Respiratory syncytial virus upper respiratory tract illnesses in ... - Nature

Bone Marrow Transplantation (2000) 25, 751–755  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt

Respiratory syncytial virus upper respiratory tract illnesses in adult blood and marrow transplant recipients: combination therapy with aerosolized ribavirin and intravenous immunoglobulin S Ghosh1, RE Champlin2, J Englund3, SA Giralt2, K Rolston1, I Raad1, K Jacobson1, J Neumann2, C Ippoliti2, S Mallik1 and E Whimbey1 1

Department of Medical Specialties and 2Department of Blood and Marrow Transplantation, The University of Texas MD Anderson Cancer Center, and 3Department of Microbiology and Immunology, The Baylor College of Medicine, Houston, TX, USA

Summary: Respiratory syncytial virus (RSV) is an important cause of serious respiratory illness in blood and marrow transplant (BMT) recipients. In some subsets of these immunocompromised patients, RSV upper respiratory illnesses frequently progress to fatal viral pneumonia. The frequency of progression to pneumonia is higher during the pre-engraftment than during the postengraftment period. Once pneumonia develops, the overall mortality is 60–80%, regardless of the treatment strategy. We performed a pilot trial of therapy of RSV upper respiratory illnesses using aerosolized ribavirin and IVIG (500 mg/kg every other day), with the goal of preventing progression to pneumonia and death. Two dosages of ribavirin were used: a conventional regimen (6 g/day at 20 mg/ml for 18 h/day) and a high-dose short-duration regimen (6 g/day at 60 mg/ml for 2 h every 8 h). Fourteen patients were treated for a mean of 13 days (range: 7–23 days). In 10 (71%) patients, the upper respiratory illness resolved. The other four (29%) patients, three of whom were in the pre-engraftment period, developed pneumonia, which was fatal in two. The most common adverse effect was psychological distress at being isolated within a scavenging tent. In conclusion, prompt therapy of RSV upper respiratory illnesses in BMT recipients with a combination of aerosolized ribavirin and IVIG was a safe and promising approach to prevent progression to pneumonia and death. Bone Marrow Transplantation (2000) 25, 751–755. Keywords: respiratory; syncytial; virus; therapy; ribavirin; transplant

Respiratory syncytial virus (RSV) is a frequent cause of acute respiratory illness in autologous as well as allogeneic blood and marrow transplant (BMT) recipients.1–11 These infections usually occur during community outbreaks, which typically occur in a seasonal fall–winter pattern. In Correspondence: Dr E Whimbey, The University of Texas MD Anderson Cancer Centre, 1515 Holcombe Blvd, Box 47, Houston, Texas 77030, USA Received 16 December 1998; accepted 18 August 1999

these immunocompromised patients, RSV infections usually present as an upper respiratory illness (URI) which frequently progresses to fatal viral pneumonia. The frequency of progression of URI to pneumonia is higher among patients who are ⭐1 month post transplant or pre-engraftment than patients who are ⬎1 month post transplant or post engraftment (70–80% vs 25–40%, respectively).5,6 Once pneumonia develops, the mortality of untreated RSV pneumonia is over 80%, regardless of the engraftment status. Even with aggressive strategies aimed at promptly treating pneumonias with the currently available drugs, the overall mortality with RSV pneumonia is approximately 60%.5,6 A favorable outcome may necessitate the initiation of therapy at an earlier stage of the respiratory illness. Aerosolized ribavirin is approved by the Food and Drug Administration (FDA) for the therapy of RSV pneumonia in high risk infants and young children.12 The standard regimen consists of a daily dose of 6 g of ribavirin delivered at a concentration of 20 mg/ml of sterile water for 18 h/day, usually within a scavenging tent to prevent environmental contamination with the drug. Such prolonged aerosol therapy is cumbersome to administer, and difficult for patients to tolerate psychologically. For ease of administration and improved compliance, shorter durations of therapy with higher concentrations of the drug have been investigated.13,14 In unintubated children, high-dose short-duration aerosolized ribavirin (6 g/day delivered at a concentration of 60 mg/ml for 2 h every 8 h) has been demonstrated to be safe and to have similar antiviral effects as the standard regimens.14 This regimen has also been found to be safe in elderly persons with chronic obstructive lung disease.13 We conducted a pilot trial of combination therapy with aerosolized ribavirin and intravenous immunoglobulin (IVIG) for RSV upper respiratory tract illnesses in adult BMT recipients with the goal of preventing progression to pneumonia and death. Ribavirin was combined with IVIG because studies in vitro, in animal models, and in children had suggested that immunoglobulin may be of benefit for RSV infections prophylactically as well as therapeutically.15–33 In addition, the University of Texas MD Anderson Cancer Center (MDACC) experience with combination aerosolized ribavirin and IVIG for the therapy of RSV pneumonia in adult BMT recipients and adults with leukemia had been favorable.6,8

RSV upper respiratory tract illnesses in BMT recipients S Ghosh et al

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Methods A prospective surveillance study for community respiratory viruses was conducted among adult BMT recipients hospitalized at MDACC, beginning in 1992.7 Patients with an acute respiratory illness had samples of respiratory secretions obtained for viral culture and rapid RSV antigen assay by means of ELISA and/or indirect immunofluorescence. In most cases, specimens consisted of combined nasopharyngeal washes and throat swabs (NPW/T). When available, endotracheal aspirates from intubated patients and bronchoalveolar lavage (BAL) fluids were also sampled. A minimum of 3 ml of fluid was inoculated into 1–3 ml of viral transport media. Specimens were transported on ice and inoculated within 4 h of collection on to tissue cultures (Madin-Darby canine kidney cells, rhesus monkey kidney continuous cell line (LLC-MK2), human laryngeal tumor cells (Hep-2) and human embryonic lung fibroblasts (WI38)). RSV was identified by characteristic cytopathic effect in cell cultures and confirmed by staining with a fluorescein-conjugated polyclonal Ab. Only cases confirmed by culture or histopathology are included in this analysis. The trial extended from the winter of 1992–1993 to the winter of 1996–1997. Therapy consisted of a daily dose of 6 g of ribavirin aerosolized via a small particle aerosol generator (SPAG-2) and administered via a face mask, and IVIG at 500 mg/kg every other day for the duration of therapy. In the initial five patients, ribavirin was administered at a concentration of 20 mg/ml for 18 h a day. In the subsequent nine patients, ribavirin was administered at 60 mg/ml for 2 h every 8 h. If the patient developed pneumonia, the high-dose short-duration regimen of ribavirin was changed to the standard regimen. The length of therapy was individualized according to the underlying immunologic status of the patient, clinical response and the duration of viral shedding. To avoid drug-related bronchospasm, inhalational bronchodilator therapy was administered every 4 h. An acute URI was defined as the recent onset of rhinorrhea, nasal or sinus congestion, otitis media, pharyngitis, and /or cough with a clear chest radiograph. Pneumonia was defined as an acute respiratory illness occurring in association with signs and/or symptoms of lower respiratory tract disease and a new radiographic infiltrate. Neutropenia was defined as ⭐500 neutrophils/ml of blood. Engraftment was defined as the resolution of neutropenia after transplantation. An infection was considered to be nosocomial if symptoms developed ⭓7 days after hospital admission.

Results During five winter seasons, from 1992–1993 to 1996–1997, 14 adult BMT recipients with RSV upper respiratory illnesses were treated with a combination of aerosolized ribavirin and IVIG for a mean of 13 days (range 7–23 days). The infections occurred in a fall–winter seasonal pattern. There were three, five, four, none and two cases, respectively, during each winter. The clinical characteristics of Bone Marrow Transplantation

these patients are summarized in Table 1. Seven patients were pre-engraftment at the onset of respiratory symptoms. The most common signs and symptoms were cough (100%), sputum (86%), rhinorrhea (86%), sinus congestion (79%) and rales or rhonchi (79%). Fifty percent of the patients had fever. Sinusitis was documented in three of four patients who underwent radiographic evaluation. The method of diagnosing RSV infection was by culture and rapid RSV Ag (n = 10); culture alone (n = 3), and rapid RSV Ag and histopathology (n = 1). In 10 (71%) patients, the URI resolved after a mean of 22 days (range 11–54 days) (Table 2). These 10 patients were treated for a mean of 11 days (range 7–18 days) beginning at a mean of 8 days (range 2–39 days) after the onset of symptoms. The mean duration of viral shedding was 10 days (range 1–19 days). RSV was identified in the following specimens: NPW/T (nine patients) and NPW/T and BAL (one patient who had tracheobronchitis without radiographic infiltrates (Table 1). The other four (29%) patients developed pneumonia associated with bilateral interstitial infiltrates on chest radiograph, two of which were fatal. These four patients had hematological malignancies and were ⭐15 days post transplant when symptoms began. Three patients had not yet engrafted. These four patients were treated for a mean of 18 days (range 14–23 days) beginning at a mean of 6 days (range 3–7 days) after the onset of symptoms. The

Table 1 Characteristics and outcome of 14 adult blood and marrow transplant recipients with RSV upper respiratory tract illnesses treated with combination aerosolized ribavirin and intravenous immunoglobulin Patients n = 14

Pneumonia 4

Deaths 2

Underlying disease Leukemia Lymphoma Breast cancer

7 6 1

2 2 0

1 1 0

Type of transplant Allogeneic HLA-matched related HLA-matched unrelated Autologous BMT PBSC

8 6 2 6 7 7

1 1 0 3 2 2

0 0 0 2 2 0

Day of onset of symptoms post transplant ⭐0a ⬎10 to ⭐+30 ⬎30–⭐100 days ⬎100 days

5 4 3 2

2 2 0 0

0 2 0 0

Pre-engraftment Post engraftment

7 7

3 1

1 1

Nosocomial infection

4

2

2

Type of specimen NPW/T NPW/T + BAL BAL + lung tissue

10 3 1

1 2 1

0 1 1

a These patients had URI symptoms when the conditioning therapy was administered or developed symptoms within 48 h of administering the therapy.


Table 2 Outcome related to engraftment status of 14 adult blood and marrow transplant recipients with RSV upper respiratory tract illnesses treated with combination aerosolized ribavirin and intravenous immunoglobulin Engraftment status Pre-engraftment 6 h/day 18 h/day n=4 n=3

Post engraftment 6 h/day 18 h/day n=5 n=2

URI⇒Resolved URI⇒Pneumonia

1 3

3 0

5 0

1 1

Pneumonia⇒ Deaths

1a

0

0

1b

A total of 6 g of aerosolized ribavirin was administered each day. The aerosol was administered at 60 mg/ml for 2 h every 8 h (6 h/day) to nine patients and at 20 mg/ml for 18 h/day to five patients. a The patient had graft failure after receiving an autologous BMT for CLL. b This patient developed RSV tracheobronchitis 15 days after receiving an autologous BMT for lymphoma. The illness resolved clinically and virologically with therapy. One month later, the patient presented with rapidly progressive RSV pneumonia (? relapse vs reinfection).

mean duration of illnesses was 28 days (range 23–34 days). The mean duration of viral shedding was 16 days (range 1–30 days). RSV was identified in the following specimens: NPW/T (one patient); NPW/T and BAL (two patients who had developed pneumonia when the BAL specimen was obtained); and BAL and post-mortem lung tissue (one patient who had tracheobronchitis without radiographic infiltrates when the BAL specimen was obtained). The two patients with pneumonia who survived had other potentially important pathogens isolated: one patient had Torulopsis glabrata and Pseudomonas aeruginosa isolated from sputum and Enterococcus spp. isolated from blood; the other patient had herpes simplex virus isolated from a nasopharyngeal wash/ throat swab. The two patients with pneumonia who died did not have any other pathogens identified pre- or post-mortem. One of these patients had prolonged pancytopenia related to graft failure. URI symptoms developed 14 days after receiving an autologous BMT for CLL, and pneumonia developed 18 days after the onset of URI symptoms and 11 days after the initiation of antiviral therapy. Death occurred 23 days after the onset of URI symptoms. Autopsy was not performed. The second patient developed URI symptoms 15 days after receiving an autologous BMT for lymphoma, post engraftment. Therapy was continued for 14 days with full resolution of symptoms and multiple negative follow-up cultures. One month later, the patient died of rapidly progressive RSV pneumonia documented at autopsy. It was unclear whether this pneumonia constituted a relapse of the previous RSV infection or a reinfection. All patients tolerated the full course of therapy. The following adverse effects were noted. All 14 patients complained of ‘hail’ and/or ‘snowflakes’ and/or ‘thick smog’ blowing into their faces. In all cases, this was minimized to a tolerable level with the assistance of the respiratory therapists. All patients complained of loneliness and anxiety due to confinement within the scavenging tent. Five of these patients required psychiatric consultation (two of the

nine patients receiving the 6 h/day regimen and three of the five patients receiving the 18 h/day regimen). Two patients (one in each group) complained of increased cough during the treatment, one of whom also had increased wheezing. One patient with extensive lymphomatous involvement of the head and neck region required an elective tracheotomy after 9 days of administering the highdose aerosol via a face mask in order to administer the aerosol more comfortably. No hematological or hepatic dysfunction was attributed to the drug.

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Discussion In these high risk immunocompromised patients, prompt therapy of RSV upper respiratory illnesses with a combination of aerosolized ribavirin and IVIG was relatively well tolerated and appeared to impact favorably on the frequency of progression to pneumonia and death. Only four (29%) patients developed pneumonia and only two (14%) patients died. The frequency of progression to pneumonia was higher in pre-engrafted than post-engrafted patients although both were less than generally reported. Among the seven pre-engrafted patients, three (43%) patients developed pneumonia and one (14%) died. Among the seven post-engrafted patients, only one (14%) patient developed pneumonia, and one (14%) died. The high-dose short-duration regimen was better tolerated because it enabled the patient to spend less time physically and psychologically isolated inside scavenging tents. It also enabled less cumbersome care by the hospital staff and more frequent visitation by family members and friends. Although all patients initially had a sensation of precipitated drug blowing into their faces, it was possible to reduce this to a tolerable level in all cases. Bronchospasm was seldom a problem with the aggressive bronchodilator therapy used in these patients. In a similar open trial conducted at the Fred Hutchinson Cancer Research Center, 25 BMT recipients with RSV upper respiratory illnesses were treated with a lower daily dose of aerosolized ribavirin and a shorter duration of therapy (2 g of ribavirin were administered at a concentration of 60 mg/ml for 2 h each day).9 The advantage of this regimen was that it could be administered in an outpatient setting. Eight (32%) patients developed pneumonia, seven (88%) of whom died. Subgrouping into pre- and post engraftment was not reported. Compared with the larger doses and longer durations of therapy at MDACC, the overall results appear similar in terms of the frequency of progression to pneumonia (32% vs 29%, respectively). Although the overall mortality was twice as high in the FHCRC study (28% vs 14%, respectively), the number of cases was too small to draw any conclusions. Other studies involving small numbers of patients have also reported on the favorable outcome of BMT recipients with RSV infections treated promptly with aerosolized ribavirin at the URI stage or at the stage of clinical but not radiographically evident acute lung injury.3,34 Studies to date are limited by the lack of randomized controls, and are not directly comparable because of differences in the underlying immunodeficiencies, differences in Bone Marrow Transplantation


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the treatment regimens, and differences in whether the therapy was administered in the inpatient or outpatient setting. Overall, the data suggest that the frequency of progression to pneumonia and the mortality can be diminished by promptly treating URIs with ribavirin. Whether larger doses, longer durations or higher concentrations of ribavirin therapy are of added benefit will need to be evaluated in larger, controlled trials, as will the benefit of combining ribavirin with immune therapy. Since the morbidity and mortality associated with RSV upper respiratory illnesses was still considerable in spite of prompt therapy of URIs, the need to investigate prophylactic strategies in BMT recipients is apparent. The role of high RSV titered IVIG or RSV monoclonal Ab in the prophylaxis or therapy of RSV infections in immunocompromised patients remains to be defined.6,27–33 The commercially available forms of these drugs are RespiGam (MedImmune, Gaithersburg, MD, USA), a pooled human polyclonal IgG intravenous hyperimmune globulin with high RSV microneutralization titers and Synagis (MedImmune), an intramuscularly administered humanized monoclonal Ab directed against the F glycoprotein of RSV. These drugs have been approved by the FDA for prophylaxis against serious complications of RSV infection in high risk infants and young children in January 1996 and June 1998. These drugs are prohibitively expensive to administer to adult-sized patients. Efficacy will need to be demonstrated in controlled trials before routine use of these drugs can be considered in adults. In conclusion, uncontrolled trials reported to date support the concept of treating high risk immunocompromised patients infected with RSV at an early stage of the respiratory illness. The cost and cumbersomeness associated with the currently available therapies render this a difficult undertaking, particularly as this infection is so common and so frequently self-limited. Controlled clinical trials are needed to confirm the efficacy of aerosolized ribavirin with or without standard IVIG, high RSV titered IVIG or monoclonal RSV antibody as well as to define risk factors for progressive disease so that therapy can be targeted appropriately. The cumulative experience from several transplant centers suggests that the patients at highest risk for severe RSV disease are those who are early post transplant or not yet engrafted. These patients have a 70–80% risk of disease progression, and need to be proactively identified and treated. The subsets of patients who are later post transplant or post-engraftment who require treatment are less welldefined. Although the frequency of progression of URI to pneumonia in these patients has been reported to be approximately 25–40%, these figures are likely to represent a considerable overestimate since many BMT recipients (particularly autologous BMT recipients) are followed less closely in the late post-transplant period. The tendency has been for more immunosuppressed patients and more serious respiratory illnesses to come to medical attention. Because host immunity plays a dominating role in the recovery from RSV infections, the benefit of any intervention in the postengraftment period will be especially difficult to evaluate outside of a controlled trial. Given the available data, it is the current practice at MDACC to individualize care for

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post-engrafted BMT recipients with RSV upper respiratory illnesses based on a constellation of risk factors for progressive disease including an estimate of the patient’s net level of immunosuppression (considering factors such as underlying disease, type of transplant, time after transplant, presence of GVHD, immunosuppressive therapies, leukocyte count); the age of the patient; the stage of the URI (searching for clinical evidence of radiographically not visible lower respiratory tract disease); the clinical course of the respiratory illness over the preceding few days; and the presence of underlying lung disease. Using this approach, the ratio of untreated to treated post-engrafted BMT recipients with documented RSV upper respiratory illnesses in our center has been approximately 3:1. All of our postengrafted BMT recipients with documented RSV upper respiratory illnesses who have not received specific antiviral therapy because they were judged to be at low risk for progression to viral pneumonia have survived. References 1 Englund JA, Sullivan CJ, Jordan C et al. Respiratory syncytial virus infections in immunocompromised adults. Ann Intern Med 1988; 109: 203–208. 2 Martin MA, Bock MJ, Pfaller MA, Wenzel RP. Respiratory syncytial virus infections in adult bone marrow transplant recipients. Lancet 1988; 1: 1396–1397. 3 Hertz MI, Englund JA, Snover D et al. Respiratory syncytial virus-induced acute lung injury in adult patients with bone marrow transplants: a clinical approach and review of the literature. Medicine 1989; 68: 269–281. 4 Fouillard L, Mouthon L, Laporte JP et al. Severe respiratory syncytial virus pneumonia after autologous bone marrow transplantation: a report of three cases and review. Bone Marrow Transplant 1992; 9: 97–100. 5 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: 987–993. 6 Whimbey E, Champlin RE, Englund JA et al. Combination therapy with aerosolized ribavirin and intravenous immunoglobulin for respiratory syncytial virus disease in adult bone marrow transplant recipients. Bone Marrow Transplant 1995; 16: 393–399. 7 Whimbey E, Champlin RE, Couch RB et al. Community respiratory virus infections among hospitalized adult bone marrow transplant recipients. Clin Infect Dis 1996; 22: 778–782. 8 Whimbey E, Englund JA, Couch RB. Community respiratory virus infections in immunocompromised patients with cancer. Am J Med 1997; 102: 10–18. 9 Bowden RA. Respiratory Virus Infections after Marrow Transplant: The Fred Hutchinson Cancer Research Center Experience. Am J Med 1997; 102: 27–30. 10 Ljungman P. Respiratory virus infections in bone marrow transplant recipients: the European perspective. Am J Med 1997; 102: 44–47. 11 Sparrelid E, Ljungman P, Ekelof-Andstrom E et al. Ribavirin therapy in bone marrow transplant recipients with viral respiratory tract infections. Bone Marrow Transplant 1997; 19: 905–908. 12 Hall CB, McBride JT, Walsh EE et al. Aerosolized ribavirin treatment of infants with respiratory syncytial virus infection. New Engl J Med 1983; 308: 1443–1447. 13 Liss HP, Bernstein J. Ribavirin aerosol in the elderly. Chest 1988; 93: 1239–1241.


14 Englund JA, Piedra PA, Ahn Y et al. High-dose, short-duration ribavirin aerosol therapy compared with standard ribavirin therapy in children with suspected respiratory syncytial virus infection. J Pediatr 1994; 125: 635–641. 15 Ogilvie MM, Vathenen AS, Radford M et al. Maternal antibody and respiratory syncytial virus infection in infancy. J Med Virol 1981; 7: 263–271. 16 Prince GA, Hemming VG, Horswood RL, Chanock RM. Immunoprophylaxis and immunotherapy of respiratory syncytial virus infection in the cotton rat. Virus Res 1985; 3: 193–206. 17 Hemming VG, Prince GA, Horswood RL et al. Studies of passive immunotherapy for infections of respiratory syncytial virus in the respiratory tract of a primate model. J Infect Dis 1985; 152: 1083–1087. 18 Hemming VG, Rodriguez W, Kim HW et al. Intravenous immunoglobulin treatment of respiratory syncytial virus infections in infants and young children. Antimicrobial Agents Chemother 1987; 31: 1882–1886. 19 Hemming VG, Prince GA, Rodriguez W et al. Respiratory syncytial virus infections and intravenous gamma-globulins. Pediatr Infect Dis J 1988; 7: S103–S106. 20 Hemming VG, Prince GA. Passive immunization for the protection of infants and young children from respiratory infection by respiratory syncytial virus. In: Imbach P (ed). Immunotherapy with Intravenous Immunoglobulins. Academic Press: New York, 1991, pp 103–112. 21 Groothuis JR, Levin MJ, Rodriguez W et al. Use of intravenous gamma globulin to passively immunize high-risk children against respiratory syncytial virus: safety and pharmacokinetics. Antimicrob Agents Chemother 1991; 35: 1469–1473. 22 Siber GR, Leszcynski J, Pena-Cruz V et al. Protective activity of a human respiratory syncytial virus immune globulin prepared from donors screened by microneutralization assay. J Infect Dis 1992: 165: 456–463. 23 Siber GR, Snydman DR. Use of immune globulins in the prevention and treatment of infections. In: Remington JS, Swartz MN (eds). Current Clinical Topics in Infectious Diseases. Blackwell Scientific Publications: Boston, 1992, pp 208–256. 24 Siber GR, Leombruno D, Leszcynski J et al. Comparison of antibody concentrations and protective activity of respiratory syncytial virus immune globulin and conventional immune globulin. J Infect Dis 1993; 169: 1368–1373.

25 Graham BS, Davis TH, Tang YW, Gruber WC. Immunoprophylaxis and immunotherapy of respiratory syncytial virus infected mice with respiratory syncytial virus specific immune serum. Pediatr Res 1993; 34: 167–172. 26 Meissner HC. Fulton DR, Groothuis JR et al. Controlled trial to evaluate protection of high-risk infants against respiratory syncytial virus disease by using standard intravenous immune globulin. Antimicrob Agents Chemother 1993; 37: 1655–1658. 27 Groothuis JR, Simoes EAF, Levin MJ et al. Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children. New Engl J Med 1993; 329: 1524–1530. 28 Groothuis JR, Simoes EAF, Hemming VG et al. Respiratory syncytial virus (RSV) infection in preterm infants and the protective effects of RSV immune globulin (RSVIG). Pediatrics 1995; 95: 463–467. 29 De Vincenzo JP, Leombruno D, Soiffer RJ, Siber GR. Immunotherapy of respiratory syncytial virus pneumonia following bone marrow transplantation. Bone Marrow Transplant 1996; 17: 1051–1056. 30 Rodriquez WJ, Gruber WC, Welliver RC et al. Respiratory syncytial virus (RSV) immune globulin intravenous therapy for RSV lower respiratory tract infection in infants and young children at high risk for severe RSV infections. Pediatrics 1997; 99: 454–461. 31 The Prevent Study Group. Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. Pediatrics 1997; 99: 93–99. 32 American Academy of Pediatrics. Prevention of respiratory syncytial virus infections: indications for the use of Palivizumab and update on the use of RSV-IGIV. Pediatrics 1998; 102: 1211–1216. 33 The Impact-RSV study group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in highrisk infants. Pediatrics 1998; 102: 531–537. 34 McColl MD, Corser RB, Bremner J, Chopra R. Respiratory syncytial virus infection in adult BMT recipients: effective therapy with short duration nebulised ribavirin. Bone Marrow Transplant 1998; 21: 423–425.

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