© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Transplant Infectious Disease, ISSN 1398-2273
Contribution of Clostridium difficile infection to the development of lower gastrointestinal adverse events during autologous stem cell transplantation S. Apewokin, J.A. Goodwin, J.Y. Lee, S.W. Erickson, N. Sanathkumar, V.R. Raj, D. Zhou, K.D. McKelvey, O. Stephens, E.A. Coleman. Contribution of Clostridium difficile infection to the development of lower gastrointestinal adverse events during autologous stem cell transplantation. Transpl Infect Dis 2015: 17: 566–573. All rights reserved Abstract: Background. Lower gastrointestinal (GI) adverse events (LGAE) are common afflictions of patients undergoing stem cell transplantation (SCT). Unfortunately, the pathophysiology remains poorly characterized. Emerging data suggest a prominent role of intestinal microbiota; however, contributions of pathogenic gut microbiota such as Clostridium difficile are not well defined. We performed a genome-wide association study (GWAS) to investigate clinical and genetic factors associated with development of LGAE. Methods. A total of 972 patients undergoing autologous SCT were graded for LGAE based on Common Terminology Criteria for Adverse Events (v 4.0). Germline DNA material was obtained from leukapharesis products and genotyped using Illuminaâ Whole Genome Genotyping Infinium chemistry and HumanOmni1-Quad Bead chips containing over 1.1 million single nucleotide polymorphisms (SNPs) (Illumina, San Diego, California, USA). Statistical models incorporating clinical factors, genetic factors, and a combination of clinical plus genetic factors were utilized to compare patients who developed severe LGAE (grade 2 or above) and others. Results. Among 972 patients, 459 (47.2%) developed severe LGAE. Baseline hemoglobin and hematocrit, estimated glomerular filtration rate, b2-microglobulin, protocol type, and C. difficile infection (CDI) were associated with severe LGAE on univariate analysis, Genomic comparisons between groups did not reveal any SNPs associated with severe LGAE and neither did incorporation of genetic factors into the clinical model. In addition, 11 candidate SNPs associated with upper GI mucositis were evaluated, alongside clinical factors in a multivariate model. Only CDI was found to be associated with severe LGAE in all models. Conclusion. CDI is a prominent factor in the development of LGAE in patients undergoing autologous SCT.
Gastrointestinal (GI) adverse events (AE) are a frequent occurrence in patients undergoing stem cell transplantation (SCT), yet therapeutic interventions to ameliorate or prevent these complications remain limited. A major impediment to the development of
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S. Apewokin1, J.A. Goodwin2, J.Y. Lee3, S.W. Erickson3, N. Sanathkumar4, V.R. Raj6, D. Zhou5, K.D. McKelvey6, O. Stephens4, E.A. Coleman2 1
Division of Infectious Diseases, University of Cincinnati, Cincinnati, Ohio, USA, 2University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA, 3Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA, 4Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA, 5Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA, 6Department of Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
Key words: GI adverse events; Clostridium difficile; GWAS; stem cell transplant; chemotherapy; cancer Correspondence to: Senu Apewokin, MD, FACP, Division of Infectious Diseases, University of Cincinnati, 231 Albert Sabin Way, MSB 6153B, Cincinnati, OH 45267, USA Tel: 513 558 4704 Fax: 513 558 2089 E-mail: [email protected]
Received 5 January 2015, revised 20 March 2015, accepted for publication 4 May 2015 DOI: 10.1111/tid.12403 Transpl Infect Dis 2015: 17: 566–573
such interventions has been the partial understanding of the pathobiology of these complications. This incomplete knowledge is primarily a result of the technological shortcomings that have prevented safe, rapid, and efficient analysis of the dynamic intra- and
Apewokin et al: GI events and CDI: GWAS study
extraluminal alimentary tract processes that occur during SCT. Recent technological innovations, such as the advent of high throughput sequencing and genome-wide sequencing, are breakthroughs that have been pivotal in overcoming some of these challenges. These tools have complemented clinical data in providing some insights into the molecular and clinical pathways that mediate entities such as oral mucositis (OM) and enhanced understanding of the ecological perturbations of the microbiome that mediate GI complications during SCT. Unfortunately, such technology has yet to be utilized in evaluating some of the lower GI AE (LGAE) that occur during SCT. Knowledge gaps thus persist and products approved to reduce such complications as mucositis have made little clinical impact. This study reports an attempt to unravel this complex pathobiology by evaluating single nucleotide polymorphisms (SNPs) alongside relevant clinical factors, including Clostridium difficile infection (CDI), that mediate the development of LGAE in autologous stem cell transplant recipients.
Materials and methods Patients and treatment regimens The study population consisted of 972 Caucasian adults with newly diagnosed multiple myeloma cared for at the Myeloma Institute for Research and Therapy (MIRT) between March 1998 and September 2010. All except 134 patients treated off protocol were enrolled in 1 of 3 consecutive clinical trials of Total Therapy (TT2, TT3, and TT4) (1, 2). All underwent high-dose melphalan (HD-MEL)-based autologous SCT, and the data are based on the first transplant (Table 1). The Institutional Review Board approved the study; genome-wide association study (GWAS) data available in dbGHP (phs000545.v1.p1). Following induction, patients received HD-MEL (140–200 mg/m2) based on body surface area (BSA), calculated according to Mosteller’s formula (3). MEL 140 mg/m2 was based on age >70 years. Patients were managed according to MIRT predefined standards of care where all patients had C-reactive protein tested daily, and beta-d-glucan, cytomegalovirus (CMV) polymerase chain reaction (PCR), and serum galactomannan were tested 3 times a week until engraftment. If a patient had diarrhea, stools were analyzed by enzyme immunoassay for C. difficile toxin A/B (3 samples), and a stool culture was done. For selected patients at risk,
stool was checked for ova and parasites or viral stool cultures were ordered. Prophylactic oral levofloxacin and fluconazole were initiated when white blood cell counts fell to
Contribution of Clostridium difficile infection to the development of lower gastrointestinal adverse events during autologous stem cell transplantation S. Apewokin, J.A. Goodwin, J.Y. Lee, S.W. Erickson, N. Sanathkumar, V.R. Raj, D. Zhou, K.D. McKelvey, O. Stephens, E.A. Coleman. Contribution of Clostridium difficile infection to the development of lower gastrointestinal adverse events during autologous stem cell transplantation. Transpl Infect Dis 2015: 17: 566–573. All rights reserved Abstract: Background. Lower gastrointestinal (GI) adverse events (LGAE) are common afflictions of patients undergoing stem cell transplantation (SCT). Unfortunately, the pathophysiology remains poorly characterized. Emerging data suggest a prominent role of intestinal microbiota; however, contributions of pathogenic gut microbiota such as Clostridium difficile are not well defined. We performed a genome-wide association study (GWAS) to investigate clinical and genetic factors associated with development of LGAE. Methods. A total of 972 patients undergoing autologous SCT were graded for LGAE based on Common Terminology Criteria for Adverse Events (v 4.0). Germline DNA material was obtained from leukapharesis products and genotyped using Illuminaâ Whole Genome Genotyping Infinium chemistry and HumanOmni1-Quad Bead chips containing over 1.1 million single nucleotide polymorphisms (SNPs) (Illumina, San Diego, California, USA). Statistical models incorporating clinical factors, genetic factors, and a combination of clinical plus genetic factors were utilized to compare patients who developed severe LGAE (grade 2 or above) and others. Results. Among 972 patients, 459 (47.2%) developed severe LGAE. Baseline hemoglobin and hematocrit, estimated glomerular filtration rate, b2-microglobulin, protocol type, and C. difficile infection (CDI) were associated with severe LGAE on univariate analysis, Genomic comparisons between groups did not reveal any SNPs associated with severe LGAE and neither did incorporation of genetic factors into the clinical model. In addition, 11 candidate SNPs associated with upper GI mucositis were evaluated, alongside clinical factors in a multivariate model. Only CDI was found to be associated with severe LGAE in all models. Conclusion. CDI is a prominent factor in the development of LGAE in patients undergoing autologous SCT.
Gastrointestinal (GI) adverse events (AE) are a frequent occurrence in patients undergoing stem cell transplantation (SCT), yet therapeutic interventions to ameliorate or prevent these complications remain limited. A major impediment to the development of
566
S. Apewokin1, J.A. Goodwin2, J.Y. Lee3, S.W. Erickson3, N. Sanathkumar4, V.R. Raj6, D. Zhou5, K.D. McKelvey6, O. Stephens4, E.A. Coleman2 1
Division of Infectious Diseases, University of Cincinnati, Cincinnati, Ohio, USA, 2University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA, 3Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA, 4Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA, 5Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA, 6Department of Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
Key words: GI adverse events; Clostridium difficile; GWAS; stem cell transplant; chemotherapy; cancer Correspondence to: Senu Apewokin, MD, FACP, Division of Infectious Diseases, University of Cincinnati, 231 Albert Sabin Way, MSB 6153B, Cincinnati, OH 45267, USA Tel: 513 558 4704 Fax: 513 558 2089 E-mail: [email protected]
Received 5 January 2015, revised 20 March 2015, accepted for publication 4 May 2015 DOI: 10.1111/tid.12403 Transpl Infect Dis 2015: 17: 566–573
such interventions has been the partial understanding of the pathobiology of these complications. This incomplete knowledge is primarily a result of the technological shortcomings that have prevented safe, rapid, and efficient analysis of the dynamic intra- and
Apewokin et al: GI events and CDI: GWAS study
extraluminal alimentary tract processes that occur during SCT. Recent technological innovations, such as the advent of high throughput sequencing and genome-wide sequencing, are breakthroughs that have been pivotal in overcoming some of these challenges. These tools have complemented clinical data in providing some insights into the molecular and clinical pathways that mediate entities such as oral mucositis (OM) and enhanced understanding of the ecological perturbations of the microbiome that mediate GI complications during SCT. Unfortunately, such technology has yet to be utilized in evaluating some of the lower GI AE (LGAE) that occur during SCT. Knowledge gaps thus persist and products approved to reduce such complications as mucositis have made little clinical impact. This study reports an attempt to unravel this complex pathobiology by evaluating single nucleotide polymorphisms (SNPs) alongside relevant clinical factors, including Clostridium difficile infection (CDI), that mediate the development of LGAE in autologous stem cell transplant recipients.
Materials and methods Patients and treatment regimens The study population consisted of 972 Caucasian adults with newly diagnosed multiple myeloma cared for at the Myeloma Institute for Research and Therapy (MIRT) between March 1998 and September 2010. All except 134 patients treated off protocol were enrolled in 1 of 3 consecutive clinical trials of Total Therapy (TT2, TT3, and TT4) (1, 2). All underwent high-dose melphalan (HD-MEL)-based autologous SCT, and the data are based on the first transplant (Table 1). The Institutional Review Board approved the study; genome-wide association study (GWAS) data available in dbGHP (phs000545.v1.p1). Following induction, patients received HD-MEL (140–200 mg/m2) based on body surface area (BSA), calculated according to Mosteller’s formula (3). MEL 140 mg/m2 was based on age >70 years. Patients were managed according to MIRT predefined standards of care where all patients had C-reactive protein tested daily, and beta-d-glucan, cytomegalovirus (CMV) polymerase chain reaction (PCR), and serum galactomannan were tested 3 times a week until engraftment. If a patient had diarrhea, stools were analyzed by enzyme immunoassay for C. difficile toxin A/B (3 samples), and a stool culture was done. For selected patients at risk,
stool was checked for ova and parasites or viral stool cultures were ordered. Prophylactic oral levofloxacin and fluconazole were initiated when white blood cell counts fell to
