EDITORIAL COMMENTARY
Respiratory Syncytial Virus in Hematopoietic Cell Transplant Recipients: Factors Determining Progression to Lower Respiratory Tract Disease Per Ljungman1,2 1
(See the major article by Kim et al on pages 1195–204.)
Keywords.
RSV; stem cell transplantation; ribavirin.
Respiratory syncytial virus (RSV) is an important pathogen in infants and young children but is also important in the elderly and in individuals with chronic obstructive pulmonary disease (COPD). It was recognized 25 years ago that RSV can cause severe disease in immunocompromised patients, especially those having undergone allogeneic hematopoietic stem cell transplantation (HSCT) [1– 3]. The early publications on this subject reported a very high mortality during lower respiratory tract disease. It has also been shown that RSV is an important nosocomial pathogen; therefore, infection control measures are very important in HSCT units. Over the last 2 decades, several studies on risk factors and outcome of HSCT have been published, and the article by Kim et al [4] in this issue of the Journal of Infectious Diseases adds important new information on the topic.
Received and accepted 16 December 2013; electronically published 23 December 2013. Correspondence: Per Ljungman, MD, PhD, Department of Hematology, Karolinska University Hospital, S-14186 Stockholm, Sweden ( [email protected]). The Journal of Infectious Diseases 2014;209:1151–2 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jit833
Kim et al [4] included both allogeneic and autologous HSCT recipients, and there was no difference in the risk of progression to lower respiratory tract disease. Other articles have suggested that autologous HSCT recipients have lower risk for poor outcome [5–7]. However, a recent publication shows no difference in the risk for lower respiratory tract disease or mortality [8]. These different results might have to do with different treatments given before autologous HSCT, such as the use of monoclonal antibodies, or the increasing age of patients undergoing autologous transplants in recent years, although in the study by Kim et al, age was not a risk factor for lower respiratory tract disease. Other risk factors for lower respiratory tract disease found in the study by Kim et al [4] were being a smoker, having received total body irradiation, and severe lymphocytopenia, 1.0 × 109/L was
completely protective against progression to lower respiratory tract disease. This finding allows risk stratification and thereby helps in patient management and in recruiting patients for future studies. The negative effect of smoking is interesting, because it has not previously been documented in immunocompromised individuals. This finding fits, however, with knowledge obtained in other contexts. It is well known that RSV disease severity is increased in infants exposed to smoking in the household. It has also been shown in vitro that the inhibitory antiviral effect of interferon-γ against RSV messenger RNA (mRNA), and protein expression is decreased by cigarette smoke [10]. The major controversy in management of RSV infection remains the effects of therapy with ribavirin or immune globulin. There has been no controlled clinical study of sufficient size to allow conclusions regarding efficacy. There have been several reports, mostly retrospective, on ribavirin therapy for RSV infection [6–8, 12–16]. The only existing controlled trial of aerosolized ribavirin in HSCT recipients was only able to recruit 14 patients [11]. In this study, there was a trend for lower viral loads in the ribavirin treated patients but no differences in outcome. Assessment of the impact of ribavirin
EDITORIAL COMMENTARY
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JID 2014:209 (15 April)
•
1151
Downloaded from http://jid.oxfordjournals.org/ at UNIVERSITY OF AUCKLAND LIBRARY on May 6, 2015
Department of Hematology, Karolinska University Hospital and 2Division of Hematology, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
1152
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JID 2014:209 (15 April)
•
ribavirin, regardless of the route of administration, has several important limitations regarding efficacy and toxicity.
9.
Note Potential conflict of interest. Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References 1. Englund J, Sullivan C, Jordan M, Dehner L, Vercelotti G, Balfour H. Respiratory syncytial virus infection in immunocompromised adults. Ann Intern Med 1988; 109:203–8. 2. Harrington RD, Hooton TM, Hackman RC, et al. An outbreak of respiratory syncytial virus in a bone marrow transplant center. J Infect Dis 1992; 165:987–93. 3. Whimbey E, Champlin RE, Couch RB, et al. Community respiratory virus infections among hospitalized adult bone marrow transplant recipients. Clin Infect Dis 1996; 22:778–82. 4. Kim Y-J, Guthrie KA, Waghmare A, et al. Respiratory syncytial virus in hematopoietic cell transplant recipients: factors determining progression to lower respiratory tract disease. J Infect Dis 2014; 209: 1195–204. 5. Anaissie EJ, Mahfouz TH, Aslan T, et al. The natural history of respiratory syncytial virus infection in cancer and transplant patients: implications for management. Blood 2004; 103:1611–7. 6. Ljungman P, Ward KN, Crooks BN, et al. Respiratory virus infections after stem cell transplantation: a prospective study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2001; 28:479–84. 7. Khanna N, Widmer AF, Decker M, et al. Respiratory syncytial virus infection in patients with hematological diseases: singlecenter study and review of the literature. Clin Infect Dis 2008; 46:402–12. 8. Lehners N, Schnitzler P, Geis S, et al. Risk factors and containment of respiratory syncytial virus outbreak in a hematology and
EDITORIAL COMMENTARY
10.
11.
12.
13.
14.
15.
16.
17.
transplant unit. Bone Marrow Transplant 2013; 48:1548–53. Martino R, Porras RP, Rabella N, et al. Prospective study of the incidence, clinical features, and outcome of symptomatic upper and lower respiratory tract infections by respiratory viruses in adult recipients of hematopoietic stem cell transplants for hematologic malignancies. Biol Blood Marrow Transplant 2005; 11:781–96. Modestou MA, Manzel LJ, El-Mahdy S, Look DC. Inhibition of IFN-gamma-dependent antiviral airway epithelial defense by cigarette smoke. Respir Res 2010; 11:64. Boeckh M, Englund J, Li Y, et al. Randomized controlled multicenter trial of aerosolized ribavirin for respiratory syncytial virus upper respiratory tract infection in hematopoietic cell transplant recipients. Clin Infect Dis 2007; 44:245–9. Garcia R, Raad I, Abi-Said D, et al. Nosocomial respiratory syncytial virus infection: prevention and control in bone marrow transplant patients. Infect Control Hosp Epidemiol 1997; 18:412–6. Chemaly RF, Torres HA, Munsell MF, et al. An adaptive randomized trial of an intermittent dosing schedule of aerosolized ribavirin in patients with cancer and respiratory syncytial virus infection. J Infect Dis 2012; 206:1367–71. Ghosh S, Champlin RE, Englund J, et al. Respiratorysyncytial virus upper respiratory tract illnesses in adult blood and marrow transplant recipients: combination therapy with aerosolized ribavirin and intravenous immunoglobulin. Bone Marrow Transplant 2000; 25:751–5. Nichols WG, Gooley T, Boeckh M. Community-acquired respiratory syncytial virus and parainfluenza virus infections after hematopoietic stem cell transplantation: the Fred Hutchinson Cancer Research Center experience. Biol Blood Marrow Transplant 2001; 7 (Suppl):11S–5S. Shah DP, Ghantoji SS, Shah JN, et al. Impact of aerosolized ribavirin on mortality in 280 allogeneic haematopoietic stem cell transplant recipients with respiratory syncytial virus infections. J Antimicrob Chemother 2013; 68:1872–80. Shah JN, Chemaly RF. Management of RSV infections in adult recipients of hematopoietic stem cell transplantation. Blood 2011; 117: 2755–63.
Downloaded from http://jid.oxfordjournals.org/ at UNIVERSITY OF AUCKLAND LIBRARY on May 6, 2015
becomes even more difficult because the treatment modalities differ, with aerosolized ribavirin used more commonly in the United States, whereas systemic ribavirin has been more commonly used in Europe. However, a recent large study of 280 patients with upper respiratory tract infections showed that use of aerosolized ribavirin was the most important factor for reducing the risk for RSV lower respiratory tract disease, RSV associated mortality, and all-cause mortality [16]. The use of ribavirin in HSCT recipients is also supported by a systematic review showing a reduction in the risk for lower respiratory tract disease when treatment is given at the upper respiratory virus stage and an improvement in outcome of RSV pneumonia by ribavirin therapy [17]. Another interesting question addressed by Kim et al [4] is the effect of specific humoral immunity on RSV outcomes; the authors were unable to find a protective effect by analyzing the levels of neutralizing antibodies or by weekly immune globulin therapy. The usefulness of immune globulin or pavilizumab added to ribavirin, either in the prevention of or as therapy for lower respiratory tract disease in HSCT recipients, is also controversial. Controlled studies are also lacking on this topic. A systematic review suggested, however, an effect of immune globulin administration, especially when treating established lower respiratory tract disease [16]. Despite 2 decades of studies, we still need to better define optimal strategies of RSV infection management in severely immunocompromised patients. New antiviral agents are also needed because
Respiratory Syncytial Virus in Hematopoietic Cell Transplant Recipients: Factors Determining Progression to Lower Respiratory Tract Disease Per Ljungman1,2 1
(See the major article by Kim et al on pages 1195–204.)
Keywords.
RSV; stem cell transplantation; ribavirin.
Respiratory syncytial virus (RSV) is an important pathogen in infants and young children but is also important in the elderly and in individuals with chronic obstructive pulmonary disease (COPD). It was recognized 25 years ago that RSV can cause severe disease in immunocompromised patients, especially those having undergone allogeneic hematopoietic stem cell transplantation (HSCT) [1– 3]. The early publications on this subject reported a very high mortality during lower respiratory tract disease. It has also been shown that RSV is an important nosocomial pathogen; therefore, infection control measures are very important in HSCT units. Over the last 2 decades, several studies on risk factors and outcome of HSCT have been published, and the article by Kim et al [4] in this issue of the Journal of Infectious Diseases adds important new information on the topic.
Received and accepted 16 December 2013; electronically published 23 December 2013. Correspondence: Per Ljungman, MD, PhD, Department of Hematology, Karolinska University Hospital, S-14186 Stockholm, Sweden ( [email protected]). The Journal of Infectious Diseases 2014;209:1151–2 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jit833
Kim et al [4] included both allogeneic and autologous HSCT recipients, and there was no difference in the risk of progression to lower respiratory tract disease. Other articles have suggested that autologous HSCT recipients have lower risk for poor outcome [5–7]. However, a recent publication shows no difference in the risk for lower respiratory tract disease or mortality [8]. These different results might have to do with different treatments given before autologous HSCT, such as the use of monoclonal antibodies, or the increasing age of patients undergoing autologous transplants in recent years, although in the study by Kim et al, age was not a risk factor for lower respiratory tract disease. Other risk factors for lower respiratory tract disease found in the study by Kim et al [4] were being a smoker, having received total body irradiation, and severe lymphocytopenia, 1.0 × 109/L was
completely protective against progression to lower respiratory tract disease. This finding allows risk stratification and thereby helps in patient management and in recruiting patients for future studies. The negative effect of smoking is interesting, because it has not previously been documented in immunocompromised individuals. This finding fits, however, with knowledge obtained in other contexts. It is well known that RSV disease severity is increased in infants exposed to smoking in the household. It has also been shown in vitro that the inhibitory antiviral effect of interferon-γ against RSV messenger RNA (mRNA), and protein expression is decreased by cigarette smoke [10]. The major controversy in management of RSV infection remains the effects of therapy with ribavirin or immune globulin. There has been no controlled clinical study of sufficient size to allow conclusions regarding efficacy. There have been several reports, mostly retrospective, on ribavirin therapy for RSV infection [6–8, 12–16]. The only existing controlled trial of aerosolized ribavirin in HSCT recipients was only able to recruit 14 patients [11]. In this study, there was a trend for lower viral loads in the ribavirin treated patients but no differences in outcome. Assessment of the impact of ribavirin
EDITORIAL COMMENTARY
•
JID 2014:209 (15 April)
•
1151
Downloaded from http://jid.oxfordjournals.org/ at UNIVERSITY OF AUCKLAND LIBRARY on May 6, 2015
Department of Hematology, Karolinska University Hospital and 2Division of Hematology, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
1152
•
JID 2014:209 (15 April)
•
ribavirin, regardless of the route of administration, has several important limitations regarding efficacy and toxicity.
9.
Note Potential conflict of interest. Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References 1. Englund J, Sullivan C, Jordan M, Dehner L, Vercelotti G, Balfour H. Respiratory syncytial virus infection in immunocompromised adults. Ann Intern Med 1988; 109:203–8. 2. Harrington RD, Hooton TM, Hackman RC, et al. An outbreak of respiratory syncytial virus in a bone marrow transplant center. J Infect Dis 1992; 165:987–93. 3. Whimbey E, Champlin RE, Couch RB, et al. Community respiratory virus infections among hospitalized adult bone marrow transplant recipients. Clin Infect Dis 1996; 22:778–82. 4. Kim Y-J, Guthrie KA, Waghmare A, et al. Respiratory syncytial virus in hematopoietic cell transplant recipients: factors determining progression to lower respiratory tract disease. J Infect Dis 2014; 209: 1195–204. 5. Anaissie EJ, Mahfouz TH, Aslan T, et al. The natural history of respiratory syncytial virus infection in cancer and transplant patients: implications for management. Blood 2004; 103:1611–7. 6. Ljungman P, Ward KN, Crooks BN, et al. Respiratory virus infections after stem cell transplantation: a prospective study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2001; 28:479–84. 7. Khanna N, Widmer AF, Decker M, et al. Respiratory syncytial virus infection in patients with hematological diseases: singlecenter study and review of the literature. Clin Infect Dis 2008; 46:402–12. 8. Lehners N, Schnitzler P, Geis S, et al. Risk factors and containment of respiratory syncytial virus outbreak in a hematology and
EDITORIAL COMMENTARY
10.
11.
12.
13.
14.
15.
16.
17.
transplant unit. Bone Marrow Transplant 2013; 48:1548–53. Martino R, Porras RP, Rabella N, et al. Prospective study of the incidence, clinical features, and outcome of symptomatic upper and lower respiratory tract infections by respiratory viruses in adult recipients of hematopoietic stem cell transplants for hematologic malignancies. Biol Blood Marrow Transplant 2005; 11:781–96. Modestou MA, Manzel LJ, El-Mahdy S, Look DC. Inhibition of IFN-gamma-dependent antiviral airway epithelial defense by cigarette smoke. Respir Res 2010; 11:64. Boeckh M, Englund J, Li Y, et al. Randomized controlled multicenter trial of aerosolized ribavirin for respiratory syncytial virus upper respiratory tract infection in hematopoietic cell transplant recipients. Clin Infect Dis 2007; 44:245–9. Garcia R, Raad I, Abi-Said D, et al. Nosocomial respiratory syncytial virus infection: prevention and control in bone marrow transplant patients. Infect Control Hosp Epidemiol 1997; 18:412–6. Chemaly RF, Torres HA, Munsell MF, et al. An adaptive randomized trial of an intermittent dosing schedule of aerosolized ribavirin in patients with cancer and respiratory syncytial virus infection. J Infect Dis 2012; 206:1367–71. Ghosh S, Champlin RE, Englund J, et al. Respiratorysyncytial virus upper respiratory tract illnesses in adult blood and marrow transplant recipients: combination therapy with aerosolized ribavirin and intravenous immunoglobulin. Bone Marrow Transplant 2000; 25:751–5. Nichols WG, Gooley T, Boeckh M. Community-acquired respiratory syncytial virus and parainfluenza virus infections after hematopoietic stem cell transplantation: the Fred Hutchinson Cancer Research Center experience. Biol Blood Marrow Transplant 2001; 7 (Suppl):11S–5S. Shah DP, Ghantoji SS, Shah JN, et al. Impact of aerosolized ribavirin on mortality in 280 allogeneic haematopoietic stem cell transplant recipients with respiratory syncytial virus infections. J Antimicrob Chemother 2013; 68:1872–80. Shah JN, Chemaly RF. Management of RSV infections in adult recipients of hematopoietic stem cell transplantation. Blood 2011; 117: 2755–63.
Downloaded from http://jid.oxfordjournals.org/ at UNIVERSITY OF AUCKLAND LIBRARY on May 6, 2015
becomes even more difficult because the treatment modalities differ, with aerosolized ribavirin used more commonly in the United States, whereas systemic ribavirin has been more commonly used in Europe. However, a recent large study of 280 patients with upper respiratory tract infections showed that use of aerosolized ribavirin was the most important factor for reducing the risk for RSV lower respiratory tract disease, RSV associated mortality, and all-cause mortality [16]. The use of ribavirin in HSCT recipients is also supported by a systematic review showing a reduction in the risk for lower respiratory tract disease when treatment is given at the upper respiratory virus stage and an improvement in outcome of RSV pneumonia by ribavirin therapy [17]. Another interesting question addressed by Kim et al [4] is the effect of specific humoral immunity on RSV outcomes; the authors were unable to find a protective effect by analyzing the levels of neutralizing antibodies or by weekly immune globulin therapy. The usefulness of immune globulin or pavilizumab added to ribavirin, either in the prevention of or as therapy for lower respiratory tract disease in HSCT recipients, is also controversial. Controlled studies are also lacking on this topic. A systematic review suggested, however, an effect of immune globulin administration, especially when treating established lower respiratory tract disease [16]. Despite 2 decades of studies, we still need to better define optimal strategies of RSV infection management in severely immunocompromised patients. New antiviral agents are also needed because
