The Use of Intravenous Palivizumab for Treatment of Persistent RSV... in Children With Leukemia
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The Use of Intravenous Palivizumab for Treatment of Persistent RSV... in Children With Leukemia
The Use of Intravenous Palivizumab for Treatment of Persistent RSV Infection in Children With Leukemia Roberto P. Santos, Jeffery Chao, Anne G. Nepo, Shafiq Butt, Kathleen A. Stellrecht, Jennifer M. Pearce and Martha L. Lepow Pediatrics 2012;130;e1695; originally published online November 12, 2012; DOI: 10.1542/peds.2011-1768 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/130/6/e1695.full.html PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2012 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Downloaded from pediatrics.aappublications.org by guest on September 9, 2014 CASE REPORT The Use of Intravenous Palivizumab for Treatment of Persistent RSV Infection in Children With Leukemia AUTHORS: Roberto P. Santos, MD, Jeffery Chao, MD, Anne G. Nepo, MD, Shafiq Butt, BS, Kathleen A. Stellrecht, PhD, Jennifer M. Pearce, MD, and Martha L. Lepow, MD Albany Medical Center, Albany, New York KEY WORDS children, intravenous palivizumab, leukemia, RSV ABBREVIATIONS ALC—absolute lymphocyte count ALL—acute lymphocytic leukemia ANC—absolute neutrophil count hMPV—human metapneumovirus IV—intravenous IVIG—intravenous immunoglobulin LRTI—lower respiratory tract infection RSV—respiratory syncytial virus www.pediatrics.org/cgi/doi/10.1542/peds.2011-1768 doi:10.1542/peds.2011-1768 Accepted for publication Jul 23, 2012 Address correspondence to Roberto Parulan Santos, MD, Department of Pediatrics, Division of Infectious Diseases, Albany Medical Center, 47 New Scotland Ave (MC 88), Albany, NY 12208. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2012 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. abstract Palivizumab is a humanized monoclonal antibody used to decrease the threat of respiratory syncytial virus (RSV) infection among children at high risk. There are no standard guidelines due to conflicting data on palivizumab’s use in the treatment of RSV lower respiratory tract infections. Intravenous (IV) palivizumab was shown to be well tolerated and associated with decreased mortality in high-risk children who have RSV disease. However, it did not prevent lower respiratory tract infections and did not affect the survival rate of allogeneic stem cell transplant recipients who had RSV infection. We present 2 children with acute lymphocytic leukemia (ALL) and persistent RSV infection while receiving chemotherapy. Patient A is a 4-year-old male with Down syndrome, ALL, and persistent RSV infection for at least 3 months. Patient B is a 3-year-old female with pre–B cell ALL whose chemotherapy intensification phase was delayed due to a month-long RSV infection. RSV infections were determined by using real-time polymerase chain reaction assays from nasopharyngeal swabs before IV palivizumab therapy; patient A was positive for RSV at 36 cycles and patient B was positive for RSV at 29 cycles. RSV infection was cleared in both patients within 72 hours after receiving IV palivizumab (patient A: 16 mg/kg; patient B: 15 mg/kg). IV palivizumab may be a treatment option for persistent RSV infection among immunocompromised patients. Pediatrics 2012;130:e1695–e1699 PEDIATRICS Volume 130, Number 6, December 2012 Downloaded from pediatrics.aappublications.org by guest on September 9, 2014 e1695 Respiratory syncytial virus (RSV) is responsible for ∼120 000 pediatric hospitalizations each year and is the most common cause of lower respiratory tract infection (LRTI) in children aged ,1 year in the United States.1,2 Palivizumab, a humanized monoclonal antibody directed against the fusion protein of RSV,3 has been successfully used as prophylaxis in high-risk pediatric populations, such as those with chronic lung disease, preterm birth, congenital heart disease, and immunocompromised states.4 A study in 2007 found that combining palivizumab with the antiviral nucleoside analogue ribavirin was effective in decreasing the mortality associated with acute RSV infections in certain high-risk children.5 However, another study in bone marrow transplant patients found that palivizumab alone had no impact on outcome.6 We report RSV eradication with palivizumab in 2 pediatric patients who were undergoing treatment for acute lymphocytic leukemia (ALL) with persistent RSV infection. CASE REPORTS Patient A is a 4-year-old male with Down syndrome; he was diagnosed with ALL 14 months previously and was receiving maintenance chemotherapy. He also had a history of reactive airway disease. The patient presented to the hospital with a 1-day history of fever (101.6°F), cough, and congestion. On admission, his absolute neutrophil count (ANC) was 4600 cells/mL and absolute lymphocytic count (ALC) was 580 cells/mL (Fig 1). Chest radiographs were normal, but a nasopharyngeal swab realtime polymerase chain reaction assay tested positive for RSV infection at 23.6 cycles. The number of cycles are inversely related to the amount of RSV RNA detected, with values $50 indicating undetectable levels.7 The results of the blood cultures were negative. The patient was stable and e1696 discharged on symptomatic treatment. He was readmitted 1 week later with fever and treated with antibiotics for 48 hours. RSV was still present (27.0 cycles) after antibiotic treatment, but he was subsequently discharged on symptomatic treatment. The patient returned 2 months later with respiratory distress, fever, tachycardia (153 beats per minute), tachypnea (36 breaths per minute), and pulmonary retractions. His lungs were clear to auscultation bilaterally, and his chest radiograph was normal. White blood cell count was 2300 cells/mL with an ANC of 1470 cells/mL, an ALC of 640 cells/mL, and immunoglobulin G of 400 mg/dL (mean for age: 780 mg/ dL). RSV (36.7 cycles) and human metapneumovirus (hMPV) PCR test results were positive. He was started on antibiotic treatment. Forty-eight hours later, after no signs of any clinical improvement and blood culture results were negative, he received a 500-mg dose of intravenous immunoglobulin (IVIG). Approximately 15 hours later, the patient received 16 mg/kg of palivizumab (250 mg). He tolerated treatment well, and rapidly improved clinically and was discharged on the fourth hospital day. Three days after discharge, his PCR assay was negative for RSV (Fig 1). He did not have a recurrence of RSV in that year. Patient B is a 3-year-old female with a history of pre–B cell ALL diagnosed 7 months earlier, who presented to the hospital for her delayed intensification chemotherapy with fever (101.7°F) of unknown source. She was neutropenic with an ANC of 8 cells/mL and lymphopenic with an ALC of 180 cells/mL. Her chest radiograph showed no evidence of pneumonia. The PCR assay tested positive for RSV infection (27.3 cycles) (Fig 1). Antibiotics were started, and the patient was discharged after the results of initial bacterial cultures were negative. The patient returned 1 week later; she was febrile (102°F) and tachycardic (121 beats per minute), with nasal congestion and cough. Lungs were clear to auscultation bilaterally. She was anemic, thrombocytopenic, her ANC was 0 cell/mL, and ALC was 500 cells/mL. RSV tested positive (36.7 cycles) and 72-hour antibiotics were empirically started and chemotherapy discontinued. The patient was still febrile after 3 days, with negative results on blood and urine cultures without any major changes in her blood counts. Her PCR assay was still positive for RSV (29.4 cycles). Intravenous (IV) palivizumab at 15 mg/kg (200 mg) was administered. She clinically improved within 24 hours after administration, and her RSV PCR was negative 72 hours after treatment (Fig 1). Her white blood cell count also improved (1900 cells/mL). DISCUSSION We report the successful use of IV palivizumab for the treatment of persistent RSV infection in children with leukemia who are undergoing chemotherapy. Previous studies have used palivizumab in conjunction with ribavirin and IVIG to treat severe RSV infection.5 Both patients were severely lymphopenic at the time of palivizumab administration, and both had an undetectable viral RNA using PCR assay within 3 days after therapy. Previous studies have demonstrated the importance of adequate CD4+ and CD8+ lymphocytes as well as RSV antibodies in terminating RSV replication. Patients who are immunosuppressed, such as those who are premature (,32 weeks’ gestation), HIV infected, or undergoing immunosuppressive therapy, are at increased risk for mortality and morbidity from RSV infection due to diminished levels of T lymphocytes.3,8 Patients with high titers of maternally derived anti-RSV antibodies or who are SANTOS et al Downloaded from pediatrics.aappublications.org by guest on September 9, 2014 CASE REPORT FIGURE 1 Serial RSV PCR determinations and IV palivizumab treatment of children who have persistent RSV infection. Less than 50 cycles (green threshold line) indicate detectable RSV RNA. Persistent RSV infections (:) were noted in both patients until IV palivizumab therapy was administered. Both patients were cleared of RSV infection (n) immediately after receiving IV palivizumab (patient A [red line]: ∼16 mg/kg; patient B [blue line]: ∼15 mg/kg). ANC measured as cells/mL; ALC measured as cells/mL administered palivizumab are better protected against infection.9 The Infectious Diseases Society of America does not routinely recommend treating RSV infections with palivizumab in neutropenic patients who have upper respiratory diseases.10 However, this action may be indicated in our patients with recurrent hospitalizations due to persistent RSV infection and severe lymphopenia. It is important to note that after treatment in patient B, there was evidence of bone marrow recovery after administration of palivizumab (Fig 1). This finding supports the use of palivizumab in our patients, as the infection may have contributed to myelosupression. One study found that up to 80% of upper respiratory infections due to RSV in hematopoietic stem cell transplant recipients and patients with hematologic malignancies can progress to LRTIs.11 Future uses of palivizumab at the time of diagnosis of RSV infection in children with malignancies who are severely lymphopenic should be considered and evaluated for effects on morbidity and prolonged delays in their chemotherapy regimen. Because palivizumab has a long half-life, it could prevent recrudescence as it seemed to do in our patients. Therefore, the use of palivizumab, not only as prophylaxis but in the setting of acute and chronic RSV infection, should be considered. Furthermore, there are cost-effective considerations in decreasing repeat hospitalizations and avoiding delays in chemotherapy with treatment of acute RSV in high-risk populations.3 The main methodologic issue is the relatively small number of patients who can benefit from IV palivizumab for treatment, including patients with leukemia undergoing chemotherapy. Furthermore, patients with Down syndrome have some immunodeficiencies, and studies have found that many may have quantitative and qualitative impairments in their lymphocyte leves.12 More specifically, it has been found that these patients have decreased absolute numbers of all CD4+ and CD8+ T cells, as well as decreased proliferation and cytotoxicity of T cells in different functional assays.13 In addition to prophylaxis, treatment of RSV with palivizumab should be considered in children with Down syndrome, which is an independent risk factor for severe RSV LRTI.14 It is important to take this into consideration in future studies, as immunologic issues can influence viral clearance and recovery time. One issue raised with our patients was the possibility of a concurrent bacterial infection because symptoms seemed to stabilize after antibiotic administration. The likelihood of simultaneous secondary bacterial infection with RSV is low (1%) in the upper respiratory tract of previously healthy children. The most common bacterial coinfection of RSV bronchiolitis is acute otitis media, with an occurrence of 57% to 76% in patients with RSV infection. Neither patient exhibited any signs or symptoms of acute otitis media.15 Furthermore, RSV infections in the upper respiratory tract usually last between 7 and 10 days.16 With patient A, the time frame between the first and second admission was fairly short (∼10 days), which suggests the possibility of persistent infection rather than a new exposure or a secondary bacterial infection. More importantly, the patient’s condition improved after palivizumab therapy. Another issue is the simultaneous infection with hMPV in patient A. Although we cannot say for certain that the cause of his hospitalization was due to RSV, a few reasons may indicate more strongly that the hospitalization was due to RSV and not to hMPV. First, the patient had a history of hospitalizations due to a persistent RSV PEDIATRICS Volume 130, Number 6, December 2012 Downloaded from pediatrics.aappublications.org by guest on September 9, 2014 e1697 infection. Second, although hMPV and RSV have similar presentations, RSV is more likely than hMPV to cause bronchiolitis.17 Finally, 1 study reported that RSV and hMPV coinfection leads to an increased severity of disease than when compared with each virus alone. During patient A’s third hospital admission, he did not exhibit any significant difference in severity of symptoms compared with previous admissions for RSV alone.18 Patient B may also have had a persistent RSV infection at her second admission. The reason the patient was readmitted much earlier may be associated with the fact that she was more lymphopenic than the first patient (Fig 1). However, due to the shortened time intervals between admissions, the infection was most likely a persistent rather than a recurrent infection and may be associated most likely with RSV because palivizumab rapidly improved the patient’s symptoms when broadspectrum antibiotics did not. The RSV PCR assay is a qualitative test (Prodesse ProFlu+, Gen-Probe, Inc, San Diego, CA)7 that can be used semiquantitatively with an inverse relationship between the amount of viral RNA in the respiratory specimens and the cycles reported. It is 1 of the most sensitive (98%) commercial tests for detection of RSV infection and has a specificity .99%.19 Less than 50 cycles indicates detectable RSV RNA, and this cutoff value is specific to our laboratory. Other cutoff values may vary depending on the assay being used. Compared with other diagnostic methods such as viral culture, enzyme immunoassay, and serology, realtime polymerase chain reaction has allowed for more accurate assessments of RSV infection and correlates well with active or recent infections.7,19 In addition, the duration of RSV shedding coincided well with the duration of symptoms among patients with severe immunodeficiency.20 The issue of PCR detecting dead virus is less of a problem for RNA viruses because RNA is labile, and once a virus is killed, its outer coat will start to break down and expose the RNA to RNases in the human body. transplant. The management of RSV in these populations has been limited to ribavirin, IVIG, and palivizumab.21 IV palivizumab may be an alternative treatment option for other populations with similar vulnerability to RSV infections. Finally, future studies should determine the usefulness of palivizumab in the prevention or treatment of acute and persistent or recurrent RSV infection in certain high-risk patients. It would be of interest to evaluate other monoclonal antibodies in development such as motavizumab against palivizumab as prevention or treatment.22 CONCLUSION Palivizumab use in 2 children with leukemia demonstrated success in treating persistent RSV infection. It is important to remember that RSV infection is not limited to the pediatric population. It is also a common cause of adult viral infections in those who have undergone hematopoietic stem cell ACKNOWLEDGMENT This case study was approved under “Expedited Review” by the Committee on Research Involving Human Subjects, Albany Medical Center (November 30, 2010). 5. Chávez-Bueno S, Mejías A, Merryman RA, Ahmad N, Jafri HS, Ramilo O. Intravenous palivizumab and ribavirin combination for respiratory syncytial virus disease in highrisk pediatric patients. Pediatr Infect Dis J. 2007;26(12):1089–1093 6. de Fontbrune FS, Robin M, Porcher R, et al. Palivizumab treatment of respiratory syncytial virus infection after allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2007;45(8):1019–1024 7. Gen-Probe, Inc. Prodesse Pro Flu+. Novato, CA: Biosearch Technologies, Inc; 2010:1–29 8. Graham BS, Bunton LA, Wright PF, Karzon DT. Role of T lymphocyte subsets in the pathogenesis of primary infection and rechallenge with respiratory syncytial virus in mice. J Clin Invest. 1991;88(3):1026– 1033 9. Stensballe LG, Ravn H, Kristensen K, et al. Respiratory syncytial virus neutralizing antibodies in cord blood, respiratory syncytial virus hospitalization, and recurrent wheeze. J Allergy Clin Immunol. 2009;123 (2):398–403 10. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011;52(4):e56–e93 11. 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(5):278–287 12. Nespoli L, Burgio GR, Ugazio AG, Maccario R. Immunological features of Down’s REFERENCES 1. Leader S, Kohlhase K. Recent trends in severe respiratory syncytial virus (RSV) among US infants, 1997 to 2000. J Pediatr. 2003;143(suppl 5):S127–S132 2. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitisassociated hospitalizations among US children, 1980-1996. JAMA. 1999;282(15): 1440–1446 3. Wright M, Piedimonte G. Respiratory syncytial virus prevention and therapy: past, present, and future. Pediatr Pulmonol. 2011;46(4):324–347 4. Weisman LE. Populations at risk for developing respiratory syncytial virus and risk factors for respiratory syncytial virus severity: infants with predisposing conditions. Pediatr Infect Dis J. 2003;22(suppl 2):S33–S37; discussion S37–S39 e1698 SANTOS et al Downloaded from pediatrics.aappublications.org by guest on September 9, 2014 CASE REPORT syndrome: a review. J Intellect Disabil Res. 1993;37(pt 6):543–551 13. Bloemers BL, Broers CJ, Bont L, Weijerman ME, Gemke RJ, van Furth AM. Increased risk of respiratory tract infections in children with Down syndrome: the consequence of an altered immune system. Microbes Infect. 2010;12(11):799–808 14. Bloemers BL, van Furth AM, Weijerman ME, et al. Down syndrome: a novel risk factor for respiratory syncytial virus bronchiolitis —a prospective birth-cohort study. Pediatrics. 2007;120(4). Available at: www.pediatrics.org/cgi/content/full/120/4/e1076 15. Andrade MA, Hoberman A, Glustein J, Paradise JL, Wald ER. Acute otitis media in children with bronchiolitis. Pediatrics. 1998;101(4 pt 1): 617–619 16. Krilov LR. Respiratory syncytial virus (RSV) infection. In: Medscape Reference; 2010. Available at: http://emedicine.medscape.com/ article/971488-overview. Accessed June 7, 2011 17. Paget SP, Andresen DN, Kesson AM, Egan JR. Comparison of human metapneumovirus and respiratory syncytial virus in children admitted to a paediatric intensive care unit. J Paediatr Child Health. 2011;47(10): 737–741 18. Greensill J, McNamara PS, Dove W, Flanagan B, Smyth RL, Hart CA. Human metapneumovirus in severe respiratory syncytial virus bronchiolitis. Emerg Infect Dis. 2003;9(3):372–375 19. Liao RS, Tomalty LL, Majury A, Zoutman DE. Comparison of viral isolation and multiplex real-time reverse transcription-PCR for confirmation of respiratory syncytial virus and influenza virus detection by antigen immunoassays. J Clin Microbiol. 2009;47(3): 527–532 20. Khanna N, Widmer AF, Decker M, et al. Respiratory syncytial virus infection in patients with hematological diseases: single-center study and review of the literature. Clin Infect Dis. 2008;46(3):402– 412 21. Shah JN, Chemaly RF. Management of RSV infections in adult recipients of hematopoietic stem cell transplantation. Blood. 2011;117(10):2755–2763 22. Lagos R, DeVincenzo JP, Muñoz A, et al. Safety and antiviral activity of motavizumab, a respiratory syncytial virus (RSV)specific humanized monoclonal antibody, when administered to RSV-infected children. Pediatr Infect Dis J. 2009;28(9):835– 837 PEDIATRICS Volume 130, Number 6, December 2012 Downloaded from pediatrics.aappublications.org by guest on September 9, 2014 e1699 The Use of Intravenous Palivizumab for Treatment of Persistent RSV Infection in Children With Leukemia Roberto P. Santos, Jeffery Chao, Anne G. Nepo, Shafiq Butt, Kathleen A. Stellrecht, Jennifer M. Pearce and Martha L. Lepow Pediatrics 2012;130;e1695; originally published online November 12, 2012; DOI: 10.1542/peds.2011-1768 Updated Information & Services including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/130/6/e1695.full. html References This article cites 18 articles, 6 of which can be accessed free at: http://pediatrics.aappublications.org/content/130/6/e1695.full. html#ref-list-1 Citations This article has been cited by 2 HighWire-hosted articles: http://pediatrics.aappublications.org/content/130/6/e1695.full. html#related-urls Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Infectious Diseases http://pediatrics.aappublications.org/cgi/collection/infectious _diseases_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xh tml Reprints Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2012 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Downloaded from pediatrics.aappublications.org by guest on September 9, 2014