 months (primary study end point) and 6/36 patients (17%) over a time span of 6 months. Including those patients, for whom lung function tests results were not sufficiently available, failures would increase at 6 months to 36%. Moreover, 7 patients received a new systemic treatment before reaching the primary endpoint and additional 4 patients before 6 months, impairing the evaluation of the activity of the FAM regimen in these patients. The latter is an issue that applies frequently to cGvHD trials evaluating organ specific interventions in patients with multiorgan-involvement as disease progression at other organ sites or toxicity of treatment may require change of treatment, yet can be accounted for by a bounteous calculation of the dropout rate and separate evaluation of patients receiving additional new treatment potentially interfering with response assessment or more conservative labeling this subgroup of patients as treatment failure.[15] Also, the follow up of 6 months precludes any direct conclusion of the effect of FAM on overall survival in newly diagnosed BO since the effect of FAM may be temporary and trials with a longer follow up are warranted. Nevertheless, the presented phase IIa trial has several strengths including standardized criteria of diagnosis of BO with centralized review [16], providing detailed toxicity-rates of FAM and most importantly documentation of the slope of FEV1 before onset of intervention. The latter approach has been proposed by the updated NIH-consensus in 2014 and is of critical relevance in a disease being associated with non-reversible lung function changes, for which stable organ function
ACCEPTED MANUSCRIPT could be either attributed to beneficial effects of the intervention or inactivity of the disease already before start of intervention.[15] What are the next potential steps:
RI PT
Since the FAM regimen clearly requires further evaluation, designing a randomized trial for newly diagnosed BO evaluating a new experimental immunosuppressive agent + FAM versus FAM alone (versus new experimental immunosuppressive agent without FAM) would be warranted. Since BO frequently presents during primary treatment of cGvHD, simply continuing prior treatment in the control arm would be unethical and impair recruitment – an issue which already was considered in the presented trial and resulted in the decision to dispense a trial design with randomization.
M AN U
SC
An additional aspect to be studied is the impact of microbiome in BO since the role genetic polymorphisms involved in innate immunity [2] and activity of an antibiotic agent in BO leads to the speculation whether microbial changes may be involved in the disease, an aspect already studied currently in acute gastrointestinal GvHD [17, 18] and the evaluation of Azithromycin prophylaxis in mice not only improved lung but also gastrointestinal disease.[10]
EP
TE D
Last but not least clinical trials may be complemented with register trials within the IBMTR or EBMT capturing patients with a longer follow up to analyze effects on overall survival and to address selection bias during recruitment of clinical trials. The presented data by Williams et al. support the idea, that novel less toxic measures, which some unknowingly call “supportive care”, may have the potential to be as effective as classic immunosuppressive intervention, and that these measures not only need to be captured as “ancillary” interventions within register studies, but should also be included in treatment guidance recommendations and future guidelines.
1.
2.
3.
4.
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ACKNOWLEDGMENTS Financial disclosure: D. Wolff received support from the German José Carreras Foundation. Conflict of interest statement: There are no conflicts of interest to report. G. Hildebrandt has nothing to disclose and no conflict of interest. Chien, J.W., et al., Bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft-versus-host disease. Biol Blood Marrow Transplant, 2010. 16(1 Suppl): p. S106-14. Hildebrandt, G.C., et al., Recipient NOD2/CARD15 variants: a novel independent risk factor for the development of bronchiolitis obliterans after allogeneic stem cell transplantation. Biol Blood Marrow Transplant, 2008. 14(1): p. 67-74. Kuzmina, Z., et al., CD19(+)CD21(low) B cells and patients at risk for NIH-defined chronic graft-versus-host disease with bronchiolitis obliterans syndrome. Blood, 2013. 121(10): p. 1886-95. Holbro, A., et al., Lung histology predicts outcome of bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant, 2013. 19(6): p. 97380.
ACCEPTED MANUSCRIPT
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13. 14.
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Hildebrandt, G.C., et al., Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD. Bone Marrow Transplant, 2011. 46(10): p. 1283-95. Palmer, J., et al., Pulmonary symptoms measured by the national institutes of health lung score predict overall survival, nonrelapse mortality, and patient-reported outcomes in chronic graft-versus-host disease. Biol Blood Marrow Transplant, 2014. 20(3): p. 337-44. Carpenter, P.A., et al., National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant, 2015. 21(7): p. 1167-87. Martin, P.J. and J.W. Chien, What we know and mostly do not know about bronchiolitis obliterans syndrome. Bone Marrow Transplant, 2012. 47(1): p. 1-4. Williams, K.M., et al., Fluticasone, Azithromycin, and Montelukast Treatment for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant, 2015. Radhakrishnan, S.V., et al., Preventive azithromycin treatment reduces noninfectious lung injury and acute graft-versus-host disease in a murine model of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant, 2015. 21(1): p. 30-8. Bergeron, A., et al., Budesonide/Formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation. Am J Respir Crit Care Med, 2015. 191(11): p. 1242-9. Lam, D.C., et al., Effects of azithromycin in bronchiolitis obliterans syndrome after hematopoietic SCT--a randomized double-blinded placebo-controlled study. Bone Marrow Transplant, 2011. 46(12): p. 1551-6. Khalid, M., et al., Azithromycin in bronchiolitis obliterans complicating bone marrow transplantation: a preliminary study. Eur Respir J, 2005. 25(3): p. 490-3. Williams, K.M.P., S.Z.; Lee, S.J., Interim analysis of a phase II trial of montelukast for the treatment of bronchiolitis obliterans syndrome after HSCTreveal immunobiology of the disease. Biol Blood Marrow Transplant, 2013: p. S143. Lee, S.J., et al., Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report. Biol Blood Marrow Transplant, 2015. 21(6): p. 984-99. Jagasia, M.H., et al., National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant, 2015. 21(3): p. 389-401 e1. Penack, O., E. Holler, and M.R. van den Brink, Graft-versus-host disease: regulation by microbe-associated molecules and innate immune receptors. Blood, 2010. 115(10): p. 186572. Holler, E., et al., Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant, 2014. 20(5): p. 640-5.
AC C
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