Cost-effectiveness analysis of phenotypic-guided versus guidelines-guided bronchodilator therapy in viral bronchiolitis.

OBJECTIVES: Although recent evidence suggests that management of viral bronchiolitis requires something other than guidelines-guided therapy, there is a lack of evidence supporting the economic benefits of phenotypic-guided bronchodilator therapy for treating this disease. The aim of the present study was to compare the cost-effectiveness of phenotypic-guided versus guidelines-guided bronchodilator therapy in infants with viral bronchiolitis. METHODS: A decision analysis model was developed to compare the cost-effectiveness of phenotypic-guided versus guidelines-guided bronchodilator therapy in infants with viral bronchiolitis. Phenotypic-guided bronchodilator therapy was defined as the administration of albuterol in infants exhibiting a profile of increased likelihood of response to bronchodilators. The effectiveness parameters and costs of the model were obtained from systematic reviews of the literature with meta-analyses and electronic medical records. The main outcome was the avoidance of hospital admission after initial care in the emergency department. RESULTS: Compared to guidelines-guided strategy, treating patients with viral bronchiolitis with the phenotypic-guided bronchodilator therapy strategy was associated with lower total costs (US$250.99; 95% uncertainty interval [UI]: US$184.37 to $336.51 vs. US$263.46; 95% UI: US$189.81 to $349.19 average cost per patient) and a higher probability of avoidance of hospital admission (0.7902; 95% UI: 0.7315-0.8356 vs. 0.7638; 95% UI: 0.7062-0.8201), thus leading to dominance. Results were robust to deterministic and probabilistic sensitivity analyses. CONCLUSIONS: Compared to guidelines-guided strategy, treating infants with viral bronchiolitis using the phenotypic-guided bronchodilator therapy strategy is a more cost-effective strategy, because it involves a lower probability of hospital admission at lower total treatment costs.

Use of palivizumab in primary practice.

OBJECTIVE: To describe the implementation of a program for the use of palivizumab in a general pediatrics office and evaluate adherence to the 2009 American Academy of Pediatrics (AAP) guidelines. METHODS: Pediatricians in a large practice were educated in the diagnosis and management of bronchiolitis, with specific attention to the AAP's palivizumab administration guidelines. During the 2009-2010 and 2010-2011 respiratory syncytial virus seasons, children were systematically identified and enrolled for palivizumab administration. Indication for administration was determined by gestational age, age at the beginning of the respiratory syncytial virus season, pertinent diagnoses, and presence of risk factors. RESULTS: In the 2009-2010 season, 161 children were enrolled to receive palivizumab, 86 of whom (53%) conformed with AAP guidelines. In contrast, in 2010-2011, a total of 85 children were enrolled to receive palivizumab, and 73 (86%) conformed with the guidelines. As a consequence, the total cost of palivizumab (US $: 511 559 vs 1 500 670) and the cost per child (US $: 6018 vs 9438) were lower in 2010-2011 than in 2009-2010. However, of the children selected within the AAP guidelines, only 29% received the appropriate number of doses, whereas 62% and 9% received fewer or excessive doses, respectively; these findings were similar for the 2 seasons. CONCLUSIONS: In a primary practice, use of palivizumab outside of the AAP guidelines was frequent and manifested as inadequate indications or inadequate number of doses. The former improved with education and standardization of care (suggesting provider problems), while the latter did not (suggesting system problems). Additional interventions are required.

Palivizumab for immunoprophylaxis of respiratory syncytial virus (RSV) bronchiolitis in high-risk infants and young children: a systematic review and additional economic modelling of subgroup analyses.

BACKGROUND: Respiratory syncytial virus (RSV) is a seasonal infectious disease, with epidemics occurring annually from October to March in the UK. It is a very common infection in infants and young children and can lead to hospitalisation, particularly in those who are premature or who have chronic lung disease (CLD) or congenital heart disease (CHD). Palivizumab (Synagis®, MedImmune) is a monoclonal antibody designed to provide passive immunity against RSV and thereby prevent or reduce the severity of RSV infection. It is licensed for the prevention of serious lower respiratory tract infection caused by RSV in children at high risk. While it is recognised that a policy of using palivizumab for all children who meet the licensed indication does not meet conventional UK standards of cost-effectiveness, most clinicians feel that its use is justified in some children. OBJECTIVES: To use systematic review evidence to estimate the cost-effectiveness of immunoprophylaxis of RSV using palivizumab in different subgroups of children with or without CLD or CHD who are at high risk of serious morbidity from RSV infection. DATA SOURCES: A systematic review of the literature and an economic evaluation was carried out. The bibliographic databases included the Cochrane Library [Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA)] and five other databases, from inception to 2009. Research registries of ongoing trials including Current Controlled Trials metaRegister, Clinical Trials.gov and the National Institute for Health Research Clinical Research Network Portfolio were also searched. REVIEW METHODS: Searches were conducted for prognostic and hospitalisation studies covering 1950-2009 (the original report searches conducted in 2007 covering the period 1950-2007 were rerun in August 2009 to cover the period 2007-9) and the database of all references from the original report was sifted to find any relevant studies that may have been missed. The risk factors identified from the systematic review of included studies were analysed and synthesised using stata. The base-case decision tree model developed in the original HTA journal publication [Health Technol Assess 2008;12(36)] was used to derive the cost-effectiveness of immunoprophylaxis of RSV using palivizumab in different subgroups of pre-term infants and young children who are at high risk of serious morbidity from RSV infection. Cost-effective spectra of prophylaxis with palivizumab compared with no prophylaxis for children without CLD/CHD, children with CLD, children with acyanotic CHD and children with cyanotic CHD were derived. RESULTS: Thirteen studies were included in this analysis. Analysis of 16,128 subgroups showed that prophylaxis with palivizumab may be cost-effective [at a willingness-to-pay threshold of £30,000/quality-adjusted life-year (QALY)] for some subgroups. For example, for children without CLD or CHD, the cost-effective subgroups included children under 6 weeks old at the start of the RSV season who had at least two other risk factors that were considered in this report and were born at 24 weeks gestational age (GA) or less, but did not include children who were > 9 months old at the start of the RSV season or had a GA of > 32 weeks. For children with CLD, the cost-effective subgroups included children < 6 months old at the start of the RSV season who were born at 28 weeks GA or less, but did not include children who were > 21 months old at the start of the RSV season. For children with acyanotic CHD, the cost-effective subgroups included children < 6 months old at the start of the RSV season who were born at 24 weeks GA or less, but did not include children who were > 21 months old at the start of the RSV season. For children with cyanotic CHD, the cost-effective subgroups included children < 6 weeks old at the start of the RSV season who were born at 24 weeks GA or less, but did not include children who were > 12 months old at the start of the RSV season. LIMITATIONS: The poor quality of the studies feeding numerical results into this analysis means that the true cost-effectiveness may vary considerably from that estimated here. There is a risk that the relatively high mathematical precision of the point estimates of cost-effectiveness may be quite inaccurate because of poor-quality inputs. CONCLUSIONS: Prophylaxis with palivizumab does not represent good value for money based on the current UK incremental cost-effectiveness ratio threshold of £30,000/QALY when used unselectively in children without CLD/CHD or children with CLD or CHD. This subgroup analysis showed that prophylaxis with palivizumab may be cost-effective (at a willingness-to-pay threshold of £30,000/QALY) for some subgroups. In summary, the cost-effective subgroups for children who had no CLD or CHD must contain at least two other risk factors apart from GA and birth age. The cost-effective subgroups for children who had CLD or CHD do not necessarily need to have any other risk factors. Future research should be directed towards conducting much larger, better powered and better reported studies to derive better estimates of the risk factor effect sizes. FUNDING: This report was funded by the HTA programme of the National Institute for Health Research.

Computerized acoustic assessment of treatment efficacy of nebulized epinephrine and albuterol in RSV bronchiolitis.

AIM: We evaluated the use of computerized quantification of wheezing and crackles compared to a clinical score in assessing the effect of inhaled albuterol or inhaled epinephrine in infants with RSV bronchiolitis. METHODS: Computerized lung sounds analysis with quantification of wheezing and crackles and a clinical score were used during a double blind, randomized, controlled nebulized treatment pilot study. Infants were randomized to receive a single dose of 1 mgr nebulized l-epinephrine or 2.5 mgr nebulized albuterol. Computerized quantification of wheezing and crackles (PulmoTrack) and a clinical score were performed prior to, 10 minutes post and 30 minutes post treatment. Results were analyzed with Student's t-test for independent samples, Mann-Whitney U test and Wilcoxon test. RESULTS: 15 children received albuterol, 12 received epinephrine. The groups were identical at baseline. Satisfactory lung sounds recording and analysis was achieved in all subjects. There was no significant change in objective quantification of wheezes and crackles or in the total clinical scores either within the groups or between the groups. There was also no difference in oxygen saturation and respiratory distress. CONCLUSION: Computerized lung sound analysis is feasible in young infants with RSV bronchiolitis and provides a non-invasive, quantitative measure of wheezing and crackles in these infants.

Bronchiolitis: assessment and evidence-based management.

Viral bronchiolitis is the commonest cause of hospital admission in young infants. Respiratory syncytial virus is responsible for most cases of bronchiolitis. Secondary bacterial infection is rare and antibiotics are seldom necessary. Most children with bronchiolitis develop only mild illness and can be managed at home. Infants born prematurely, those with pre-existing cardiac or respiratory disease, and infants in the first three months of life are more likely to need hospital admission. On current evidence, nebulised adrenaline, inhaled and systemic corticosteroids, and inhaled bronchodilators do not have a role in the routine management of infants with bronchiolitis.

Comparison of nebulized adrenaline versus salbutamol in wheeze associated respiratory tract infection in infants.

OBJECTIVE: (i) To assess the efficacy of bronchodilators in wheeze associated respiratory tract infection (WRTI); and (ii) To compare L-adrenaline with salbutamol in wheeze associated respiratory tract infection. DESIGN: Randomized controlled trial. METHOD: Ninety one children in age group of 2 months to 2 years with their 1st or 2nd episode of wheezing in association with fever and/or coryza were enrolled. Of these, 45 received L-adrenaline (0.1ml/kg/dose in 1 in 10,000 solution) (Group A) and 46 received salbutamol (0.1mg/kg/dose) (Group B). Three doses of each drug were given, nebulized with oxygen at 20 minutes intervals. Respiratory rate, RDAI score, clinical status and pulse oxymetry was recorded before intervention and 10 minutes after each dose. Patients who showed significant relief were discharged after an observation period of three hours while those who did not were admitted. RESULTS: Both L-adrenaline and salbutamol caused significant improvement in mean symptom score and oxygenation. However, the adrenaline group showed a significantly better improvement in the study parameters than the salbutamol group. More children in the adrenaline group could be sent home after the emergency treatment. CONCLUSION: Adrenergic agonists both specific and non specific are beneficial in WRTI. Adrenaline is more effective than salbutamol and is thus a better, inexpensive and relatively safe alternative.

Respiratory syncytial virus immune globulin: decisions and costs.

A decision analysis was used to evaluate the economic effectiveness of respiratory syncytial virus immune globulin (RSVIG) prophylaxis on selected pediatric populations at risk for developing RSV bronchiolitis or all respiratory illness-related hospitalizations. We compared costs, outcomes, and cost-effectiveness of administering RSVIG to no treatment in different pediatric populations, including those at risk of developing RSV-bronchiolitis and those at risk of developing any respiratory illness-related hospitalization. We observed that if only infants at high risk of severe RSV infections received treatment with RSVIG, a calculated cost saving of about 27,000 dollars per hospitalization prevented were realized. If the Food and Drug Administration (FDA)-approved indications for RSVIG were followed, the cost to prevent one hospitalization due to RSV bronchiolitis would be over 53,000 dollars. If the aim, however, was to prevent all respiratory illness-related hospitalizations for this broader population, a much lower cost (4,000 dollars) to prevent one hospitalization would result. In this situation, cost neutrality was possible, with a therapy cost of 2,843 dollars compared to the actual average therapy cost of 4,444 dollars. Sensitivity analysis showed that the model was relatively insensitive to all variables, with the exceptions of costs related to RSVIG and intensive care unit (ICU) admissions. We conclude that RSVIG resulted in cost savings if therapy were reserved for the infants who are at highest risk for developing severe RSV infections. RSVIG is not cost-effective for preventing RSV bronchiolitis when used according to the FDA-approved indications. Education that emphasizes frequent hand-washing, avoidance of passive smoking, and lessening exposure to sick children remains the least expensive prevention tool.

Efficacy of metered-dose inhaler administration of albuterol in intubated infants.

STUDY OBJECTIVE: To compare the safety and efficacy of metered-dose inhaler (MDI) albuterol to nebulized (NEB) albuterol administration. DESIGN: A randomized, triple-blinded, crossover study. SETTING: A pediatric ICU in a tertiary care children's hospital. PATIENTS: Eleven intubated infants with bronchiolitis. INTERVENTIONS: Subjects received four puffs of MDI albuterol (360 microg) and 3 mL of NEB saline solution placebo or 0.3 mL of NEB albuterol (1.5 mg) and MDI saline solution placebo. Each set of albuterol and saline solution placebo was administered after direct attachment of delivery device to the endotracheal tube and bag-valve system. Subjects received the opposite sequence 4 h after the initial sequence. The second sequence was given first the next day, and the first sequence was administered 4 h later. MEASUREMENTS AND RESULTS: Respiratory system compliance and resistance were measured at baseline and 30 min, 1 h, 2 h, and 4 h after each set of placebo and albuterol. There was an appreciable improvement in compliance and resistance for up to 2 h following both methods of administration. However, the degree of improvement was not significantly different (p>0.05) between the two methods. Neither method caused a significant change in resistance when measured at 4 h after albuterol/placebo administration. No evidence of toxicity was detected. CONCLUSIONS: MDI-administered albuterol is as safe and efficacious as nebulized-administered albuterol in intubated infants with bronchiolitis. Generalizability of these results is limited by differences in drug delivery with different brands of nebulizers and spacers and sites of attachment.

Treatment of respiratory syncytial virus bronchiolitis: 1995 poll of members of the European Society for Paediatric Infectious Diseases.

BACKGROUND: Among the lower respiratory tract infections during infancy requiring hospitalization, respiratory syncytial virus (RSV) bronchiolitis is the most frequent disease entity. Nevertheless treatment remains controversial. METHODS: A poll among the European Society for Paediatric Infectious Diseases (ESPID) members was conducted to determine the respective local and national treatment policies of RSV bronchiolitis. RESULTS: The questionnaire was returned by 88 centers represented in ESPID (response rate 64%). Ribavirin was used occasionally for high risk patients in 34 centers although 16 hospitals follow the guidelines of the Red Book Committee of the American Academy of Pediatrics. There were no centers using ribavirin for all patients. Bronchodilator treatment was used universally in various combinations for all patients in 54 centers and for all high risk patients in 15. Corticosteroids were used by > 80% of ESPID colleagues in various combinations of administration routes. CONCLUSION: The lack of effective treatment for RSV bronchiolitis and the controversy in the literature concerning antiviral, bronchodilator and antiinflammatory therapy leads to inconsistent treatment strategies.

Acute viral bronchiolitis in infancy: epidemiology and management.

Acute bronchiolitis due to viral agents (RSV, parainfluenza, influenza, adenovirus) is a relatively frequent disease of infancy. Seasonal epidemic pattern have been recognized, and nosocomial infections in pediatric wards occur. Until age 2 years most children have experienced some form of airway disease attributable to RSV. Some patients require hospital treatment; about 15% of our patients had to be transferred to the intensive care unit. Bronchiolitis seems to be frequently the first manifestation of asthma and we found higher IgG antibody titers to viruses causing bronchiolitis in children with asthma than in controls. Retrospective analysis of the charts of 147 cases of bronchiolitis revealed considerable uncertainty regarding therapeutic concepts. Mainstays of conservative therapy include oxygen, adequate hydration (often IV), and sometimes bronchodilators (based on the clinical impression of effectiveness in the individual patient). Mist therapy and secretolytic agents remain popular, although no clinical effect has been demonstrated. Attention should be directed toward the relief of upper airway obstruction caused by swelling, secretions, and nasogastric tubes. Oxygen administration in infants with coexisting chronic airway disease (e.g., BPD) and bronchiolitis may cause CO2 retention. Bronchodilators can cause hypoxia and increase bronchial compressibility by reducing smooth muscle tone. However, in severe cases a trial under pulse oximetry control seems worthwhile. Steroids seem to bring no clinical improvement, except in infants with protracted wheezing after bronchiolitis and patients with preexisting BPD.

Economic and long-term benefits of ribavirin therapy on respiratory syncytial virus infection.

Ribavirin is a broad-spectrum antiviral agent. Administered as an aerosol, it has been shown to be clinically effective in improving the signs and symptoms of viral bronchiolitis in infancy, particularly cases due to respiratory syncytial virus (RSV). This paper reviews the evidence for economic and/or long-term clinical benefits from using ribavirin in the acute illness. There are data to suggest that use of ribavirin may lead to a reduction in therapeutic interventions and duration of hospital stay, with associated savings in hospital costs. Ribavirin reduces the production of RSV-specific IgE, and (in vitro) inhibits the release of inflammatory mediators from mast cells, suggesting that there could be beneficial effects on the incidence of postbronchiolitis wheezing. Confirmatory studies are in progress.