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.
cystic fibrosis; immunosuppression; palivizumab; respiratory syncytial virus
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.
Palivizumab; Prophylaxis; Cost-effectiveness; Respiratory syncytial virus; United Kingdom
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.
monoclonal antibodies; palivizumab; respiratory syncytial virus; immunoprophylaxis; pediatrics
Respiratory Syncytial Virus (RSV) is a common virus that infects children and adults; however, children younger than two years of age tend to develop more serious respiratory symptoms. RSV is responsible for thousands of outpatient visits (e.g., emergency room/primary care physician), hospitalizations and can result in death. Treatment is primarily supportive care and the illness resolves without complications in most children. RSV prophylaxis with palivizumab is an option for high-risk infants and children, which can decrease hospitalization and length of stay. Immunocompromised patients are a special population of which ribavirin and palivizumab may be used for treatment. Currently, no medication or vaccine available has been able to show a reduction in mortality from RSV. Future vaccines are in the developmental stage and will hopefully decrease the symptomatic and economic burden of this disease.
child; infant; palivizumab; ribavirin; motavizumab
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.
To assess the cost effectiveness of palivizumab for prevention of severe respiratory syncytial virus (RSV) disease in high-risk infants in Spain, incorporating country-specific observational hospitalisation data.
An existing decision tree model, designed using data from a large international clinical trial of palivizumab versus no prophylaxis, was updated to include Spanish observational hospitalisation data. The analysis was performed for preterm children born at or before 32 weeks gestational age, who are at high risk of developing severe RSV disease requiring hospitalisation. Data sources included published literature, official price/tariff lists and national population statistics. The primary perspective of the study was that of the Spanish National Health Service in 2006.
The base-case analysis included the direct medical costs associated with palivizumab prophylaxis and hospital care for RSV infections. Use of palivizumab produces an undiscounted incremental cost-effectiveness ratio (ICER) of €6,142 per quality-adjusted life-year (QALY), and a discounted ICER of €12,814/QALY.
Palivizumab provides a cost-effective method of prophylaxis against severe RSV disease requiring hospitalisation among preterm infants in Spain.
Cost-effectiveness; Model; Respiratory syncytial virus; Palivizumab; Spain; I18
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.
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.
Chronic Lung Disease; Preterm Children; Palivizumab Prophylaxis, Respiratory Syncytial Viruses; Hospitalization
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.
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.
Chronic lung disease; Palivizumab; Prematurity; Respiratory syncytial virus
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.
Respiratory syncytial virus; Palivizumab; Premature; Special populations
Respiratory Syncytial Virus (RSV) is the leading cause of hospitalization for lower respiratory tract infections (LRTI) in young children worldwide.
We evaluate the epidemiological and clinical patterns of RSV infection in infants hospitalized for LRTI in in Palermo, South Italy, Sicily.
We collected the demographic details of infants hospitalized to G. Di Cristina Children's Hospital in Palermo for LRTI between November 2005 and May 2006. We also included all cases occurred in newborns hospitalized in the Neonatal Intensive Care Unit (NICU) Of Palermo.
During the studied period, 335/705 hospitalized infants for LRTI were enrolled in the study. The trend of hospitalization started in late winter and lasting until May 2006 with an epidemic peak in spring. 178/335 infants tested for viral infection showed RSV disease. Three cases occurred in preterm newborns hospitalized from birth in NICU. The likelihood to be RSV+, rather than RSV negative (RSV-) was higher for infants < 6 months and lower for infants with history of breast feeding (P < 0.05). RSV infection was associated with a higher likelihood to be admitted to intensive care unit and to a longer hospitalization and oxygen therapy.
The study shows that, in Sicily, RSV is an important cause of LRTI in infants. The seasonal distribution shows that both LRTI and RSV infections peak in late spring, in contrast to Northern Italy. Our data could help to define the regional appropriate start of prophylactic interventions.
Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections among infants and young children, and is responsible for an estimated four million deaths per year globally. A monthly injection of palivizumab has been used for prophylaxis of serious RSV infections among high-risk children in 71 countries since 1998 and approval for use in the Russian Federation was obtained in February 2010. A recommendation for RSV prophylaxis in the Russian Federation would require knowledge of the prevalence and seasonality of RSV in that country.
In a prospective, multicenter, epidemiological study of the prevalence, seasonality, and peak occurrence of RSV infection, children aged ≤2 years hospitalized for lower respiratory tract infections in three regions of the Russian Federation, from September 2008 through April 2009, were screened and tested for RSV using rapid immunochromatography of nasopharyngeal lavage. For subjects who were tested positive, hospitalization data were collected.
Of 519 children aged ≤2 years enrolled from September 11, 2008 through April 26, 2009, 197 tested positive for RSV (38.0%, 95% CI: 33.8, 42.3). The onset of the 2008–2009 RSV season in the Russian Federation occurred in late October 2008, similar to what is observed in other northern temperate zones. Peak activity occurred in early April 2009, when 62% of children enrolled tested positive for RSV.
The prevalence of serious RSV infections in the Russian Federation is similar to the prevalence previously identified in other temperate zones of the northern hemisphere. The seasonality of disease shifted towards early spring, with peak activity later in the season, within a range reported in other countries. These data provide further evidence of serious RSV infection in children in the Russian Federation, as well as guidance for timing of seasonal RSV prophylaxis, especially among individuals at high risk for serious RSV infection.
RSV; prophylaxis; prevalence; seasonality; palivizumab
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.
Respiratory syncytial virus (RSV) is a major cause of respiratory infection in children. Most of the pediatric population have RSV infection before the age of 2, and recurrent infections are common even within one season. Chronic lung disease, prematurity, along with congenital heart disease (CHD) are major risk factors in severe lower respiratory infection. In hemo-dynamically significant CHD patients with RSV infection, hospitalization is usually needed and the possibility of treatment in intensive care unit and the use of mechanical ventilator support are known to increase. Therefore the prevention of RSV infection in CHD patients is mandatory. The current standard for RSV prevention is immunoprophylaxis by palivizumab. Immunoprophylaxis is recommended monthly in hemodynamically significant CHD patients, up to 5 months. Motabizumab, a second generation drug and newly developing RSV vaccines are also expected to play a key role in RSV prevention in the future. The prophylaxis of RSV infection in CHD patients is cost-effective in both the medical aspect of the patients as well as the socio-economic aspect. Therefore an effort to promote prevention should be made by not only the family of the patients but also by the government.
Respiratory syncytial virus; Congenital heart defect; Prevention; Child
Respiratory syncytial virus (RSV) is a major cause of virus-induced respiratory disease and hospitalization in infants. Palivizumab, an RSV-neutralizing monoclonal antibody, is used clinically to prevent serious RSV-related respiratory disease in high-risk infants. Motavizumab, an affinity-optimized version of palivizumab, was developed to improve protection against RSV. These antibodies bind RSV F protein, which plays a role in virus attachment and mediates fusion. Determining how these antibodies neutralize RSV is important to help guide development of new antibody drugs against RSV and, potentially, other viruses. This study aims to uncover the mechanism(s) by which palivizumab and motavizumab neutralize RSV. Assays were developed to test the effects of these antibodies at distinct steps during RSV replication. Pretreatment of virus with palivizumab or motavizumab did not inhibit virus attachment or the ability of F protein to interact with the target cell membrane. However, pretreatment of virus with either of these antibodies resulted in the absence of detectable viral transcription. These results show that palivizumab and motavizumab act at a point after F protein initiates interaction with the cell membrane and before virus transcription. Palivizumab and motavizumab also inhibited F protein-mediated cell-to-cell fusion. Therefore, these results strongly suggest that these antibodies block both cell-to-cell and virus-to-cell fusion, since these processes are likely similar. Finally, palivizumab and motavizumab did not reduce viral budding. Based on models developed from numerous studies of viral fusion proteins, our results indicate that these antibodies may prevent conformational changes in F protein required for the fusion process.
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.
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.
Respiratory syncytial virus (RSV) is the leading viral pathogen responsible for bronchiolitis and pneumonia in infants and young children worldwide. We have previously shown in the mouse model that treatment with an anti-RSV neutralizing monoclonal antibody (MAb) against the F glycoprotein of RSV, palivizumab, decreased lung inflammation, airway obstruction, and postmethacholine airway hyperresponsiveness. MEDI-524, or Numax, is a new MAb derived from palivizumab with enhanced neutralizing activity against RSV. We compared the effects of these two MAbs on different markers of disease severity using the murine model of RSV infection. BALB/c mice were intranasally inoculated with RSV A2. Palivizumab or MEDI-524 was administered once at either 24 h before or 48 h after RSV inoculation. Regardless of the time of administration, all treated mice showed significantly decreased RSV loads in bronchoalveolar lavage samples measured by plaque assay. Only MEDI-524 given at −24 h significantly decreased lung RSV RNA loads on days 5 and 28 after RSV inoculation. Pulmonary histopathologic scores, airway obstruction, and postmethacholine airway hyperresponsiveness were significantly reduced in mice treated with MEDI-524 at 24 h before inoculation, compared with untreated controls and the other regimens evaluated. MEDI-524 was superior to palivizumab on several outcome variables of RSV disease assessed in the mouse model: viral replication, inflammatory and clinical markers of acute disease severity, and long-term pulmonary abnormalities.
Respiratory syncytial virus (RSV) lower respiratory tract infection is the most common viral respiratory infection in infants. Several authors have sought to determine which risk factors are the best predictors for severe RSV disease. Our aim was to evaluate if a specific chest radiographic pattern in RSV disease can predict the disease severity. We conducted a multicenter retrospective cohort study in term and preterm neonates with confirmed lower respiratory tract RSV infection, admitted to neonatal intensive care units (NICU) from 2000 to 2010. To determine which factors independently predicted the outcomes, multivariate logistic regression analysis was performed. A total of 259 term and preterm neonates were enrolled. Patients with a consolidation pattern on the chest radiograph at admission (n = 101) had greater need for invasive mechanical ventilation (OR: 2.5; P = .015), respiratory support (OR: 2.3; P = .005), supplemental oxygen (OR: 3.0; P = .008), and prolonged stay in the NICU (>7 days) (OR: 1.8; P = .025). Newborns with a consolidation pattern on admission chest radiograph had a more severe disease course, with greater risk of invasive mechanical ventilation, respiratory support, supplemental oxygen, and prolonged hospitalization.
Diminished lung function appears to be a risk factor for respiratory syncytial virus (RSV) infection/bronchiolitis in term born infants.
To determine if diminished lung function prior to neonatal unit discharge was associated with subsequent symptomatic RSV lower respiratory tract infection (LRTI) and respiratory morbidity in prematurely born infants.
Of 39 infants in a tertiary neonatal intensive care unit (median gestational age 28 weeks, range 23–31), 20 had bronchopulmonary dysplasia. Lung function (compliance and resistance of the respiratory system (Crs and Rrs) and functional residual capacity (FRC)) was measured on the neonatal unit at 36 weeks postmenstrual age (PMA). Following neonatal unit discharge, nasopharyngeal aspirates were obtained on every occasion, at home or in hospital, an infant had an LRTI. RSV was identified by immunofluorescence and/or culture.
The 15 infants who suffered a symptomatic RSV LRTI had a higher mean Rrs and suffered more wheeze at follow up than the rest of the cohort. Regression analysis showed that a high Rrs was significantly associated with a symptomatic RSV LRTI; significant factors for cough were a high Rrs and a symptomatic RSV LRTI, and for wheeze were a high Rrs.
Prematurely born infants, who had a symptomatic RSV LRTI and/or respiratory morbidity at follow up, had worse lung function prior to neonatal unit discharge.
respiratory syncytial virus; lung function; prematurity; cough; wheeze
QUESTION Palivizumab, a specific monoclonal antibody for respiratory syncytial virus (RSV), is available for prevention of pediatric respiratory tract infections. What are the indications for its use and can it be used for treatment of RSV infections?
ANSWER Most infants should not be considered for RSV prophylaxis with palivizumab. The drug is approved for use for different indications in different Canadian provinces. The drug should be administered only in the context of infants most vulnerable to severe RSV illness with a high likelihood of hospital admission, particularly in the first 6 months of life. It is not effective in the treatment of RSV disease and it is not approved or recommended for this indication.
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.
Respiratory syncytial viruses; Palivizumab; Patient compliance; Hospitalization; Infants
Background. Palivizumab is a US Food and Drug Administration–approved monoclonal antibody for the prevention of respiratory syncytial virus (RSV) lower respiratory disease in high-risk infants. Motavizumab, derived from palivizumab with enhanced antiviral activity, has recently been tested in humans. Although palivizumab escape mutants have been generated in the laboratory, the development of resistant RSV in patients receiving palivizumab has not been reported previously.
Methods. We generated palivizumab and motavizumab escape mutants in vitro and examined the development of resistant mutants in RSV-breakthrough patients receiving immunoprophylaxis. The effect of these mutations on neutralization by palivizumab and motavizumab and in vitro fitness was studied.
Results. Antibody-resistant RSV variants selected in vitro had mutations at position 272 of the fusion protein, from lysine to asparagine, methionine, threonine, glutamine, or glutamate. Variants containing mutations at positions 272 and 275 were detected in breakthrough patients. All these variants were resistant to palivizumab, but only the glutamate variant at position 272 demonstrated resistance to motavizumab. Mixtures of wild-type and variant RSV soon lost the resistant phenotype in the absence of selection.
Conclusions. Resistant RSV variants were detected in a small subset (∼5%) of RSV breakthrough cases. The fitness of these variants was impaired, compared to wild-type RSV.
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.
Bronchopulmonary dysplasia; Congenital heart disease; Immunoprophylaxis; Lower respiratory tract infection; Preterm infant
We sought to determine the frequency and effects of nosocomial respiratory viral infections (RVIs) in premature neonates, including those who may be asymptomatic.
We performed a year-long surveillance for RVIs in infants <33 weeks gestational age admitted to two Syracuse neonatal intensive care units (NICUs). Infants were enrolled within 3 days of NICU admission and were sampled for RVIs until discharge using a multiplex PCR assay capable of detecting 17 different respiratory viruses or subtypes.
26 of 50 prematurely born infants (52%) tested positive for a respiratory virus at least once during their birth hospitalization. Testing positive for a respiratory virus was significantly associated with longer length of stay (70 days vs. 35 days, p = 0.002) and prolonged ventilatory support (51 vs. 13 days, p = 0.002). Infants who tested positive for a respiratory virus during their birth hospitalization had more than twice the rate of developing bronchopulmonary dysplasia (BPD; p < 0.05).
Nosocomial RVIs were frequent in our study population, despite the absence of clinical indicators of illness. Length of hospital stay was significantly longer and a diagnosis of BPD was more common in those premature infants who had respiratory viruses detected.
neonatal infection; respiratory viral infection; premature newborn