Incidence, risk factors, and outcome of pulmonary invasive fungal disease after respiratory virus infection in allogeneic hematopoietic stem cell transplantation recipients

José Luis Piñana, María Dolores Gómez, Juan Montoro, Ignacio Lorenzo, Ariadna Pérez, Estela Giménez, Eva María González-Barberá, Carlos Carretero, Manuel Guerreiro, Miguel Salavert, Guillermo Sanz, Juan Carlos Hernández-Boluda, Rafael Borrás, Jaime Sanz, Carlos Solano, David Navarro, José Luis Piñana, María Dolores Gómez, Juan Montoro, Ignacio Lorenzo, Ariadna Pérez, Estela Giménez, Eva María González-Barberá, Carlos Carretero, Manuel Guerreiro, Miguel Salavert, Guillermo Sanz, Juan Carlos Hernández-Boluda, Rafael Borrás, Jaime Sanz, Carlos Solano, David Navarro

Abstract

Background: There is growing evidence that community-acquired respiratory virus (CARV) increases the risk of pulmonary invasive fungal disease (IFD) in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) setting. To date, there is a lack of knowledge regarding the risk factors (RFs), as well as the most critical period for subsequent onset of IFD after CARV infections in allo-HSCT recipients.

Methods: In this prospective longitudinal observational CARV survey, we analyzed the effect of CARV on subsequent IFD development in 287 adult allo-HSCT recipients diagnosed with 597 CARV episodes from December 2013 to December 2018. Multiplex PCR panel assays were used to test CARVs in respiratory specimens.

Findings: Twenty-nine out of 287 allo-HSCT recipients (10%) developed IFD after a CARV episode. The median time of IFD onset was 21 days (range, 0-158 days) from day of the first CARV detection. Generalized estimating equation model identified 4 risk factors for IFD: ATG-based conditioning regimen [odds ratio (OR) 2.34, 95% confidence interval (CI) 1.05-5.2, P = .038], CARV lower respiratory tract disease (OR 10.6, 95% CI 3.7-30.8, P < .0001), CARV infection during the first year after transplant (OR 5.34, 95% CI 1.3-21.8, P = .014), and corticosteroids during CARV (OR 2.6, 95% CI 1.1-6.3, P = .03).

Conclusion: Allo-HSCT recipients conditioned with ATG and under corticosteroid therapy at the time of CARV LRTD during the first year after transplant may require close monitoring for subsequent IFD.

Keywords: allogeneic hematopoietic stem cell transplantation; community-acquired respiratory virus; immunodeficiency score index; invasive Aspergillosis; invasive pulmonary fungal disease.

© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Cumulative incidence of developing invasive fungal disease according to the the presence of risk factors
Figure 2
Figure 2
Overall survival according to development of fungal infectious disease after A, communityacquired respiratory virus (CARV) infection and B, CARV lower respiratory tract disease (LRTD)

References

    1. Upton A, Kirby KA, Carpenter P, Boeckh M, Marr KA. Invasive aspergillosis following hematopoietic cell transplantation: outcomes and prognostic factors associated with mortality. Clin Infect Dis. 2007;44:531‐540.
    1. Kuster S, Stampf S, Gerber B, et al. Incidence and outcome of invasive fungal diseases after allogeneic hematopoietic stem cell transplantation: a Swiss transplant cohort study. Transpl Infect Dis. 2018;20(6):e12981.
    1. Barnes PD, Marr KA. Risks, diagnosis and outcomes of invasive fungal infections in haematopoietic stem cell transplant recipients. Br J Haematol. 2007;139:519‐531.
    1. Fukuda T, Boeckh M, Carter RA, et al. Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning. Blood. 2003;102:827‐833.
    1. Garcia‐Vidal C, Upton A, Kirby KA, Marr KA. Epidemiology of invasive mold infections in allogeneic stem cell transplant recipients: biological risk factors for infection according to time after transplantation. Clin Infect Dis. 2008;47:1041‐1050.
    1. Jantunen E, Nihtinen A, Anttila VJ. Changing landscape of invasive aspergillosis in allogeneic stem cell transplant recipients. Transpl Infect Dis. 2008;10:156‐161.
    1. Mihu CN, King E, Yossepovitch O, et al. Risk factors and attributable mortality of late aspergillosis after T‐cell depleted hematopoietic stem cell transplantation. Transpl Infect Dis. 2008;10:162‐167.
    1. Martino R, Subira M, Rovira M, et al. Invasive fungal infections after allogeneic peripheral blood stem cell transplantation: incidence and risk factors in 395 patients. Br J Haematol. 2002;116:475‐482.
    1. Marr KA, Carter RA, Boeckh M, Martin P, Corey L. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood. 2002;100:4358‐4366.
    1. Hasejima N, Yamato K, Takezawa S, Kobayashi H, Kadoyama C. Invasive pulmonary aspergillosis associated with influenza B. Respirology. 2005;10:116‐119.
    1. Vandenbos F, Mondain‐Miton V, Roger PM, Saint‐Paul MC, Dellamonica P. Invasive pulmonary aspergillosis during influenza: a fortuitous association? Presse Med. 1999;28:1755.
    1. Alba D, Gomez‐Cerezo J, Cobo J, Ripoll MM, Molina F, Vazquez JJ. Invasive pulmonary aspergillosis associated with influenza virus. An Med Interna. 1996;13:34‐36.
    1. Shapiro D, Ferriss J. Influenza A and aspergillosis. Chest. 1986;89:318‐319.
    1. Lewis M, Kallenbach J, Ruff P, Zaltzman M, Abramowitz J, Zwi S. Invasive pulmonary aspergillosis complicating influenza A pneumonia in a previously healthy patient. Chest. 1985;87:691‐693.
    1. Mezger M, Steffens M, Beyer M, et al. Polymorphisms in the chemokine (C‐X‐C motif) ligand 10 are associated with invasive aspergillosis after allogeneic stem‐cell transplantation and influence CXCL10 expression in monocyte‐derived dendritic cells. Blood. 2008;111:534‐536.
    1. Milano F, Campbell AP, Guthrie KA, et al. Human rhinovirus and coronavirus detection among allogeneic hematopoietic stem cell transplantation recipients. Blood. 2010;115(10):2088‐2094.
    1. Piñana JL, Pérez A, Montoro J, et al. Clinical effectiveness of influenza vaccination after allogeneic hematopoietic stem cell transplantation: a cross‐sectional prospective observational study. Clin Infect Dis. 2019;68(11):1894‐1903.
    1. Piñana JL, Madrid S, Pérez A, et al. Epidemiologic and clinical characteristics of coronavirus and bocavirus respiratory infections after allogeneic stem cell transplantation: a prospective single‐center study. Biol Blood Marrow Transplant. 2018;24(3):563‐570.
    1. Shah DP, Ghantoji SS, Ariza‐Heredia EJ, et al. Immunodeficiency scoring index to predict poor outcomes in hematopoietic cell transplant recipients with RSV infections. Blood. 2014;123:3263‐3268.
    1. Montoro J, Sanz J, Lorenzo JI, et al. Invasive fungal disease in patients undergoing umbilical cord blood transplantation after myeloablative conditioning regimen. Eur J Haematol. 2019;102(4):331‐340.
    1. Seo S, Xie HU, Campbell AP, et al. Parainfluenza virus lower respiratory tract disease after hematopoietic cell transplant: viral detection in the lung predicts outcome. Clin Infect Dis. 2014;58:1357‐1368.
    1. Hirsch HH, Martino R, Ward KN, Boeckh M, Einsele H, Ljungman P. Fourth European Conference on Infections in Leukaemia (ECIL‐4): guidelines for diagnosis and treatment of human respiratory syncytial virus, parainfluenza virus, metapneumovirus, rhinovirus, and coronavirus. Clin Infect Dis. 2013;56(2):258‐266.
    1. Piñana JL, Hernández‐Boluda JC, Calabuig M, et al. A risk‐adapted approach to treating respiratory syncytial virus and human parainfluenza virus in allogeneic stem cell transplantation recipients with oral ribavirin therapy: a pilot study. Transpl Infect Dis. 2017;19(4):e12729.
    1. De Pauw B, Walsh T, Donnelly J, et al. Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46(12):1813‐1821.
    1. Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft‐versus‐host disease in human recipients of marrow from HL‐A‐matched sibling donors. Transplantation. 1974;18:295‐304.
    1. Liang K‐Y, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika. 1986;73(1):13‐22.
    1. Pan W. Akaike’s information criterion in generalized estimating equations. Biometrics. 2001;57(1):120‐125.
    1. R Core Team . R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2013.
    1. Halekoh U, Højsgaard S, Yan J, et al. The r package geepack for generalized estimating equations. J Stat Softw. 2006;15(2):1‐11.
    1. Barton K, Barton MK.Package ‘mumin’. Version, 1:18; 2015.
    1. Klein JP, Rizzo JD, Zhang M‐J, Keiding N. Statistical methods for the analysis and presentation of the results of bone marrow transplants. Part I: unadjusted analysis. Bone Marrow Transplant. 2001;28:909‐915.
    1. Klein JP, Rizzo JD, Zhang M‐J, Keiding N. Statistical methods for the analysis and presentation of the results of bone marrow transplants. Part 2: Regression modeling. Bone Marrow Transplant. 2001;28:1001‐1011.
    1. Martino R, Piñana JL, Parody R, et al. Lower respiratory tract respiratory virus infections increase the risk of invasive aspergillosis after a reduced‐intensity allogeneic hematopoietic SCT. Bone Marrow Transplant. 2009;44(11):749‐756.
    1. Alonso JM. Immunity and pathophysiology of respiratory tract infections. Med Mal Infect. 2008;38:433‐437.
    1. Boeckh M. The challenge of respiratory virus infections in hematopoietic cell transplant recipients. Br J Haematol. 2008;143:455‐467.
    1. Thomson BG, Robertson KA, Gowan D, et al. Analysis of engraftment, graft‐versus‐host disease, and immune recovery following unrelated donor cord blood transplantation. Blood. 2000;96(8):2703‐2711.
    1. Mohty M, Bay JO, Faucher C, et al. Graft‐versus‐host disease following allogeneic transplantation from HLA‐identical sibling with antithymocyte globulin‐based reduced‐intensity preparative regimen. Blood. 2003;102(2):470‐476.
    1. Rivera A, Epps HV, Hohl T, Rizzuto G, Pamer E. Distinct CD4+ T cell responses to live and heat‐inactivated Aspergillus fumigatus conidia. Infect Immun. 2005;73:7170‐7179.
    1. Rivera A, Hohl T, Pamer EG. Immune responses to Aspergillus fumigatus infections. Biol Blood Marrow Transplant. 2006;12(Suppl 1):47‐49.
    1. Beck O, Topp MS, Koehl U, et al. Generation of highly purified and functionally active human TH1 cells against Aspergillus fumigatus . Blood. 2006;107:2562‐2569.
    1. Fukuda T, Boeckh M, Guthrie KA, et al. Invasive aspergillosis before allogeneic hematopoietic stem cell transplantation: 10‐year experience at a single transplant center. Biol Blood Marrow Transplant. 2004;10(7):494‐503.

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