Respiratory syncytial virus immune globulin treatment of lower respiratory tract infection in pediatric patients undergoing bone marrow transplantation – a compassionate use experience

105

Although most children are infected with RSV by 2 years of age and produce neutralizing antibodies, life-long immunity is not induced. [1][2][3][4][5] Re-infection in immunocompetent adults exposed to an RSV-positive child, manifesting primarily as an upper respiratory tract illness, can be as high as 47%. 6 Whereas mortality rates in previously healthy infants with RSV pneumonia and/or bronchiolitis are less than 0.5%, approximately 3 to 5% of

Section: Discussionsupporting

confidence: 79%

Respiratory syncytial virus infection following hematopoietic stem cell transplantation

Small

Casson

Malak

et al. 2002

105

“…Recent attempts to treat stem cell transplant patients with severe RSV pneumonia have relied on regimens which combine large doses of RSVIG and aerosolized ribavirin. 8,9 Replacement of RSVIG with palivizumab could allow the delivery of large amounts of anti-RSV antibody activity, possibly through multiple repeat doses, without the significant fluid/protein challenge posed by large amounts of RSVIG. These studies suggest a role for palivizumab immunoprophylaxis and therapy in stem cell transplant patients.…”

Section: Discussionmentioning

confidence: 99%

Palivizumab is highly effective in suppressing respiratory syncytial virus in an immunosuppressed animal model

Ottolini

Curtis²,

Mathews³

et al. 2002

Summary:Respiratory syncytial virus (RSV) is widely recognized as a leading cause of pneumonia, with substantial mortality, in bone marrow transplant recipients. We tested the efficacy of a systemic monoclonal antibody (MAB) preparation possessing a high titer of anti-RSV neutralizing antibody, palivizumab (Synagis) for prophylaxis and therapy of RSV infection in cytoxan (CY) immunosuppressed cotton rats, a model in which the efficacy of a polyclonal anti-RSV product (Respigam) has been demonstrated. Both prophylaxis and therapy with this MAB were highly effective in reducing pulmonary viral replication. However, multiple sequential therapeutic doses of MAB were necessary to control rebound viral replication in continually suppressed animals. Bone Marrow Transplantation (2002) 29, 117-120. DOI: 10.1038/sj/bmt/1703326 Keywords: RSV; BMT; immunotherapy; palivizumab; Synagis; cotton rat Respiratory syncytial virus (RSV) is widely recognized as one of the major causes of pneumonia in immunocompromised cancer patients. 1 The most striking impact of this pathogen to be identified over the last decade has been its propensity to lead to severe pneumonia during the early period post stem cell transplantation, with a high morbidity and mortality. 1-3 A recent case review reported three deaths among seven patients who developed RSV infections in the post-engraftment period, suggesting a continued significant impact of this pathogen. 4 Those authors also reported an association between RSV infection and both primary and secondary graft failure in four patients. The opinions or assertions contained herein are those of the author(s) and are not to be construed as official or reflecting the views of the Department of Defense, the United States Air Force, or the Uniformed Services University.The cotton rat model has been a useful tool in the study of RSV pathogenesis and therapy for over 30 years. 5 We recently reported a modification of the use of that model where, by prolonged high-dose cytoxan immunosuppression, we replicated the persistent RSV pneumonia seen in stem cell transplant recipients. 6 In that paper, we demonstrated the ability of a human commercial polyclonal high anti-RSV activity IgG preparation (RSVIG or Respigam) to control RSV replication when given either prophylactically or therapeutically. We return to that model to test the use of the next generation of the product, the humanized anti-RSV monoclonal antibody (MAB) palivizumab (Synagis). Materials and methods AnimalsWeanling inbred cotton rats (Sigmodon hispidus) were obtained from Virion Systems Incorporated. Animals were housed in large polycarbonate cages in small groups, and were provided water and rat chow ad libitum. ImmunosuppressionAnimals were treated with intraperitoneal (i.p.) injections of cyclophosphamide (CY) at a dose of 50 mg/kg three times weekly for at least 21 days prior to viral challenge. Immunosuppressive therapy was continued until the end of each experiment. Prior and current use of this regimen has consistently led to the develo...

“…16 The same author recently presented a series of pediatric BMT recipients who received combination ribavirin and RSVIG therapy for RSV pneumonia, which resulted in survival in 10 of 11 patients, a marked improvement compared with historical survival rates in similar patients. 17 In the cotton rat model, using cytotoxic immunosuppression comparable to that used in BMT regimens, we were able to establish a prolonged high-titer pulmonary RSV infection, which may in some ways parallel the disease seen in BMT recipients. Both prophylactic and therapeutic RSVIG, even in modest doses, were effective in reducing or eliminating viral replication in suppressed animals.…”

Section: Discussionmentioning

confidence: 84%

Effectiveness of RSVIG prophylaxis and therapy of respiratory syncytial virus in an immunosuppressed animal model

Hemming

et al. 1999

Summary:Respiratory syncytial virus (RSV) has emerged as a leading cause of pneumonia, with high mortality, in bone marrow transplant (BMT) recipients, as well as in other profoundly immunocompromised patients, such as myelosuppressed adults with leukemia. We tested the efficacy of immunoglobulin with high anti-RSV neutralizing antibody levels (RSVIG) for prophylaxis and therapy of RSV infection in cotton rats undergoing prolonged immunosuppression with cyclophosphamide. These animals experience persistent infection, a model which is similar to the disease seen in post-BMT humans. Both prophylaxis and therapy reduced pulmonary viral replication over 500-fold to nearly undetectable levels. In animals receiving continual immunosuppression, the use of multiple therapeutic doses of RSVIG was able to prevent rebound viral replication, though virus was not completely eliminated. Keywords: RSV; BMT; immunotherapy; RSVIG; cyclophosphamide; cotton rat Advances in bone marrow transplantation (BMT) have led to a large increase in the number of procedures done, partially due to increasingly aggressive attempts to cure patients of several types of malignancy as well as a variety of other systemic diseases. However, gains due to improvements in BMT are still offset by high rates of morbidity and mortality due to infectious diseases in the immediate post-transplant period. A variety of methods have been effective in reducing rates of some early opportunistic infections, such as cytomegalovirus and Pneumocystis carinii. 1 In contrast, respiratory syncytial virus (RSV), a ubiquitous respiratory virus considered by many to be a significant pathogen only during infancy, has emerged as a major cause of morbidity and mortality in BMT recipients of all ages. 2 Attempts to treat this infection with the antiviral agent ribavirin have been largely unsuccessful, and BMT patients who develop RSV pneumonia have extremely high rates of mortality. [3][4][5][6] IVIG with high anti-RSV activity (RSVIG) is effective Materials and methods AnimalsWeanling inbred cotton rats (Sigmodon hispidus) were obtained from Virion Systems Inc. Animals were housed in large polycarbonate cages in small groups, and were provided water and rat chow ad libitum. ImmunosuppressionAnimals were treated with intraperitoneal (i.p.) injections of cyclophosphamide (CY) at a dose of 50 mg/kg three times weekly for at least 21 days prior to viral challenge. Immunosuppressive therapy was continued until the end of each experiment. To monitor the level of immunosuppression during these experiments, selected suppressed and control animals were bled for complete blood count (CBC) and white blood cell differential counts at the time of viral challenge. Nasal and pulmonary virus titers were determined at several intervals post viral challenge. VirusThe long strain of RSV (Group A), obtained from the American Type Culture Collection, was used as the challenge virus. A single pool propagated in HEp-2 cells containing 1 × 10 6 plaque forming units (p.f.u.) per ml was used for all ...