Accepted Manuscript Cytomegalovirus infection in allogeneic hematopoietic stem cell transplanted patients from portugal: a 5-year retrospective review Hugo Sousa, PhD, MD Student David Boutolleau, PharmD PhD Joana Ribeiro, PhD Student Ana L. Teixeira, PhD Student Carlos Pinho Vaz, MD Fernando Campilho, MD Rosa Branca, MD António Campos Jr., MD Inês Baldaque, MD Rui Medeiros, PharmD PhD PII:
S1083-8791(14)00509-6
DOI:
10.1016/j.bbmt.2014.08.010
Reference:
YBBMT 53566
To appear in:
Biology of Blood and Marrow Transplantation
Received Date: 19 May 2014 Accepted Date: 12 August 2014
Please cite this article as: Sousa H, Boutolleau D, Ribeiro J, Teixeira AL, Vaz CP, Campilho F, Branca R, Campos A Jr, Baldaque I, Medeiros R, Cytomegalovirus infection in allogeneic hematopoietic stem cell transplanted patients from portugal: a 5-year retrospective review, Biology of Blood and Marrow Transplantation (2014), doi: 10.1016/j.bbmt.2014.08.010. 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 TITLE CYTOMEGALOVIRUS INFECTION IN ALLOGENEIC HEMATOPOIETIC STEM CELL
TRANSPLANTED
PATIENTS
FROM
PORTUGAL:
A
5-YEAR
RI PT
RETROSPECTIVE REVIEW
Hugo Sousa, PhD, MD Student 1,2,3, 1
M AN U
Cytomegalovirus infection in aHSCT in Portugal
SC
SHORT TITLE:
Virology Service and 2 Molecular Oncology Group, Portuguese Institute of Oncology of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, PORTUGAL
3
TE D
Faculty of Medicine of University of Porto, Alameda Prof. Hernâni Monteiro, 4200319 Porto, PORTUGAL David Boutolleau, PharmD PhD 4,5,6
4
Sorbonne Universités, UPMC Université Paris 06, CR7, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), F-75013, Paris, France 6
INSERM, U1135, CIMI-Paris, F-75013, Paris, France
EP
5
AC C
AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière – Charles Foix, Service de Virologie, F-75013, Paris, France Joana Ribeiro, PhD Student 1,2,3 1
Virology Service and 2 Molecular Oncology Group, Portuguese Institute of Oncology of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, PORTUGAL
3
Faculty of Medicine of University of Porto, Alameda Prof. Hernâni Monteiro, 4200319 Porto, PORTUGAL Ana L Teixeira, PhD Student1,2
1
Virology Service and 2 Molecular Oncology Group, Portuguese Institute of Oncology of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, PORTUGAL
ACCEPTED MANUSCRIPT Carlos Pinho Vaz, MD 7 7
Bone Marrow Transplantation Unit, Portuguese Institute of Oncology of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, PORTUGAL Fernando Campilho, MD 7
7
RI PT
Bone Marrow Transplantation Unit, Portuguese Institute of Oncology of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, PORTUGAL Rosa Branca, MD 7
7
SC
Bone Marrow Transplantation Unit, Portuguese Institute of Oncology of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, PORTUGAL
M AN U
António Campos Jr, MD 7 7
Bone Marrow Transplantation Unit, Portuguese Institute of Oncology of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, PORTUGAL Inês Baldaque, MD1
1
TE D
Virology Service, Portuguese Institute of Oncology of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, PORTUGAL Rui Medeiros, PharmD PhD 1,2,8
Virology Service and 2 Molecular Oncology Group, Portuguese Institute of Oncology of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, PORTUGAL
EP
1
8
AC C
Research Department, Portuguese League Against Cancer (LPCC-NRNorte), Estrada Interior da Circunvalação 6657, 4200 Porto, PORTUGAL Correspondence to: Dr. Hugo Sousa
Serviço de Virologia, Laboratórios 4º Piso Instituto Português de Oncologia do Porto FG EPE Rua Dr. António Bernardino Almeida 4200-072 Porto, Portugal. Phone: +351 22 508 4000 (ext 5410) Fax: +351 22 508 4001 E-mail: [email protected] or [email protected]
ACCEPTED MANUSCRIPT Abstract (word count): 199 words Text (word count): 4076 Figures (number): 1 Tables (number): 5+1
RI PT
FINANCIAL DISCLOSURE
AC C
EP
TE D
M AN U
SC
All authors declare no competing financial interests.
ACCEPTED MANUSCRIPT ABBREVIATIONS aGVHD, Acute GVHD aHSCT, Allogeneic Hematopoietic Stem Cell Transplantation ATG, antithymocyte globulin cGVHD, Chronic GVHD
RI PT
CI, Confidence Interval CMV, Cytomegalovirus CsA, Cyclosporine D, Donor
SC
D/R, Donor/Recipient DOI, Duration of Infection
FOS, Foscarnet GCV, Ganciclovir GVHD, graft-versus-host disease HSV, Herpes Simplex Virus HBV, Hepatitis B Virus
TE D
HCV, Hepatitis C Virus
M AN U
EBV, Epstein-Barr Virus
HR, Hazard Ratio
HSCT, Hematopoietic Stem Cell Transplantation MTX, Methotrexate
OR, Odds Ratio
EP
MMF, Mycophenolate Mofetil
AC C
pp65, matrix phosphoprotein 65 PTS, Post-Transplant Survival R, Recipient
RIC, Reduced Intensity Conditioning TTI, Time To Infection VGCV, Valganciclovir VZV, Varicella Zoster Virus WBC, White Blood Cell
ACCEPTED MANUSCRIPT ABSTRACT Cytomegalovirus (CMV) infection is one of the leading causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (aHSCT), mainly within the first 100 days after transplant. We aimed to characterize CMV infection in
RI PT
a cohort of 305 patients with different malignancies undergoing aHSCT at the Portuguese Institute of Oncology of Porto between January 2008 and December 2012. 184 patients (60.3%) developed CMV infection, mainly viral reactivations
SC
rather than primary infections (96.2% vs 3.8%, respectively). The majority of patients
M AN U
(166/184) developed CMV infection ≤100days post-transplant with median time to infection of 29 days (range: 0-1285) and median duration of infection of 10 days (range: 2-372). Multivariate analysis revealed that CMV infection was over 10-fold increased in D-/R+ and D+/R+ (OR=10.5; 95%CI 4.35-25.4; p38 years (OR=1.89; 95%CI 1.14-3.12; p=0.0137) transplanted with peripheral blood (OR=3.02; 95%CI 1.33-6.86; p=0.008), with mismatched or
EP
unrelated donor (OR=2.16; 95%CI 1.48-3.13; p38 years of age (OR=1.94; 95%CI 0.97-3.87; p=0.062).
CMV infection
SC
Our case-series revealed that 184 patients (60.3%) developed CMV infection, consisting in great majority of viral reactivations rather than primary infection (96.2%
M AN U
vs 3.8%, respectively). Table III details the statistical analysis of the association of CMV infection with clinical variables. The statistical analysis revealed no significant association of CMV infection development with gender, age, underlying disease, stem cell source, phase at transplantation, conditioning regimen, donor CMV
TE D
seropositivity and GVHD development. Nevertheless, the risk of CMV infection was significantly increased in CMV seropositive recipients (p
S1083-8791(14)00509-6
DOI:
10.1016/j.bbmt.2014.08.010
Reference:
YBBMT 53566
To appear in:
Biology of Blood and Marrow Transplantation
Received Date: 19 May 2014 Accepted Date: 12 August 2014
Please cite this article as: Sousa H, Boutolleau D, Ribeiro J, Teixeira AL, Vaz CP, Campilho F, Branca R, Campos A Jr, Baldaque I, Medeiros R, Cytomegalovirus infection in allogeneic hematopoietic stem cell transplanted patients from portugal: a 5-year retrospective review, Biology of Blood and Marrow Transplantation (2014), doi: 10.1016/j.bbmt.2014.08.010. 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 TITLE CYTOMEGALOVIRUS INFECTION IN ALLOGENEIC HEMATOPOIETIC STEM CELL
TRANSPLANTED
PATIENTS
FROM
PORTUGAL:
A
5-YEAR
RI PT
RETROSPECTIVE REVIEW
Hugo Sousa, PhD, MD Student 1,2,3, 1
M AN U
Cytomegalovirus infection in aHSCT in Portugal
SC
SHORT TITLE:
Virology Service and 2 Molecular Oncology Group, Portuguese Institute of Oncology of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, PORTUGAL
3
TE D
Faculty of Medicine of University of Porto, Alameda Prof. Hernâni Monteiro, 4200319 Porto, PORTUGAL David Boutolleau, PharmD PhD 4,5,6
4
Sorbonne Universités, UPMC Université Paris 06, CR7, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), F-75013, Paris, France 6
INSERM, U1135, CIMI-Paris, F-75013, Paris, France
EP
5
AC C
AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière – Charles Foix, Service de Virologie, F-75013, Paris, France Joana Ribeiro, PhD Student 1,2,3 1
Virology Service and 2 Molecular Oncology Group, Portuguese Institute of Oncology of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, PORTUGAL
3
Faculty of Medicine of University of Porto, Alameda Prof. Hernâni Monteiro, 4200319 Porto, PORTUGAL Ana L Teixeira, PhD Student1,2
1
Virology Service and 2 Molecular Oncology Group, Portuguese Institute of Oncology of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, PORTUGAL
ACCEPTED MANUSCRIPT Carlos Pinho Vaz, MD 7 7
Bone Marrow Transplantation Unit, Portuguese Institute of Oncology of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, PORTUGAL Fernando Campilho, MD 7
7
RI PT
Bone Marrow Transplantation Unit, Portuguese Institute of Oncology of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, PORTUGAL Rosa Branca, MD 7
7
SC
Bone Marrow Transplantation Unit, Portuguese Institute of Oncology of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, PORTUGAL
M AN U
António Campos Jr, MD 7 7
Bone Marrow Transplantation Unit, Portuguese Institute of Oncology of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, PORTUGAL Inês Baldaque, MD1
1
TE D
Virology Service, Portuguese Institute of Oncology of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, PORTUGAL Rui Medeiros, PharmD PhD 1,2,8
Virology Service and 2 Molecular Oncology Group, Portuguese Institute of Oncology of Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, PORTUGAL
EP
1
8
AC C
Research Department, Portuguese League Against Cancer (LPCC-NRNorte), Estrada Interior da Circunvalação 6657, 4200 Porto, PORTUGAL Correspondence to: Dr. Hugo Sousa
Serviço de Virologia, Laboratórios 4º Piso Instituto Português de Oncologia do Porto FG EPE Rua Dr. António Bernardino Almeida 4200-072 Porto, Portugal. Phone: +351 22 508 4000 (ext 5410) Fax: +351 22 508 4001 E-mail: [email protected] or [email protected]
ACCEPTED MANUSCRIPT Abstract (word count): 199 words Text (word count): 4076 Figures (number): 1 Tables (number): 5+1
RI PT
FINANCIAL DISCLOSURE
AC C
EP
TE D
M AN U
SC
All authors declare no competing financial interests.
ACCEPTED MANUSCRIPT ABBREVIATIONS aGVHD, Acute GVHD aHSCT, Allogeneic Hematopoietic Stem Cell Transplantation ATG, antithymocyte globulin cGVHD, Chronic GVHD
RI PT
CI, Confidence Interval CMV, Cytomegalovirus CsA, Cyclosporine D, Donor
SC
D/R, Donor/Recipient DOI, Duration of Infection
FOS, Foscarnet GCV, Ganciclovir GVHD, graft-versus-host disease HSV, Herpes Simplex Virus HBV, Hepatitis B Virus
TE D
HCV, Hepatitis C Virus
M AN U
EBV, Epstein-Barr Virus
HR, Hazard Ratio
HSCT, Hematopoietic Stem Cell Transplantation MTX, Methotrexate
OR, Odds Ratio
EP
MMF, Mycophenolate Mofetil
AC C
pp65, matrix phosphoprotein 65 PTS, Post-Transplant Survival R, Recipient
RIC, Reduced Intensity Conditioning TTI, Time To Infection VGCV, Valganciclovir VZV, Varicella Zoster Virus WBC, White Blood Cell
ACCEPTED MANUSCRIPT ABSTRACT Cytomegalovirus (CMV) infection is one of the leading causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (aHSCT), mainly within the first 100 days after transplant. We aimed to characterize CMV infection in
RI PT
a cohort of 305 patients with different malignancies undergoing aHSCT at the Portuguese Institute of Oncology of Porto between January 2008 and December 2012. 184 patients (60.3%) developed CMV infection, mainly viral reactivations
SC
rather than primary infections (96.2% vs 3.8%, respectively). The majority of patients
M AN U
(166/184) developed CMV infection ≤100days post-transplant with median time to infection of 29 days (range: 0-1285) and median duration of infection of 10 days (range: 2-372). Multivariate analysis revealed that CMV infection was over 10-fold increased in D-/R+ and D+/R+ (OR=10.5; 95%CI 4.35-25.4; p38 years (OR=1.89; 95%CI 1.14-3.12; p=0.0137) transplanted with peripheral blood (OR=3.02; 95%CI 1.33-6.86; p=0.008), with mismatched or
EP
unrelated donor (OR=2.16; 95%CI 1.48-3.13; p38 years of age (OR=1.94; 95%CI 0.97-3.87; p=0.062).
CMV infection
SC
Our case-series revealed that 184 patients (60.3%) developed CMV infection, consisting in great majority of viral reactivations rather than primary infection (96.2%
M AN U
vs 3.8%, respectively). Table III details the statistical analysis of the association of CMV infection with clinical variables. The statistical analysis revealed no significant association of CMV infection development with gender, age, underlying disease, stem cell source, phase at transplantation, conditioning regimen, donor CMV
TE D
seropositivity and GVHD development. Nevertheless, the risk of CMV infection was significantly increased in CMV seropositive recipients (p
