Respiratory Syncytial Virus Infections in Children With Cancer Roy F. Chemaly, MD, MPH, FACP, FIDSA,* Shashank S. Ghantoji, MD, MPH,* Dimpy P. Shah, MD, MSPH,* Jharna N. Shah, MD,w Katia K. El Taoum, MD,* Richard E. Champlin, MD,z Cesar A. Nunez, MD,y Victor Mulanovich, MD,* and Ella Ariza-Heredia, MD*

Summary: Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections (LRTIs) in children, especially those with cancer. Data on RSV infections in this vulnerable population is limited. We conducted a retrospective study of all RSV infections in children with cancer from 1998 to 2009 to determine characteristics and outcomes of these infections, identify risk factors for LRTI and mortality, and the effect of antiviral therapy on these outcomes. We identified 59 patients with a median age of 5 years; 53% had hematologic malignancy, 32% were hematopoietic stem cell transplant recipients, 39% had received corticosteroids, and 76% cytotoxic chemotherapy within 1 month before RSV infection. LRTI developed in 22 (37%) patients with a trend of higher rate in males (odds ratio = 2.57 [0.86-7.62], P = 0.09) and children with lymphocytopenia (odds ratio = 2.95 [0.86-10.12], P = 0.085). No significant differences were observed in the rates of progression to LRTI (3/10 [30%] vs. 19/49 [39%], P = 0.729) and RSV-associated mortality (0/10 [0%] vs. 3/49 [6%], P = 0.422) for patients receiving antiviral therapy at upper respiratory tract infection stage compared with those who did not. However, patients with LRTI had significantly better outcomes when treated with aerosolized ribavirin plus immunomodulators (mainly palivizumab) when compared with aerosolized ribavirin alone (mortality rates: 0/6 [0%] vs. 3/4 [75%], P = 0.03). Ribavirin did not show any benefit in reducing LRTI or mortality; however, addition of palivizumab to the treatment regimen may be potentially beneficial, especially for children with LRTI. Key Words: RSV, hematopoietic cell transplant, antiviral therapy, ribavirin, immunocompromised

(J Pediatr Hematol Oncol 2014;36:e376–e381)


espiratory syncytial virus (RSV) is a common cause of lower respiratory tract infection (LRTI) in infants.1 In healthy children and infants, it usually causes upper respiratory tract infection (URTI); however, it may present as bronchiolitis or pneumonia in 25% to 40% of patients,2 with a mortality rate of 15, were neutropenic and lymphocytopenic at the time of first assessment of respiratory symptoms, and had coinfections within 1 month of RSV diagnosis. Two patients had undergone allogeneic HSCT (1 matched related bone marrow transplant and 1 mismatched related peripheral blood stem cell transplant) and one was suffering from HM. None of the 3 patients had been treated at the URTI stage. They all required an intensive care unit stay with mechanical ventilation for respiratory support despite ribavirin therapy at LRTI stage. r

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RSV in Children With Cancer

TABLE 2. Bivariable Regression Analysis for Risk Factors of RSV-LRTI in Children With Cancer

Risk Factors Age (median [range]) (y) Male sex Type of malignancy Hematologic malignancy Solid tumor HSCT Preengraftment HSCT donorw Matched related Mismatched related Matched unrelated Stem cell sourcew Peripheral blood Bone marrow Cord blood Cytotoxic chemotherapyz Corticosteroidsz Neutropeniay Lymphocytopeniay APACHE II scorey >15 Coinfections8 Antiviral therapy at URTI stage

URTI (n [%]) (n = 37)

LRTI (n [%]) (n = 22)

Odds Ratio (95% CI)


5 (1-18) 15 (41)

6 (1-18) 14 (64)

1.38 (0.52-3.65)* 2.57 (0.86-7.62)

0.516 0.09

18 (49) 7 (19) 12 (32) 0

13 2 7 2

(59) (9) (32) (9)

1.00 (Reference) 0.39 (0.07-2.22) 0.81 (0.25-2.61)

— 0.292 0.721 —

2 (40) 1 (20) 2 (40)

1.00 (Reference) 2 (0.08-51.59) 0.57 (0.06-5.77)

0.676 0.635

1.00 1.00 1.33 2.68 1.54 1.19 2.95 1.23 0.69 0.68

1.00 0.835 0.17 0.433 0.758 0.085 0.706 0.583 0.602

4 (33) 1 (8) 7 (58) 2 4 6 26 13 12 6 20 9 7

(17) (33) (50) (76) (35) (32) (16) (54) (24) (19)

1 2 4 19 10 8 8 13 4 3

(14) (29) (57) (86) (45) (36) (36) (59) (18) (14)

(Reference) (0.05-18.91) (0.09-20.11) (0.66-10.94) (0.52-4.52) (0.39-3.6) (0.86-10.12) (0.42-3.57) (0.19-2.58) (0.16-2.94)

*Per 10-year interval. wAnalysis restricted to 17 patients who underwent allogeneic HSCT. zWithin 1 month before RSV diagnosis. yAt the time of first assessment of respiratory symptoms. 8Only coinfections occurring within 1 month before RSV-LRI were included for risk factor analysis. These included 8 bacteremia (4 coagulase-negative staphylococcus, 1 Stomatococcus species, 1 Enterococcus faecium, 1 Candida krusei, and 1 a-hemolytic streptococcus); 2 CMV reactivations; 1 upper respiratory tract infection (Streptococcus pneumoniae); 2 lower respiratory tract infections (Mycobacterium fortuitum and methicillin-resistant Staphylococcus aureus); 2 cystitis (BK virus); 2 gastrointestinal infections (Clostridium difficile); and 1 soft-tissue infection (coagulase-negative staphylococcus, and Enterococcus species). Four patients had >1 copathogens. APACHE II score indicates acute physiology and chronic health evaluation II score; CI, confidence interval; HSCT, hematopoietic stem cell transplantation; LRTI, lower respiratory tract infection; RSV, respiratory syncytial virus; URTI, upper respiratory tract infection.

Because the number of deaths was low, we did not attempt a multivariable analysis to identify predictors of mortality.

HM Versus HSCT When we compared patients with hematologic malignancies, patients with solid tumors and HSCT recipients, no significant differences in characteristics or outcome of RSV infection were noted (data not shown).

DISCUSSION Our study includes a large number of children with cancer and RSV infections. We found that 1/3 had pneumonia with 5% mortality rate. Mortality rate was much higher for patients progressing to LRTI (3/22, 14%). No significant risk factors for progression to RSV-LRTI, except for higher trend in males and lymphocytopenic children, were observed. No significant difference in outcomes was observed with respect to antiviral therapy administered at URTI stage. Interestingly, no deaths occurred when children with RSV-LRTI were treated with palivizumab with or without ribavirin. Overall, 59% of patients with HM and about 32% of HSCT patients developed RSV-LRTI. This finding is consistent with the results of previous studies, which reported progression to LRTI in 8% to 58% of pediatric cancer patients6,12,13 but up to 100% of pediatric patients with HM.14 The severity of immunodeficiency plays an r

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important role in increasing the risk of RSV infection, of progression to LRTI, and of RSV-related mortality. Lymphocytopenia15 has often been identified as a predictor of progression to LRTI, not only in the pediatric population but also in adult HSCT recipients as well as patients with leukemia.16 Severe RSV infection has been described as more likely in children with cancer who were receiving immunosuppressive chemotherapy.6,17–20 Although neutropenia has not been conclusively established to be an independent risk factor for the development of LRTI or for RSV-related mortality, it may be considered to play a role in the development of coinfections, especially bacterial infections, which may contribute to higher morbidity and mortality. In contrast, more than half of our patients were admitted because of RSV infection with a median length of stay for patients with LRTI of 6 days, which is shorter than that reported in other studies (7 to 19 d).6,8,12,18 The mortality rate in our cohort of patients was low (5%). This finding is consistent with the results of previous studies in high-risk children with cancer, which report overall mortality rates of 0% to 20%. Mortality rates of up to 50% in patients who progress to LRTI have been reported6,12,17; however, we observed a rate of 14% (3 deaths in 22 children with LRTI) which is at the lower end of that reported.6,12,17 High mortality rates have also been reported for children who have undergone HSCT and progressed to LRTI,5 but most studies including ours had small number of HSCT recipients. RSV infections may www.jpho-online.com |


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Chemaly et al

Total number of children

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N = 59

Site of infection at diagnosis

URTI 48 (81)

Initiation of AVT at URTI stage

Yes 10 (21)

No 38 (79)

Progression to LRTI

3 (30)

8 (21)

Initiation of AVT at LRTI stage

RSV-attributable Death


LRTI 11 (19)

Yes 4 (50)

Yes 9 (82)

1 (25)

2 (22)

AVT indicates any type of antiviral therapy FIGURE 2. Outcomes of respiratory syncytial virus (RSV) infections in children with cancer by any antiviral therapy administered at upper respiratory tract infection (URTI) stage. AVT indicates any type of antiviral therapy; LRTI, lower respiratory tract infection.

follow a more severe course in immunocompromised adult patients than in immunocompromised pediatric patients; in adults, 50% to 80% of patients develop LRTI, and mortality rates may reach 100% when treatment is initiated late in the course of the disease, especially in HSCT recipients.21 Ribavirin treatment, alone or in combination with immunomodulators, has been shown to prevent progression to LRTI and mortality in adults22,23; however, its benefit in children has not be demonstrated yet. Some studies have indicated that RSV-specific antiviral therapy improves outcomes in children with cancer,5,13 but those studies included only small numbers of patients and lacked control groups. The efficacy of AR in reducing the severity of RSV infection in high-risk patients has not been established, and no specific recommendations exist on the use of AR in immunocompromised children. Although immunomodulators have been shown to reduce pulmonary viral loads of RSV in immunocompromised animal models,24,25 they have demonstrated variable success in pediatric patients. Palivizumab, a humanized RSV-specific monoclonal antibody, has been approved for prophylaxis of severe RSV infection in high-risk children.26 Palivizumab has been shown to reduce respiratory syncytial viral loads and reduce mortality when used alone or in combination with ribavirin.6 Polyclonal immunoglobulins have also been studied in HSCT children with LRTI and have been shown to produce modest reductions (9%) in mortality.8 Although, our data did not show significant differences in the rates of progression to LRTI (30% vs. 39%) and 60-day RSV-associated mortality rate (0% vs. 6%) for patients receiving antiviral therapy at URTI stage compared with those who did not, no deaths were observed in group receiving palivizumab alone or in combination with ribavirin. We observed that children who developed LRTI had

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significantly better survival rates when treated with ribavirin plus immunomodulators compared with ribavirin alone. A limitation of our study is being retrospective and with small number of patients, hence caution is recommended while interpreting our results. In summary, ribavirin alone did not show any benefit in reducing LRTI or mortality in children with cancer; however, addition of palivizumab to the treatment regimen may be potentially beneficial, especially for children with LRTI but further studies are needed to establish efficacy. ACKNOWLEDGMENT The authors thank Karen Muller for editorial support. REFERENCES 1. Nair H, Nokes DJ, Gessner BD, et al. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet. 2010;375:1545–1555. 2. Centers for Disease Control and Prevention. Respiratory syncytial virus: infection and incidence. 2010. Available at: http://www.cdc.gov/rsv/about/infection.html. Accessed April 2, 2013. 3. Stensballe LG, Devasundaram JK, Simoes EA. Respiratory syncytial virus epidemics: the ups and downs of a seasonal virus. Pediatr Infect Dis J. 2003;22:S21–S32. 4. Anak S, Atay D, Unuvar A, et al. Respiratory syncytial virus infection outbreak among pediatric patients with oncologic diseases and/or BMT. Pediatr Pulmonol. 2010;45:307–311. 5. Adams R, Christenson J, Petersen F, et al. Pre-emptive use of aerosolized ribavirin in the treatment of asymptomatic pediatric marrow transplant patients testing positive for RSV. Bone Marrow Transplant. 1999;24:661–664. 6. Cha´vez-Bueno S, Mejı´ as A, Merryman RA, et al. Intravenous palivizumab and ribavirin combination for respiratory r

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syncytial virus disease in high-risk pediatric patients. Pediatr Infect Dis J. 2007;26:1089–1093. Randolph AG, Wang EE. Ribavirin for respiratory syncytial virus lower respiratory tract infection. A systematic overview. Arch Pediatr Adolesc Med. 1996;150:942–947. DeVincenzo JP, Hirsch RL, Fuentes RJ, et al. Respiratory syncytial virus immune globulin treatment of lower respiratory tract infection in pediatric patients undergoing bone marrow transplantation—a compassionate use experience. Bone Marrow Transplant. 2000;25:161–165. Go¨kalp C, Go¨kahmetog˘lu S, Deniz ES, et al. Investigation of respiratory syncytial virus by three different methods in children with lower respiratory tract infection. Mikrobiyol Bul. 2009;43: 433–438. Shetty AK, Treynor E, Hill DW, et al. Comparison of conventional viral cultures with direct fluorescent antibody stains for diagnosis of community-acquired respiratory virus infections in hospitalized children. Pediatr Infect Dis J. 2003; 22:789–794. Chemaly RF, Ghosh S, Bodey GP, et al. Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center. Medicine (Baltimore). 2006;85:278–287. Cole PD, Suh JS, Onel K, et al. Benign outcome of RSV infection in children with cancer. Med Pediatr Oncol. 2001;37: 24–29. Vettenranta K, Ukkonen P, Saarinen UM. RSV infection complicating the therapy of pediatric malignancies: report of six cases. Med Pediatr Oncol. 1996;26:261–263. Hall CB, Powell KR, MacDonald NE, et al. Respiratory syncytial viral infection in children with compromised immune function. N Engl J Med. 1986;315:77–81. El Saleeby CM, Somes GW, DeVincenzo JP, et al. Risk factors for severe respiratory syncytial virus disease in children with cancer: the importance of lymphopenia and young age. Pediatrics. 2008;121:235–243. Torres HA, Aguilera EA, Mattiuzzi GN, et al. Characteristics and outcome of respiratory syncytial virus infection in patients with leukemia. Haematologica. 2007;92:1216–1223.

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RSV in Children With Cancer

17. Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus infection in young children. N Engl J Med. 2009;360:588–598. 18. El Saleeby CM, Suzich J, Conley ME, et al. Quantitative effects of palivizumab and donor-derived T cells on chronic respiratory syncytial virus infection, lung disease, and fusion glycoprotein amino acid sequences in a patient before and after bone marrow transplantation. Clin Infect Dis. 2004;39:e17–e20. 19. Craft AW, Reid MM, Gardner PS, et al. Virus infections in children with acute lymphoblastic leukaemia. Arch Dis Child. 1979;54:755–759. 20. Taylor CE, Sviland L, Pearson AD, et al. Virus infections in bone marrow transplant recipients: a three year prospective study. J Clin Pathol. 1990;43:633–637. 21. Champlin RE, Whimbey E. Community respiratory virus infections in bone marrow transplant recipients: the M.D. Anderson Cancer Center experience. Biol Blood Marrow Transplant. 2001;7(suppl):8S–10S. 22. Shah JN, Chemaly RF. Management of RSV infections in adult recipients of hematopoietic stem cell transplantation. Blood. 2011;117:2755–2763. 23. 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;68:1872–1880. 24. Siber GR, Leombruno D, Leszczynski J, et al. Comparison of antibody concentrations and protective activity of respiratory syncytial virus immune globulin and conventional immune globulin. J Infect Dis. 1994;169:1368–1373. 25. Ottolini MG, Porter DD, Hemming VG, et al. Effectiveness of RSVIG prophylaxis and therapy of respiratory syncytial virus in an immunosuppressed animal model. Bone Marrow Transplant. 1999;24:41–45. 26. American Academy of Pediatrics Committee on Infectious Diseases and Committee on Fetus and Newborn. Revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections. Pediatrics. 2003;112: 1442–1446.

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Respiratory syncytial virus infections in children with cancer.

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections (LRTIs) in children, especially those with cancer. Data on RS...
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