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1.  Safety and Effectiveness of Palivizumab in Children at High Risk of Serious Disease Due to Respiratory Syncytial Virus Infection: A Systematic Review 
Infectious Diseases and Therapy  2014;3(2):133-158.
Lower respiratory tract infection (LRTI) is the leading cause of infant mortality globally in post-neonatal infants (i.e., 28–364 days of age). Respiratory syncytial virus (RSV) is the most commonly identified pathogen for infant LRTI and is the second most important cause of death in post-neonatal infants. Despite 50 years of RSV vaccine research, there is still no approved vaccine. Therefore, passive immunity with the monoclonal antibody palivizumab is the sole regulatory-approved option for the prevention of serious LRTI caused by RSV in pediatric patients at high risk of RSV disease.
We conducted a comprehensive systematic literature review of randomized controlled trials (RCTs), open-label non-comparative clinical trials, and prospective observational studies/registries, and summarized the evidence related to the safety, efficacy, and effectiveness of palivizumab.
The efficacy of palivizumab, as measured by the relative reduction in RSV-related hospitalization rate compared with placebo ranged from 39% to 78% (P < 0.05) in the 2 pivotal RCTs. A meta-analysis of the RSV-related hospitalization rate from 5 randomized placebo-controlled trials yielded an overall odds ratio of 0.41 (95% CI, 0.31–0.55) in favor of palivizumab prophylaxis over placebo (P < 0.00001). Low rates of RSV-related hospitalizations were observed in palivizumab recipients consistently over time in more than 42,000 pediatric subjects across 7 RCTs, 4 open-label non-comparative trials, and 8 observational studies/registries conducted in 34 countries. In addition, among palivizumab-prophylaxed subjects with breakthrough RSV LRTI, rates of intensive care unit admission and mechanical ventilation from RSV hospitalization also were low and consistent across studies. With respect to safety, no differences were observed between palivizumab and placebo in the blinded RCTs.
Rates of RSV hospitalizations and RSV hospitalization-related endpoints in pediatric subjects who received prophylaxis with palivizumab were low and constant over time and across RCTs, open-label non-comparative trials, and observational studies/registries.
Electronic supplementary material
The online version of this article (doi:10.1007/s40121-014-0046-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4269625  PMID: 25297809
Efficacy; Palivizumab; Respiratory syncytial virus; Safety; Serious lower respiratory tract infection; Systematic review
2.  The real-life effectiveness of palivizumab for reducing hospital admissions for respiratory syncytial virus in infants residing in Nunavut 
Respiratory syncytial virus (RSV) infection is the leading cause of hospitalization among infants, and is the cause of considerable morbidity in the Artic regions. Although a safe and effective RSV vaccine remains elusive, palivizumab has shown considerable promise as a prophylactic agent in previous randomized controlled trials. Prompted by the lack of published data involving Inuit or Aboriginal infants, this prospective, observational study aimed to estimate the effectiveness of palivizumab against RSV in this population.
Nunavut has the highest hospitalization rates for respiratory syncytial virus (RSV) worldwide, with rates of 166 per 1000 live births per year <1 year of age. Palivizumab was implemented in Nunavut primarily for premature infants, or those with hemodynamically significant cardiac or chronic lung disease; however, the effectiveness of the program is unknown. The objective of the present multisite, hospital-based surveillance study was to estimate the effectiveness of palivizumab in infants <6 months of age in Nunavut for the 2009 and 2010 RSV seasons.
Infants identified as palivizumab candidates who were <6 months of age were compared with all admissions for lower respiratory tract infection through multisite, hospital-based surveillance documenting the adequacy of palivizumab prophylaxis, admission for lower respiratory tract infection and the results of RSV testing. The OR for RSV admission in unprophylaxed infants was compared with those who were prophylaxed, and the effectiveness of palivizumab was estimated.
Within the study cohort (n=101) during the two RSV seasons, five of the 10 eligible infants who did not receive adequate prophylaxis were admitted with RSV while two of the 91 infants <6 months of age eligible for palivizumab who were adequately prophylaxed were hospitalized with RSV (OR 22.3 [95% CI 3.8 to 130]; P=0.0005). The estimated effectiveness of palivizumab for the cohort was as high as 96%. Eight eligible infants were missed by the program and did not receive prophylaxis.
Palivizumab was highly effective in reducing hospitalizations due to RSV infection in Nunavut. Further efforts need to be made to ensure that all eligible infants are identified.
PMCID: PMC4128465  PMID: 24367792
Effectiveness; Inuit; Nunavut; Palivizumab; Respiratory syncytial virus
3.  A Novel Six Consecutive Monthly Doses of Palivizumab Prophylaxis Protocol for the Prevention of Respiratory Syncytial Virus Infection in High-Risk Preterm Infants in Taiwan 
PLoS ONE  2014;9(6):e100981.
Respiratory syncytial virus (RSV) circulates year round in Taiwan. A novel six consecutive monthly doses of palivizumab for RSV prevention protocol has been approved for high risk preterm infants since December 2010. This study aimed to determine the clinical effectiveness and safety of this novel protocol for the prevention of RSV infection.
From April 2011 to March 2013, we enrolled infants born at ≤28 weeks gestation and infants born at ≤35 weeks gestation with chronic lung disease (CLD) who received palivizumab prophylaxis as study group and followed up for 12 months. Historic control, those who were born and followed up between July 2000 and June 2008, were retrieved for propensity score matching. Primary endpoint was RSV-related hospitalization, and secondary endpoints included the length of hospital stay and intensive care unit (ICU) care.
We enrolled 127 infants (108 infants born at ≤28 weeks and 19 infants born at 29–35 weeks with CLD). They completed 6-dose palivizumab as scheduled. Among the study group, the RSV-related hospitalizations were 2 (1.6%) within 6 months and 5 (3.9%) within 12 months after discharge. We matched 127 infants in the control group with 127 infants in the study group by propensity score matching. The reduction of RSV-related hospitalization rates were 86% (10.2% vs 1.6%, p = 0.002) within 6 months after discharge and 78% (15.7% vs 3.9%, p = 0.004) within 12 months after discharge. Compared to the control group, the rate of ICU care significantly decreased from 7.1% to 0.8% (p = 0.024) within 6 months after discharge and from 7.9% to 0.8% (p = 0.014) within 12 months after discharge. Adverse events were recorded in 6.4% injections.
Six monthly intramuscular administration of palivizumab is effective for prevention of RSV hospitalization in regions with no single seasonal peak of RSV infection such as Taiwan.
PMCID: PMC4074126  PMID: 24971565
4.  Partial palivizumab prophylaxis and increased risk of hospitalization due to respiratory syncytial virus in a Medicaid population: a retrospective cohort analysis 
BMC Pediatrics  2014;14(1):261.
Infection with respiratory syncytial virus (RSV) is common among young children insured through Medicaid in the United States. Complete and timely dosing with palivizumab is associated with lower risk of RSV-related hospitalizations, but up to 60% of infants who receive palivizumab in Medicaid population do not receive full prophylaxis. The purpose of this study was to evaluate the association of partial palivizumab prophylaxis with the risk of RSV hospitalization among high-risk Medicaid-insured infants.
Claims data from 12 states during 6 RSV seasons (October 1st to April 30th in the first year of life in 2003–2009) were analyzed. Inclusion criteria were birth hospital discharge before October 1st, continuous insurance eligibility from birth through April 30th, ≥ one palivizumab administration from August 1st to end of season, and high-risk status (≤34 weeks gestational age or chronic lung disease of prematurity [CLDP] or hemodynamically significant congenital heart disease [CHD]). Fully prophylaxed infants received the first palivizumab dose by November 30th with no gaps >35 days up to the first RSV-related hospitalization or end of follow-up. All other infants were categorized as partially prophylaxed.
Of the 8,443 high-risk infants evaluated, 67% (5,615) received partial prophylaxis. Partially prophylaxed infants were more likely to have RSV-related hospitalization than fully prophylaxed infants (11.7% versus 7.9%, p< 0.001). RSV-related hospitalization rates ranged from 8.5% to 24.8% in premature, CHD, and CLDP infants with partial prophylaxis. After adjusting for potential confounders, logistic regression showed that partially prophylaxed infants had a 21% greater odds of hospitalization compared with fully prophylaxed infants (odds ratio 1.21, 95% confidence interval 1.09-1.34).
RSV-related hospitalization rates were significantly higher in high-risk Medicaid infants with partial palivizumab prophylaxis compared with fully prophylaxed infants. These findings suggest that reduced and/or delayed dosing is less effective.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2431-14-261) contains supplementary material, which is available to authorized users.
PMCID: PMC4287588  PMID: 25308481
Prophylaxis; Respiratory syncytial virus; Palivizumab; Non-compliance
5.  A meta-analysis of the effect of antibody therapy for the prevention of severe respiratory syncytial virus infection 
The primary objective of this meta-analytic study was to determine the impact of RSV-IGIV and palivizumab on risk of respiratory syncytial virus (RSV)-related hospitalization. Secondary objectives were to determine if antibody therapy decreases the risk of RSV infection, intensive care admission, mechanical ventilation, and mortality in high risk infant populations.
We performed searches of electronic data bases from 1966 to April 2009. Inclusion and exclusion criteria were defined a priori. Inclusion criteria were as follows: 1) There was randomization between polyclonal or monoclonal antibodies and placebo or no therapy, and 2) Polyclonal or monoclonal antibodies were given as prophylaxis.
Of the six included studies, three utilized RSV-IGIV (total of 533 randomized to treatment groups) and three utilized palivizumab (total of 1,663 randomized to treatment groups). The absolute risk of hospitalization in the control arms was 12% and overall RR for all 2,196 children who received one of the antibody products was 0.53 (95% CI 0.43, 0.66), P < 0.00001. When looking only at the children who received palivizumab, the RR for hospitalization was 0.50 (95% CI 0.38, 0.66), P < 0.00001. For the children receiving RSV-IGIV, the RR for hospitalization was 0.59 (95% CI 0.42, 0.83, P < 0.002). The use of palivizumab resulted in a significant decrease in admission to the ICU (RR 0.29 (95% CI 0.14, 0.59; P = 0.0007). There was no significant reduction in the risk of mechanical ventilation or mortality with the use of antibody prophylaxis. Infants born at less than 35 weeks gestational age, and those with chronic lung and congenital heart disease all had a significant reduction in the risk of RSV hospitalization with children born under 35 weeks gestational age showing a trend towards the greatest benefit.
Both palivizumab and RSV-IGIV decrease the incidence of RSV hospitalization and ICU admission and their effect appears to be qualitatively similarly. There was neither a statistically significant reduction in the incidence of mechanical ventilation nor in all cause mortality. This meta-analysis separately quantifies the impact of RSV-IGIV and palivizumab on various measures of severe RSV disease and builds upon a previous study that was only able to examine the pooled effect of all antibody products together.
PMCID: PMC2720977  PMID: 19575815
6.  Respiratory Syncytial Virus Prophylaxis in Special Populations: Is it Something Worth Considering in Cystic Fibrosis and Immunosuppression? 
Respiratory syncytial virus (RSV) bronchiolitis is the leading cause of infant hospitalization in the United States. Prophylaxis with palivizumab is effective in reducing RSV hospitalizations in premature infants and in infants or children with chronic lung disease or congenital heart disease. Patients with CF or those who are immunocompromised may be at increased risk for RSV infection–related complications; hence, prophylaxis may prove beneficial to these populations. The extent of palivizumab use in the CF and immunocompromised populations is variable. Palivizumab appears to be safe and may be effective in infants and young children with CF and immunocompromise. However, well-designed, randomized, controlled trials published in peer-reviewed journals are lacking, and its routine use can therefore not be recommended at this time. If used in patients with CF or those who are immunocompromised, RSV prophylaxis should be restricted to peak outbreak months in order to optimize the cost benefit of palivizumab.
PMCID: PMC3208444  PMID: 22477829
cystic fibrosis; immunosuppression; palivizumab; respiratory syncytial virus
7.  A cost-effectiveness analysis of respiratory syncytial virus (RSV) prophylaxis in infants in the United Kingdom 
Respiratory syncytial virus (RSV) is a common cause of respiratory infection that is highly prevalent in infants. Severe cases of RSV infection require hospitalisation; this is most likely to occur in infant populations at high risk. The study assesses the cost-effectiveness of palivizumab versus no prophylaxis in infants at high risk of hospitalisation with RSV in the United Kingdom (UK).
A decision tree model was developed to reflect the clinical pathway of infants at high risk of severe RSV infection who receive either prophylaxis with palivizumab or no prophylaxis. The main outcome was the incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were performed to assess the degree of uncertainty surrounding the results. A threshold analysis considered the impact of clinical and environmental risk factors on the cost-effectiveness in the subgroup of preterm infants 33–35 weeks gestational age (wGA).
Prophylaxis with palivizumab compared with no prophylaxis is associated with the following ICERs; £33,216 for infants with congenital heart disease; £19,168 for infants with chronic lung disease; £3,845 for preterm infants < 29 wGA; £30,205 for preterm infants 29–32 wGA; and £99,056 for preterm infants 33–35 wGA. One-way sensitivity analysis suggests that these results are highly sensitive to the input data. Threshold analysis in the preterm 33–35 wGA subgroup demonstrates that an adjusted RSV-hospitalisation baseline risk of 17.94% or higher would result in an ICER below the £30,000 per quality-adjusted life-year threshold.
Palivizumab is cost-effective compared to no prophylaxis in the United Kingdom in many of the subgroups considered, showing that palivizumab would be a cost-effective use of National Health Service resources.
PMCID: PMC3735492  PMID: 23919494
Palivizumab; Prophylaxis; Cost-effectiveness; Respiratory syncytial virus; United Kingdom
8.  A phase 2, randomized, double-blind safety and pharmacokinetic assessment of respiratory syncytial virus (RSV) prophylaxis with motavizumab and palivizumab administered in the same season 
BMC Pediatrics  2010;10:38.
Respiratory syncytial virus (RSV) is an important pathogen causing annual epidemics of bronchiolitis and pneumonia among infants worldwide. High-risk infants currently receive RSV prophylaxis with palivizumab, a humanized RSV monoclonal antibody (MAb). In preclinical in vitro and in vivo (cotton-rat model) studies, motavizumab, a new RSV MAb, was shown to have greater anti-RSV activity than palivizumab. Motavizumab is currently under review for licensing approval. Since both MAbs may be available concurrently, this study evaluated their safety and tolerability when administered sequentially during the same RSV season.
Between April 2006 and May 2006, 260 high-risk infants were randomly assigned 1:1:1 to receive monthly intramuscular injections: 2 doses of motavizumab followed by 3 doses of palivizumab (M/P); 2 doses of palivizumab followed by 3 doses of motavizumab (P/M); or 5 doses of motavizumab (control). Adverse events (AEs, serious AEs [SAEs]), development of antidrug antibody (ADA), and serum drug trough concentrations were assessed.
Most children received all 5 doses (246/260 [94.6%]) and completed the study (241/260 [92.7%]). While overall AE rates were similar (mostly level 1 or 2 in severity), SAEs and level 3 AEs occurred more frequently in the M/P group (SAEs: 22.9% M/P, 8.4% P/M, 11.8% motavizumab only; level 3 AEs: 15.7% M/P, 6.0% P/M, 6.5% motavizumab only). This trend in AE rates occurred before and after switching from motavizumab to palivizumab, suggesting a cause other than the combined regimen. Frequencies of AEs judged by the investigator to be related to study drug were similar among groups. Two deaths occurred on study (both in the M/P group, before palivizumab administration); neither was considered by the site investigator to be related to study drug. Mean serum drug trough concentrations were comparable among groups; ADA detection was infrequent (5.1% or less of any group).
The conclusions drawn from this study are limited by the small sample size per group. However, within this small study, overall AE rates, serum drug trough concentrations, and development of ADA associated with administering motavizumab and palivizumab sequentially to high-risk children appear comparable to administering motavizumab alone during the same RSV season.
Trial Registration NCT00316264
PMCID: PMC2898783  PMID: 20525274
9.  Respiratory syncytial virus infection in children with congenital heart disease: global data and interim results of Korean RSV-CHD survey 
Korean Journal of Pediatrics  2011;54(5):192-196.
Respiratory syncytial virus (RSV) is a main cause of hospitalization for bronchiolitis and pneumonia in infants worldwide. Children with hemodynamically significant congenital heart disease (HS-CHD), as well as premature infants are at high risk for severe RSV diseases. Mortality rates for CHD patients hospitalized with RSV have been reported as about 24 times higher compared with those without RSV infection. Recently with advances in intensive care, mortality rates in CHD patients combined with RSV have decreased below 2%. The requirements of intensive care and mechanical ventilation for CHD patients with RSV infection were still higher than those without RSV infection or with non-CHD children. RSV infection has frequently threatened CHD infants with congestive heart failure, cyanosis, or with pulmonary hypertension. As a progressive RSV pneumonitis in those infants develops, the impairment of oxygen uptake, the breathing workload gradually increases and eventually causes to significant pulmonary hypertension, even after the operation. Preventing RSV infection as much as possible is very important, especially in infants with HS-CHD. A humanized monoclonal antibody, palivizumab, has effective in preventing severe RSV disease in high-risk infants, and progressive advances in supportive care including pulmonary vasodilator have dramatically decreased the mortality (<1%). Depending on the global trend, Korean Health Insurance guidelines have approved the use of palivizumab in children <1 year of age with HS-CHD since 2009. Korean data are collected for RSV prophylaxis in infants with CHD.
PMCID: PMC3145902  PMID: 21829409
Respiratory syncytial virus; Congenital heart diseases; Pediatric
10.  Whole Blood Gene Expression Profiles to Assess Pathogenesis and Disease Severity in Infants with Respiratory Syncytial Virus Infection 
PLoS Medicine  2013;10(11):e1001549.
In this study, Mejias and colleagues found that specific blood RNA profiles of infants with RSV LRTI allowed for specific diagnosis, better understanding of disease pathogenesis, and better assessment of disease severity.
Please see later in the article for the Editors' Summary
Respiratory syncytial virus (RSV) is the leading cause of viral lower respiratory tract infection (LRTI) and hospitalization in infants. Mostly because of the incomplete understanding of the disease pathogenesis, there is no licensed vaccine, and treatment remains symptomatic. We analyzed whole blood transcriptional profiles to characterize the global host immune response to acute RSV LRTI in infants, to characterize its specificity compared with influenza and human rhinovirus (HRV) LRTI, and to identify biomarkers that can objectively assess RSV disease severity.
Methods and Findings
This was a prospective observational study over six respiratory seasons including a cohort of infants hospitalized with RSV (n = 135), HRV (n = 30), and influenza (n = 16) LRTI, and healthy age- and sex-matched controls (n = 39). A specific RSV transcriptional profile was identified in whole blood (training cohort, n = 45 infants; Dallas, Texas, US) and validated in three different cohorts (test cohort, n = 46, Dallas, Texas, US; validation cohort A, n = 16, Turku, Finland; validation cohort B, n = 28, Columbus, Ohio, US) with high sensitivity (94% [95% CI 87%–98%]) and specificity (98% [95% CI 88%–99%]). It classified infants with RSV LRTI versus HRV or influenza LRTI with 95% accuracy. The immune dysregulation induced by RSV (overexpression of neutrophil, inflammation, and interferon genes, and suppression of T and B cell genes) persisted beyond the acute disease, and immune dysregulation was greatly impaired in younger infants (<6 mo). We identified a genomic score that significantly correlated with outcomes of care including a clinical disease severity score and, more importantly, length of hospitalization and duration of supplemental O2.
Blood RNA profiles of infants with RSV LRTI allow specific diagnosis, better understanding of disease pathogenesis, and assessment of disease severity. This study opens new avenues for biomarker discovery and identification of potential therapeutic or preventive targets, and demonstrates that large microarray datasets can be translated into a biologically meaningful context and applied to the clinical setting.
Please see later in the article for the Editors' Summary
Editors' Summary
Lower respiratory tract infections (LRTIs)—bacterial and viral infections of the lungs and airways (the tubes that take oxygen-rich air to the lungs)—are major causes of illness and death in children worldwide. Pneumonia (infection of the lungs) alone is responsible for 14% of all child deaths. The leading cause of viral LTRIs in children is respiratory syncytial virus (RSV), which is readily transmitted from person to person by direct contact with nasal fluids or airborne droplets. Almost all children have an RSV infection before their second birthday, but most have only minor symptoms similar to those of a common cold and are cared for at home. Unfortunately, some children develop more serious conditions when they become infected with RSV, such as pneumonia or bronchiolitis (swelling and mucus build-up in the bronchioles, the smallest air passages in the lungs). These children have to be admitted to the hospital for supportive care—there is no specific treatment for RSV infection—such as the provision of supplemental oxygen.
Why Was This Study Done?
The lack of a treatment (and of a vaccine) for RSV is largely due to our incomplete understanding of the cellular events and reactions, including the host immune response, that occur during the development of an RSV infection (disease pathogenesis). Moreover, based on physical examination and available diagnostic tools, it is impossible to predict which children infected with RSV will develop a serious condition that requires hospitalization and which ones can be safely nursed at home. Here, the researchers use microarrays to analyze the global host response to acute RSV LTRI in infants, to define gene expression patterns that are specific to RSV infection rather than infection with other common respiratory viruses, and to identify biomarkers that indicate the severity of RSV infection. “Microarray” analysis allows researchers to examine gene expression patterns (“RNA transcriptional profiles”) in, for example, whole blood; a biomarker is a molecule whose level in bodily fluids or tissues indicates how a disease might develop and helps with patient classification.
What Did the Researchers Do and Find?
The researchers compared the RNA transcriptional profile in whole blood taken from children less than two years old hospitalized with RSV, human rhinovirus, or influenza virus infection (rhinovirus and influenza are two additional viral causes of LRTI), and from healthy infants. Using “statistical group comparisons,” they identified more than 2,000 transcripts that were differentially expressed in blood from 45 infants with RSV infection and from 14 healthy matched controls. Genes related to interferon function (interferons are released by host cells in response to the presence of disease-causing organisms) and neutrophil function (neutrophils are immune system cells that, like interferons, are involved in the innate immune response, the body's first line of defense against infection) were among the most overexpressed genes in infants infected with RSV. Genes regulating T and B cells (components of the adaptive immune response, the body's second-line of defense against infection) were among the most underexpressed genes. This specific transcriptional profile, which was validated in three additional groups of infants, accurately distinguished between infants infected with RSV and those infected with human rhinovirus or influenza virus. Finally, a “molecular distance to health” score (a numerical score that quantifies the transcriptional perturbation associated with an illness) was correlated with the clinical disease severity score of the study participants, with how long they needed supplemental oxygen, and with their duration of hospitalization.
What Do These Findings Mean?
These findings suggest that it might be possible to use whole blood RNA transcriptional profiles to distinguish between infants infected with RSV and those with other viruses that commonly cause LRTI. Moreover, if these findings can be replicated in more patients (including non-hospitalized children), gene expression profiling might provide a strategy for triaging patients with RSV infections when they first present to an emergency department and for monitoring clinical changes during the course of the infection, particularly given the development of molecular tools that might soon enable the “real time” acquisition of transcriptional profiles in the clinical setting. Finally, although certain aspects of the study design limit the accuracy and generalizability of the study's findings, these data provide new insights into the pathogenesis of RSV infection and open new avenues for the discovery of biomarkers for RSV infection and for the identification of therapeutic and preventative targets.
Additional Information
Please access these websites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Peter Openshaw
The US Centers for Disease Control and Prevention provides information about RSV infection
The US National Heart, Lung, and Blood Institute provides information about the respiratory system and about RSV infections
The UK National Health Service Choices website provides information about bronchiolitis
The British Lung Foundation also provides information on RSV and on bronchiolitis
MedlinePlus provides links to other resources about RSV infections and about pneumonia (in English and Spanish); the MedlinePlus encyclopedia has a page on bronchiolitis (in English and Spanish)
PATH is an international non-profit organization investigating new RSV vaccines
PMCID: PMC3825655  PMID: 24265599
11.  Outcomes of Palivizumab Prophylaxis for Respiratory Syncytial Virus Infection in Preterm Children with Bronchopulmonary Dysplasia at a Single Hospital in Korea from 2005 to 2009 
Journal of Korean Medical Science  2010;25(2):251-256.
This study was performed to evaluate the utilization and outcomes of palivizumab in high risk children born prematurely with chronic lung disease (CLD). A retrospective review of 128 patients was conducted from September 2004 to March 2009 at the Ajou University Hospital. All patients were diagnosed with CLD, were born at ≤35 weeks of gestation, were <2 yr old at the onset of respiratory syncytial virus (RSV) season, and had received medical therapy within six months prior to the RSV season. Fifty-three patients did not receive palivizumab prophylaxis and 75 patients received at least one dose of palivizumab. There were no statistically significant differences between the patients with and without palivizumab prophylaxis with regard to demographic characteristics and risk factors for RSV infection. There were no systemic adverse responses. Compliance with the course of prophylaxis was 92.2%. Hospitalization associated with RSV occurred in 12 cases (22.6%) in the group without prophylaxis and in three cases (4.0%) with prophylaxis. Palivizumab prophylaxis significantly reduced the frequency of RSV-related hospitalization in preterm children with CLD. This is the first retrospective review of palivizumab prophylaxis in Korea. Palivizumab is effective and well tolerated in high risk prematurely born children.
PMCID: PMC2811293  PMID: 20119579
Chronic Lung Disease; Preterm Children; Palivizumab Prophylaxis, Respiratory Syncytial Viruses; Hospitalization
12.  Hospital admission of high risk infants for respiratory syncytial virus infection: implications for palivizumab prophylaxis 
Objectives: To determine the rates of hospital admission for respiratory syncytial virus (RSV) infection among children born at different gestational ages. To assess the theoretical impact of palivizumab prophylaxis on admissions for RSV infection.
Design: Retrospective cohort study of children born in 1991–2000.
Setting: Tertiary care university hospital.
Methods: Data on all children born during the 10 year period were combined with information on laboratory confirmed RSV infections in these children until the end of 2002. The theoretical impact of palivizumab on RSV associated admissions was estimated by applying the current recommendations for prophylaxis to the study population and using the observed rates of admission in the calculations.
Interventions: None.
Main outcome measures: Rates of RSV infection and hospital admission in different subgroups of children.
Results: Children with chronic lung disease (CLD) were admitted for RSV infection at a rate of 12.0%. The corresponding rates in children born at ⩽28 or 29–32 weeks gestation were 7.1% and 6.8% respectively. Children born at ⩽32 weeks gestation accounted for 6.6% of all admissions due to RSV. Of 586 children who would have met the criteria for palivizumab prophylaxis, 27 (4.6%) were admitted with RSV during the presumed prophylactic period. The number needed to treat to prevent one admission for RSV infection was 15 for children with CLD (with a total cost of €75 000) and 43 for children without CLD born at ⩽32 weeks gestation (with a total cost of €215 000).
Conclusions: The rates of hospital admission for RSV infection in premature infants were substantially lower than those in most previous reports from other countries. Determination of the local rates of RSV admissions in different groups of children would be useful in making decisions about the use of palivizumab.
PMCID: PMC1721807  PMID: 15613580
13.  Net cost of palivizumab for respiratory syncytial virus prophylaxis during the 1998/99 season in northern Alberta 
Paediatrics & Child Health  2001;6(8):525-532.
Palivizumab has been shown to decrease respiratory syncytial virus (RSV) hospitalization rates in preterm infants and infants with chronic lung disease. The objective of the present study was to determine whether the use of palivizumab during the 1998/99 RSV season would have resulted in a cost-saving in infants discharged from Edmonton hospitals.
A retrospective study of RSV hospitalizations was performed by contacting parents and reviewing hospital lists. The net cost of using palivizumab was determined by comparing the cost of giving the drug from November 1, 1998 to April 1, 1999 with the cost of potentially averted medical transports and hospitalizations.
One hundred fifty-nine infants discharged from Edmonton hospitals who met the Canadian Paediatric Society’s criteria for receiving palivizumab during the 1998/99 RSV season were studied.
The cost of using palivizumab in these 159 study infants would have been $753,300. The infants had 21 RSV hospitalizations and required four medical transports. The estimated cost of RSV hospital-based care for these infants was $168,888. Assuming a drug efficacy of 39% in infants with chronic lung disease and 78% in infants born before 33 weeks’ gestation with no chronic lung disease, $121,147 of these costs could have been averted if palivizumab had been used.
The net cost to the health care system of using palivizumab, as recommended in the Canadian Paediatric Society guidelines, in study infants in northern Alberta during the 1998/99 RSV season would have been $632,153.
PMCID: PMC2805588  PMID: 20084122
Chronic lung disease; Palivizumab; Prematurity; Respiratory syncytial virus
14.  A prospective, open-label, non-comparative study of palivizumab prophylaxis in children at high risk of serious respiratory syncytial virus disease in the Russian Federation 
BMC Research Notes  2012;5:484.
Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections (LRTIs) in children globally. Predisposing conditions for the development of serious RSV disease include preterm infants and those with cardiopulmonary illness, including congenital heart disease (CHD) and bronchopulmonary dysplasia (BPD). No vaccine is currently approved for the prevention of RSV infection. It is recommended that children at high risk be prophylactically administered palivizumab, a monoclonal antibody that has been shown in a number of clinical studies to reduce hospitalization rates due to serious RSV infection. The objective of the current study was to determine the safety and effectiveness of palivizumab in preventing serious RSV disease in high-risk children in the Russian Federation. Children at high risk of serious RSV disease (ie, born at ≤35 wk gestational age and ≤6 mo of age, and/or aged ≤24 mo with BPD or hemodynamically significant CHD) were enrolled. Subjects were to receive 3 to 5 monthly injections of palivizumab 15 mg/kg (depending on the month of the initial injection) over the RSV season. The primary endpoint was RSV-related hospitalizations. Adverse events (AEs) were reported through 100 days following the final injection.
One hundred subjects received ≥1 injection of palivizumab; 94 completed their dosing schedule. There were no RSV hospitalizations or deaths. Six of 7 subjects hospitalized for respiratory/cardiac conditions had an RSV test, which was negative in all cases. Three non-serious AEs (acute intermittent rhinitis and rhinitis, 1 subject; atopic dermatitis, 1 subject) were considered possibly related to palivizumab. All other AEs were mild or moderate and considered not related/probably not related to palivizumab.
Palivizumab was generally well tolerated and effectively prevented serious RSV infection in a mixed population of high-risk children in the Russian Federation.
Trial registration NCT01006629
PMCID: PMC3532356  PMID: 22943074
Bronchopulmonary dysplasia; Congenital heart disease; Immunoprophylaxis; Lower respiratory tract infection; Preterm infant
15.  Population Pharmacokinetics of Palivizumab, a Humanized Anti-Respiratory Syncytial Virus Monoclonal Antibody, in Adults and Children 
Although it has been on the market for over a decade, confusion remains regarding the pharmacokinetics (PK) and optimal dosing of palivizumab, a humanized IgG1κ monoclonal antibody indicated for the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in pediatric patients at high risk of RSV disease. The objectives of this analysis were to characterize the population PK of palivizumab in adults and children using nonlinear mixed-effect modeling, quantify the effects of individual covariates on variability in palivizumab disposition, and compare palivizumab exposures for various dosing scenarios. Palivizumab PK data from 22 clinical studies were used for model development. The model was developed using a two-stage approach: (i) a 2-compartment model with first-order absorption after intramuscular administration was fitted to adult data, and (ii) the same structural model was fitted to the sparse pediatric data using the NONMEM $PRIOR subroutine, with informative priors obtained from the adult analysis. Body weight and an age descriptor that combines gestational age and postnatal age (PAGE) using an asymptotic-exponential model best described palivizumab clearance in pediatric patients. Palivizumab clearance increased slightly from 10.2 ml/day to 11.9 ml/day as a function of PAGE ranging from 7 to 18 months. Covariate analysis indicated a 20% higher clearance in children with chronic lung disease and in children with antidrug antibody titer values of ≥80. These covariates did not substantially explain interindividual variability. In the label-indicated pediatric population, body weight was the primary demographic factor affecting palivizumab PK. Body weight-based dosing of 15 mg/kg yields similar palivizumab concentrations in children of different gestational and postnatal ages. Simulations demonstrated that there was little difference in palivizumab PK between healthy term and premature infants. Simulations also demonstrated that the 5 monthly palivizumab doses of 15 mg/kg, consistent with the label and studied in two randomized, clinical trials, provided greater and more prolonged palivizumab exposure than did an abbreviated dosing regimen of 3 monthly doses.
PMCID: PMC3421858  PMID: 22802243
16.  Respiratory syncytial virus hospitalization trends in infants with chronic lung disease of infancy, 1998–2008 
Clinical Epidemiology  2011;3:245-250.
Infants with chronic lung disease of infancy (CLDI) are at high risk for severe respiratory syncytial virus (RSV) illness requiring hospitalization. Palivizumab was first licensed in 1998 for the prevention of RSV disease in high-risk infants, including those with CLDI. We performed a retrospective cohort study of all hospitalized children with CLDI aged <2 years between 1998 and 2008 in the USA to determine trends in rates of hospitalizations due to RSV (RSVH) since the launch of palivizumab.
Materials and methods:
Data from the United States National Hospital Discharge Survey, a multistage systematic survey sample of US hospitals, were assembled. We defined RSVH using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes of 079.6 (RSV), 466.11 (acute bronchiolitis due to RSV), and 480.1 (pneumonia due to RSV). Quarterly rates of RSVH were assessed for children with CLDI (ICD-9-CM code 770.7) and calculated between 1998 and 2008. Because RSV may be miscoded, the analysis was repeated after expanding the definition of RSVH to include all acute bronchitis and acute bronchiolitis (ABH) (ICD-9-CM = 466). Trends were described using linear regression with seasonal indicators included in the model.
On average, about 966 RSVH (range 98–1373 RSVH) per year were found for children <2 years with CLDI in the USA between 1998 and 2008. Over the 11-year period, the predicted rate of RSVH statistically significantly decreased by 48% (from 93.78 to 49.06 RSVH per 1 million children) (P = 0.013). Addition of ABH resulted in a nonstatisically significant decrease of 32% over the 10-year period (P = 0.102).
These results suggest that there has been a decrease in the rate of RSVH in infants with CLDI between 1998 and 2008. The reasons for this decrease may include improved neonatal intensive care unit and outpatient management of CLDI, and possibly increased use of palivizumab in this high-risk population.
PMCID: PMC3191114  PMID: 22003308
bronchiolitis; CLDI; RSV; palivizumab
17.  Prophylactic and therapeutic testing of Nicotiana-derived RSV-neutralizing human monoclonal antibodies in the cotton rat model 
mAbs  2013;5(2):263-269.
Severe lower respiratory tract infection in infants and small children is commonly caused by respiratory syncytial virus (RSV). Palivizumab (Synagis®), a humanized IgG1 monoclonal antibody (mAb) approved for RSV immunoprophylaxis in at-risk neonates, is highly effective, but pharmacoeconomic analyses suggest its use may not be cost-effective. Previously described potent RSV neutralizers (human Fab R19 and F2–5; human IgG RF-1 and RF-2) were produced in IgG format in a rapid and inexpensive Nicotiana-based manufacturing system for comparison with palivizumab. Both plant-derived (palivizumab-N) and commercial palivizumab, which is produced in a mouse myeloma cell line, showed protection in prophylactic (p < 0.001 for both mAbs) and therapeutic protocols (p < 0.001 and p < 0.05 respectively). The additional plant-derived human mAbs directed against alternative epitopes displayed neutralizing activity, but conferred less protection in vivo than palivizumab-N or palivizumab. Palivizumab remains one of the most efficacious RSV mAbs described to date. Production in plants may reduce manufacturing costs and improve the pharmacoeconomics of RSV immunoprophylaxis and therapy.
PMCID: PMC3893236  PMID: 23396091
RSV; monoclonal; antibody; prophylaxis; therapy; Nicotiana
18.  Respiratory-Related Hospitalizations following Prophylaxis in the Canadian Registry for Palivizumab (2005–2012) Compared to Other International Registries 
Respiratory syncytial virus (RSV) infection occurs commonly in infants aged ≤2 years, and severe infection results in hospitalization with accompanying morbidity and mortality. Palivizumab has been available for prophylaxis for the past 15 years. Prospective data on patients who received palivizumab from 2005 to 2012 has been assembled in the Canadian registry (CARESS) to document utilization, compliance, and health outcomes in both hospital and community settings. Long-term data is necessary to evaluate the impact of palivizumab on the incidence of RSV infections, minimize healthcare resources, and identify which infant subpopulations are receiving prophylaxis. A database search was also conducted for similar information from published registries, and hospitalization rates were compared to results from randomized clinical trials (RCTs).Overall hospitalization rates (percent; range) for respiratory-related illnesses and RSV-specific infection in infants who meet standard indications for prophylaxis were 6.6 (3.3–7.7) and 1.55 (0.3–2.06), respectively, in CARESS, which closely aligns with registry data from 4 other countries, despite the former comprising the largest cohort of complex patients internationally. Overall RSV-related hospitalization rates were lower across registries compared to equivalent patients in RCTs. Registry data provides valuable information regarding real-world experience with palivizumab, while facilitating the genesis of new research themes.
PMCID: PMC3703731  PMID: 23861694
19.  Palivizumab: a review of its use in the protection of high risk infants against respiratory syncytial virus (RSV) 
Biologics : Targets & Therapy  2007;1(1):33-43.
Respiratory syncytial virus (RSV) is a leading cause of hospitalization in children less than 1 year of age and causes substantial morbidity. Although there is not currently a vaccine available to prevent RSV infection, prophylaxis with the humanized monoclonal antibody palivizumab has been shown to reduce the rate of RSV hospitalization in premature infants and those infants with chronic lung disease or congenital heart disease. Because palivizumab has not been shown to have a beneficial clinical effect on established RSV disease such as reducing the rate of mechanical ventilation and mortality in children afflicted with RSV, there has been considerable debate as to the cost-benefit ratio of administering palivizumab according to international guidelines. Palivizumab has demonstrated a favorable side-effect profile in clinical trials without the development of anti-palivizumab antibodies. Future studies are needed to determine whether palivizumab, or other more potent monoclonal antibodies which are currently undergoing clinical trials, will reduce the long-term sequelae of RSV infection such as the development of wheezing and asthma.
PMCID: PMC2721348  PMID: 19707346
monoclonal antibodies; palivizumab; respiratory syncytial virus; immunoprophylaxis; pediatrics
20.  Respiratory infections in children up to two years of age on prophylaxis with palivizumab 
Revista Paulista de Pediatria  2014;32(2):152-158.
To identify the viruses involved in acute respiratory tract infections and to analyze the rates of hospitalization and death in children on palivizumab prophylaxis.
Prospective cohort of 198 infants up to one year old who were born before 29 weeks of gestational age and infants under two years old with hemodynamically unstable cardiopathy or chronic pulmonary disease who received prophylactic palivizumab against severe respiratory syncytial virus infections in 2008. During the study period, in each episode of acute respiratory tract infection, nasopharyngeal aspirate was collected to identify respiratory syncytial virus, adenovirus, parainfluenza 1, 2 and 3, influenza A and B by direct immunofluorescence, rhinovirus and metapneumovirus by polymerase chain reaction preceded by reverse transcription. Data regarding hospitalization and deaths were monitored.
Among the 198 studied infants, 117 (59.1%) presented acute respiratory tract infections, with a total of 175 episodes. Of the 76 nasopharyngeal aspirates collected during respiratory tract infections, 37 were positive, as follow: rhinovirus (75.7%), respiratory syncytial virus (18.9%), parainfluenza (8.1%), adenovirus 2 (2.7%), metapneumovirus (2.7%) and three samples presented multiple agents. Of the 198 children, 48 (24.4%) were hospitalized: 30 (15.2%) for non-infectious etiology and 18 (9.1%) for respiratory causes. Among these 18 children, one case of respiratory syncytial virus was identified. Two deaths were reported, but respiratory syncytial virus was not identified.
During the prophylaxis period, low frequency of respiratory syncytial virus infections and low rates of hospitalization were observed, suggesting the benefit of palivizumab prophylaxis.
PMCID: PMC4183017  PMID: 25119744
respiratory syncytial viruses; antibodies, monoclonal; respiratory tract infections/prevention & control; infant
21.  Risk Factors for Hospitalization due to Lower Respiratory Tract Infection in Preterm Infants on Palivizumab Prophylaxis 
Iranian Journal of Pediatrics  2013;23(6):693-700.
To determine the risk factors associated with lower respiratory tract infections (LRTI) related hospitalizations in preterm infants receiving palivizumab throughout the high season for respiratory syncytial virus (RSV) infection.
Premature infants who were commenced on palivizumab prophylaxis during the RSV season were included in the study following parental consent. Information on demographic, social, prenatal and postnatal clinical characteristics was recorded and risk factors associated with hospitalization were evaluated for each patient.
While 234 participants (Group 1, 92.8%) did not require hospitalization during the study period, 18 patients (Group 2, 7.2%) were hospitalized at least once for LRTI during the RSV season. The rate of moderate-severe bronchopulmonary dysplasia (BPD) was significantly higher in group 2 compared to group 1 (38.9% vs 16.2%; P=0.016). Of the 18 infants who were hospitalized, 6 (33.3%) tested positive for RSV while the remaining 12 patients (66.7%) were negative for RSV. Odds ratio (OR) analysis of several risk factors revealed the presence of BPD (OR: 3.28; 95%CI: 1.19-9), being from a family with low socioeconomic status (OR: 3.64; 95%CI 1.08-12.3) to be associated with a higher likelihood of LRTI-related hospitalization.
Our data demonstrated that RSV is an important LRTI agent and cause of hospitalization especially in preterm infants with additional risks such as BPD, gestational age of <28 weeks and low socioeconomic status. We suggest that improving care conditions and decreased BPD with prematurity would help in prevention of LRTI hospitalization.
PMCID: PMC4025129  PMID: 24910750
Respiratory syncytial virus; Lower respiratory tract infection; Risk Factors; Preterm Infants
22.  A comparative study of respiratory syncytial virus (RSV) prophylaxis in premature infants within the Canadian Registry of Palivizumab (CARESS) 
We examined the dosing regimens, compliance, and outcomes of premature infants who received palivizumab within the Canadian Registry of Palivizumab (CARESS). Infants receiving ≥1 dose of palivizumab during the 2006–2011 respiratory syncytial virus (RSV) seasons were recruited across 30 sites. Respiratory illness events were captured monthly. Infants ≤32 completed weeks gestational age (GA) (Group 1) were compared to 33–35 completed weeks GA infants (Group 2) following prophylaxis. In total, 6,654 patients were analyzed (Group 1, n = 5,183; Group 2, n = 1,471). The mean GA was 29.9 ± 2.9 versus 34.2 ± 2.2 weeks for Groups 1 and 2, respectively. Group differences were significant (all p-values <0.05) for the following: proportion of males, Caucasians, siblings, multiple births, maternal smoking, smoking during pregnancy, household smokers, >5 household individuals, birth weight, and enrolment age. Overall, infants received 92.6 % of expected injections. Group 1 received significantly more injections, but a greater proportion of Group 2 received injections within recommended intervals. The hospitalization rates were similar for Groups 1 and 2 for respiratory illness (4.7 % vs. 3.7 %, p = 0.1) and RSV (1.5 % vs. 1.4 %, p = 0.3). Neither the time to first respiratory illness [hazard ratio = 0.9, 95 % confidence interval (CI) 0.7–1.2, p = 0.5] nor to first RSV hospitalization (hazard ratio = 1.3, 95 % CI 0.8–2.2, p = 0.3) were different. Compliance with RSV prophylaxis is high. Despite the higher number of palivizumab doses in infants ≤32 completed weeks GA, the two groups’ respiratory illness and RSV-positive hospitalization rates were similar.
PMCID: PMC3456915  PMID: 22546928
23.  Respiratory hospitalizations and respiratory syncytial virus prophylaxis in special populations 
European Journal of Pediatrics  2011;171(5):833-841.
Palivizumab utilization, compliance, and outcomes were examined in infants with preexisting medical diseases within the Canadian Registry Database (CARESS) to aid in developing guidelines for potential “at-risk” infants in the future. Infants who received ≥1 dose of palivizumab during the 2006–2010 respiratory syncytial virus (RSV) seasons at 29 sites were recruited and utilization, compliance, and outcomes related to respiratory infection/illness (RI) events were collected monthly. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for premature infants ≤35 completed weeks gestational age (GA) who met standard approval criteria (group 1) compared to those with medical disorders (group 2) using Cox proportional hazards regression models with adjustment for potential confounding factors. Of 7,339 registry infants, 4,880 were in group 1 and 952 in group 2, which included those with Down syndrome (20.3%), upper airway anomalies (18.7%), pulmonary diseases (13.3%), and cystic fibrosis (12.3%). Group 2 were older at enrolment (10.2 ± 9.2 vs. 3.5 ± 3.1 months, p < 0.0005), had higher GA (35.9 ± 6.0 vs. 31.0 ± 5.4 weeks, p < 0.0005), and were less compliant with treatment intervals (69.4% vs. 72.6%, p = 0.048). A greater proportion of group 2 infants were hospitalized for RI (9.0% vs. 4.2%, p < 0.0005) and RSV (2.4% vs. 1.3%, p = 0.003) (unadjusted). Being in group 2 was associated with an increased risk of RI (HR = 2.0, 95%CI 1.5–2.5, p < 0.0005), but not RSV hospitalization (HR = 1.6, 95%CI 0.9–2.8, p = 0.106). In infants receiving palivizumab, those with underlying medical disorders, though not currently approved for prophylaxis, are at higher risk for RI events compared with preterm infants. However, risk of RSV hospitalizations is similar.
PMCID: PMC3327836  PMID: 22203430
Respiratory syncytial virus; Palivizumab; Premature; Special populations
24.  Effectiveness of Palivizumab in Preventing RSV Hospitalization in High Risk Children: A Real-World Perspective 
Infection with respiratory syncytial virus (RSV) is one of the major causes globally of childhood respiratory morbidity and hospitalization. Palivizumab, a humanized monoclonal antibody, has been recommended for high risk infants to prevent severe RSV-associated respiratory illness. This recommendation is based on evidence of efficacy when used under clinical trial conditions. However the real-world effectiveness of palivizumab outside of clinical trials among different patient populations is not well established. We performed a systematic review focusing on postlicensure observational studies of the protective effect of palivizumab prophylaxis for reducing RSV-associated hospitalizations in infants and children at high risk of severe infection. We searched studies published in English between 1 January 1999 and August 2013 and identified 420 articles, of which 20 met the inclusion criteria. This review supports the recommended use of palivizumab for reducing RSV-associated hospitalization rates in premature infants born at gestational age < 33 weeks and in children with chronic lung and heart diseases. Data are limited to allow commenting on the protective effect of palivizumab among other high risk children, including those with Down syndrome, cystic fibrosis, and haematological malignancy, indicating further research is warranted in these groups.
PMCID: PMC4274815  PMID: 25548575
25.  Association of RSV-related hospitalization and non-compliance with Palivizumab among commercially insured infants: a retrospective claims analysis 
BMC Infectious Diseases  2013;13:334.
Palivizumab has been shown to decrease the incidence of hospitalization due to respiratory syncytial virus (RSV) in infants at risk of severe RSV disease. We examined the association between compliance with palivizumab dosing throughout the RSV season and risk of RSV-related hospitalization in clinical practice.
Subjects who were born and discharged from the hospital before the RSV season and received ≥1 palivizumab dose during their first RSV season were identified from a large US commercial health insurance database between 01/01/03 and 12/31/09. Subjects were deemed compliant if they received ≥5 palivizumab doses without gaps (>35 days) and their first dose was received by November 30. RSV-related hospitalizations were identified using ICD-9-CM diagnosis codes and examined over 2 observation periods: post-index dose and RSV season. A Cox proportional hazard model was used to evaluate the association between non-compliance and RSV-related hospitalization.
Of the 5,003 subjects who received palivizumab, 62% were deemed non-compliant. Non-compliant subjects had significantly higher unadjusted rates of RSV-related hospitalizations compared to compliant subjects during both observation periods (post-index: 6.1 vs. 2.8 per 100 infant seasons, p < 0.001; RSV season: 5.9% vs. 2.3%; p < 0.001). In multivariate analyses, non-compliance was significantly associated with higher risk of RSV-related hospitalization (HR = 2.01; p < 0.001). Of the 225 RSV-related hospitalizations observed during the RSV season, 61 (27%) occurred before the first dose of palivizumab.
Subjects who did not receive monthly dosing of palivizumab throughout the RSV season had significantly higher rates of RSV-related hospitalizations. The RSV-related hospitalizations prior to the first dose of palivizumab suggest some dosing was started too late.
PMCID: PMC3727980  PMID: 23870086
Respiratory syncytial viruses; Palivizumab; Patient compliance; Hospitalization; Infants

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