key: cord-021894-lq8yr710 authors: Cunningham, Steve title: Bronchiolitis date: 2018-03-13 journal: Kendig's Disorders of the Respiratory Tract in Children DOI: 10.1016/b978-0-323-44887-1.00024-9 sha: doc_id: 21894 cord_uid: lq8yr710 Acute viral bronchiolitis is a common viral lower respiratory tract infection in young children. Most typically caused by respiratory syncytial virus in 70% of cases, the condition lasts for 4 to 7 days, with a prolonged cough in many. Children with comorbidity, particularly those born prematurely or with significant congenital heart disease, are at risk of more severe disease. Nasal obstruction progresses over 3 to 4 days to difficulty with feeding and increased work of breathing with hypoxemia. Crackles and/or wheeze may be auscultated. Apnoea may be a presenting sign in those less than 3 months of age. Viral load is highest at peak of symptoms and in those with more severe disease. Approximately 2% to 3% of all children are admitted to hospital with bronchiolitis. The differential diagnosis may include bacterial pneumonia, congenital lesions of the lung or heart, or an interstitial lung disease. There are no effective treatments, and admission is for feeding support (by nasogastric or intravenous fluids) or treatment of hypoxemia. Critical care support is required for some infants experiencing respiratory failure, though mortality rates remain unchanged. Practice within and between countries varies significantly and alignment of practice is a common goal of guidelines. Vaccines for RSV are in advanced development, as are several antiviral therapies for RSV. In most children, acute symptoms improve within 5 to 7 days and cough by 2 weeks. Recurrent wheeze is common following acute bronchiolitis and a good association with a diagnosis of asthma in childhood. RSV infects 69% to 98% of infants in the first year of life. 18, 19 The rapid development of vaccines and treatment therapies for RSV has added impetus to the need to better define the burden of RSV disease. Globally there are an estimated 33.8 million cases of RSV lower respiratory tract infection each year in children under 5 years of age, resulting in 3.4 million admissions to the hospital and 66 to 199 thousand deaths (with the majority in low-and middle-income countries). 20 In the United States an estimated 20% of children will attend primary care each year with RSV bronchiolitis, and up to 7% attend an Emergency Department (ED). 21 Admission to hospital with RSV bronchiolitis is typically around 2.4% of all infants, 15, 22 though in previously healthy term infants, the admission rate to hospital with RSV bronchiolitis can be as low as 0.7%. 23 In infants who are born preterm at 32 to 35 weeks' gestation, 48% will develop bronchiolitis and 6% require admission to the hospital. 24 The risk of bronchiolitis is increased in a range of conditions compared with term infants, including preterm birth (respiratory rate [RR] 1. 89) , cystic fibrosis (RR 2.45), congenital heart disease (RR 3.35), chronic lung disease (RR 1.61), immunodeficiency (RR 1.73), Down syndrome (RR 2.53), and cerebral palsy (RR 2.43). 25, 26 Epidemiology Bronchiolitis is the most common lower respiratory tract infection in children. The condition forms part of the spectrum of viral lower respiratory tract infection that includes bronchiolitis, viral pneumonia, and viral-induced wheeze. In polar hemispheres (north and south), bronchiolitis is a seasonal disease, dominating winter months, with a peak over 6 to 8 weeks around the winter solstice. In tropical climates, the disease is associated with rainy months and is seasonally more dispersed. 1 Climate and environment appear to influence both season and severity. 2, 3 Bronchiolitis is diagnosed clinically by integrating characteristic but variable signs and symptoms across a broad age range, though the majority of cases occur in children under 1 year of age. The condition can be caused by any respiratory virus and has a wide spectrum of disease severity. 4 A "classic" case would be an infant aged 3 to 5 months of age 5 who develops coryza and over the subsequent 3 to 4 days has increased difficulty with breathing, and consequent inability to maintain adequate oral feeding. Wheeze or crackles can be heard on auscultation. Improvement occurs by days 5 to 7, though a characteristic harsh cough may persist for 21 days or more. 6, 7 While the diagnosis often appears straightforward, the wide range of disease severity across a skewed but broad age range and the need for clinical diagnosis (with associated inconsistency) creates difficulty in establishing precise data. 8 In addition, while bronchiolitis is a clinical diagnosis applied to any infecting agent, the majority of data available relate to bronchiolitis caused by respiratory syncytial virus (RSV) infection; and within RSV bronchiolitis is a focus on those at high risk, in particular, those born prematurely. Reference to these groups synonymously with bronchiolitis can make interpretation of epidemiological data difficult and may reduce the understanding of bronchiolitis caused by non-RSV and in lower risk patients (particularly children born at term). There are only limited estimates of population risk for bronchiolitis associated with all respiratory virus infections, but approximately 40% of infants are affected by bronchiolitis in the first year of life. 9 In the United Kingdom, using primary care databases, the 1 year incidence of children given a specific diagnosis of bronchiolitis is 58 to 65 per 1000 children, 8, 10 rising to 204 per 1000 when a broader definition of bronchiolitis was used to capture potential cases. 8 This study highlights that in children with typical lower respiratory tract signs and symptoms, clinicians may not ascribe the discrete diagnosis of bronchiolitis; a finding also found KEYWORDS bronchiolitis viral lower respiratory tract infection wheeze respiratory syncytial virus ABSTRACT Acute viral bronchiolitis is a common viral lower respiratory tract infection in young children. Most typically caused by respiratory syncytial virus in 70% of cases, the condition lasts for 4 to 7 days, with a prolonged cough in many. Children with comorbidity, particularly those born prematurely or with significant congenital heart disease, are at risk of more severe disease. Nasal obstruction progresses over 3 to 4 days to difficulty with feeding and increased work of breathing with hypoxemia. Crackles and/or wheeze may be auscultated. Apnoea may be a presenting sign in those less than 3 months of age. Viral load is highest at peak of symptoms and in those with more severe disease. Approximately 2% to 3% of all children are admitted to hospital with bronchiolitis. The differential diagnosis may include bacterial pneumonia, congenital lesions of the lung or heart, or an interstitial lung disease. There are no effective treatments, and admission is for feeding support (by nasogastric or intravenous fluids) or treatment of hypoxemia. Critical care support is required for some infants experiencing respiratory failure, though mortality rates remain unchanged. Practice within and between countries varies significantly and alignment of practice is a common goal of guidelines. Vaccines for RSV are in advanced development, as are several antiviral therapies for RSV. In most children, acute symptoms improve within 5 to 7 days and cough by 2 weeks. Recurrent wheeze is common following acute bronchiolitis and a good association with a diagnosis of asthma in childhood. For infants born ≤ 32 weeks gestation, 75% of infants will have a lower respiratory tract infection in the first year of life, with 35% RSV positive and 40% RSV negative; of these infants, 41% of RSV positive will be admitted to the hospital versus 18% of RSV negative. 27 Recent studies suggest that hospitalization rates for high-risk infants due to RSV are reducing over time and are now similar to those for RSV negative, possibly as a result of improvements in neonatal care or immunoprophylaxis in high-risk groups ( Fig. 24 .1). 28, 29 Risk of death is much higher amongst high-risk groups who are RSV positive, including preterm (1.2%), congenital heart disease (5.2%), and bronchopulmonary dysplasia (7.0%). 17 Bronchiolitis has a viral etiology, with RSV the most common cause, reported in 43% to 75% 30,31 of cases. Other viruses associated with bronchiolitis are human rhinovirus (18%), influenza, coronavirus, human metapneumovirus, adenovirus, parainfluenza virus and human Boca virus 30, 31 ; that is, "any respiratory virus." RSV has two strains, A and B, with RSV A associated with more severe disease. 32, 33 Reinfection in the same season with the same or different strain is possible. 34 As a sole infecting agent, RSV is associated with more severe bronchiolitis than other single respiratory virus infections. 5 Coinfection of RSV with rhinovirus can produce even more severe disease. 35 RSV is the most common infectious agent in children admitted to the hospital with radiological features consistent with pneumonia (occurring in 28% of children-most commonly those under 5 years of age). 36 In young children who are well immunized, RSV represents the most common cause of lower respiratory tract infection. 37 What commences as an upper respiratory tract infection becomes a lower respiratory tract infection over the course of 2 to 5 days. Infants are particularly susceptible as they have small bronchi that are more likely to become blocked by secretions and edema, and a less well-developed ability to respond to and clear viral infection. 38 Histopathology is naturally limited to the most severe cases who have died, where the bronchioles are edematous and blocked by necrotic epithelium and neutrophils, with some mucus binding this debris together. 39 Airway obstruction is intensified by poor airway clearance associated with loss of cilia function occurring within 24 hours and persisting for up to 3 months after the illness. 40 Destruction of cilia is considered to be caused by virus replication and not mediated by inflammation. 38 RSV is associated with more severe airway pathology than that found in children dying from other respiratory viruses, even in those not mechanically ventilated. 39 Viral shedding is higher and more prolonged in younger infants and those with more severe disease. 41 Increased disease severity, longer hospital stay and use of intensive care is associated with higher viral load for RSV in nasopharyngeal secretions. 42, 43 Severity of disease is associated with both infant risk factors (including lack of adaptive T cell response), 26,44 but also RSV virus specific factors (viral antigen load and direct cytotoxic effects). 45 Determining the relative contribution of both of these to disease severity will be important; if the latter is dominant, antiviral agents provided early in the course of the disease may reduce severity, whereas dominance of the former might need additional immunomodulators. 4 Biomarkers are now sought to better characterize those at risk of greater disease severity and to indicate recovery. Infants hospitalized with RSV bronchiolitis have increased interleukin (IL)-33 and IL-13 in secretions. 46 Polymorphisms of surfactant protein A are associated with increased risk of intensive care admission. 47 Cysteinyl leukotrienes are increased in infants with RSV bronchiolitis and are still increased 1 month following infection. 48 More severe disease is also associated with increased serum cathelicidin, 49 lactate dehydrogenase, caspase 50 and IL-15. 51 There is some evidence that more severe disease may be associated with an insufficient inflammatory response. 52 The interrelationship of the microbiome in bronchiolitis is also being actively explored. 53 Bronchiolitis is diagnosed clinically. Variance in the clinical interpretation of symptoms and physical findings lead to inconsistency in diagnosis, particularly in milder cases and children over 1 year of age. Typical symptoms are rhinorrhea, proceeding over 2 to 4 days to a characteristic harsh moist cough with pyrexia that is typically below 39°C, although fever above 38.5°C is seen in 50% of infants. 54 Ability to achieve adequate oral feeding declines as nasal obstruction with secretions develops and work of breathing increases. The time to peak symptoms of 4 days is associated with the peak in viral load, 42, 55 varying from infant to infant. In younger children (particularly <6 weeks of age), apnea may be a presenting sign, sometimes in the absence of other features of bronchiolitis. Apnea may be temporarily improved by nasal suctioning, but it is most likely a direct viral effect in young infants. 56 Apnea is a "red flag" sign in bronchiolitis that warrants a period of review in a supervised clinical setting to ensure that it has resolved. Patients more likely to require intensive care include preterm infants and those with apnea, low birth weight, or a respiratory rate greater than 70/min. 57, 58 Children tend not to relapse during the improving phase of the illness, which should give confidence to clinicians when considering discharge from ED or hospital. 58, 59 Physical findings include an increased respiratory rate, chest recession, use of accessory muscles, hyperinflation, wheezing, crackles, and reduced arterial oxygen saturations. 60 Physical findings vary depending on sleep state (and associated changes in tidal volume). Respiratory rate is a key marker of disease severity, with ≥60/min considered severe and ≥70/ min critical. 26, 61 Oxygen saturation may be improved (at least temporarily) by removal of nasal secretions. 62 Bronchiolitis is a highly variable disease that requires assessment of disease severity by clinicians for decision making, some of which is subjective. Clinical scoring systems have been developed in an attempt to standardize care and minimize variance. Many early scores derived from asthma scores. The most commonly applied scores for bronchiolitis are outlined in 65 ) and to improve the ability to identify those at risk of deterioration. The ability of clinical scores to retain precision and reliability, when scoring is performed by larger numbers of health care professionals in the context of multicenter Phase III trials, is of current interest. Symptoms in bronchiolitis vary across a wide but skewed continuum from mildly increased work of breathing with cough to respiratory failure and death. Often divided into mild, moderate, and severe disease, the perspective on these gradations varies across health care systems. A World Health Organization (WHO) workshop has provided candidate definitions differentiating a diagnosis of RSV lower respiratory tract infection (SpO 2 <95%) from severe (<93%) and very severe RSV disease (SpO 2 <90%, inability to feed orally, or reduced level of consciousness). 66 Infants can display variance in SpO 2 within this range (90% to 95%) over short periods of observation without significant change in clinical status, 58,62,67 which may limit the discriminatory reliability of these definitions. From a secondary care perspective, moderate severity is often considered a need for admission to hospital and severe by need for critical care (positive pressure support). Clinical scores are often designed to identify transition points in the level of care required. 64 The currently available evidence concerning transition points in level of care is poor. Treatment guidance, particularly benefit from use of interventions at the ED/Ward (i.e., SpO 2 ) 68 and ward/critical care floor interface (i.e., highflow nasal cannula [HFNC] oxygen and continuous positive airway pressure [CPAP]) is much needed. Guidelines have provided signs and symptoms that should alert clinicians to a child at risk of deterioration and suggested criteria for admission to the hospital. 26 In hospitals, those most likely to deteriorate to the extent of being provided with critical care support are of lower birth weight (<5 lbs, 2.25 kg) and/or have a respiratory rate ≥70/min on day 1 of admission. 57 Chest radiography is not required to confirm a diagnosis of bronchiolitis. A chest radiograph often leads to increased diagnostic uncertainty as the features may be similar to those of pneumonia (atelectasis, mucous plugging, and loss of volume) and consequently lead to greater inappropriate use of antibiotics. 69 Chest radiography should be reserved for a child who is atypical, for example, showing persistently focal crackles, a temperature remaining above 39°C despite antipyretics, or respiratory failure requiring critical care support. 26, 70 Laboratory tests do not aid in the clinical diagnosis of bronchiolitis. Serious bacterial infection is unusual and complete blood counts and blood cultures are unhelpful (though recent evidence suggests that although still uncommon, it may be more frequent than previously considered). 65 Dehydration is usually mild and best assessed clinically without electrolyte measurement. Approximately 6% of infants with bronchiolitis can have concurrent urinary tract infection, so urine culture may be of value in persistently febrile infants, particularly those under 3 months of age. 71 Measurement of arterial/capillary carbon dioxide is commonly performed, but can be restricted to those children with increased respiratory rate and work of breathing despite oxygen supplementation. 72 The clinical interpretation of signs and symptoms is difficult in a condition where age boundaries are loose (and skew to older ages in those with comorbidity) and symptoms vary from patient to patient and time to time. This naturally leads to variation in diagnosis and differential diagnosis. There is a common understanding that a clearer diagnosis is possible in those under 1 year of age and most guidelines reflect this. However, constraining a diagnosis of bronchiolitis to those less than 1 year of age may reduce the ability to identify the whole population of children with bronchiolitis who could benefit from potential interventions. In general, a broader bronchiolitis) is often performed to aid cohorting of patients within hospitals. The increasing recognition that multiple viruses may be identified in those with acute bronchiolitis has called into question the benefit of cohorting based on RSV status. 78 PCR diagnostics may sometimes be considered oversensitive to the detection of virus fragments postinfection, and multiplex PCR results should be interpreted with this understanding. Differential diagnosis includes bacterial pneumonia or an alternative cause of crackles, wheeze, and increased work of breathing in a young child. Persisting crackles (crepitations) in one lung zone, fixed focal wheeze, persistent pyrexia (>39°C) or persistently increased work of breathing in a child who appears otherwise recovered warrant further evaluation. Prescient in the mind of most clinicians is that a bacterial pneumonia may be missed. Chest radiographs have similar appearances and are poor discriminators. We can assume that bacterial coinfection risk is low, as the use of antibiotics in bronchiolitis is not associated with faster recovery. 79 Further investigation could be limited to those with the persisting clinical features noted above. In children with more severe disease, there may be a role for antibiotics as bacteria are isolated in 33% to 44% of lavage samples in children with severe bronchiolitis who are intubated and ventilated. [80] [81] [82] definition of bronchiolitis is used in North America and Asia that captures a higher percentage of older children with wheezing, where rhinovirus is the dominant infecting agent. 73 Such children may be given a diagnosis of viral induced wheeze in other countries. There is most likely a continuum of viral lower respiratory tract infection across age ranges that moves from current diagnoses of viral bronchiolitis to viral pneumonia and viral-induced wheeze/wheezy bronchitis. 74, 75 The clinical features consistent with a diagnosis of bronchiolitis across different guidelines are presented in Table 24 .2. Diagnosis has a typical onset of a viral respiratory tract prodrome proceeding to lower respiratory symptoms over 3 to 4 days. The South African guideline (2010) considers hyperinflation the most reliable clinical sign in bronchiolitis. 76 The UK guideline (2015) provides a more proscriptive definition. 26 Testing of nasal secretions for virus may help consolidate the clinical diagnosis of bronchiolitis and inform health care logistics. Most commonly used, and with highest precision, are polymerase chain reaction (PCR) diagnostics for a range of respiratory viruses, but point of care (PoC) testing for a more limited range of viruses (most often RSV) is increasingly precise and cost effective. 77 Testing for RSV (as the most common infecting agent in therapies in addition to supplemental oxygen and hydration are poorly supported by current evidence. There is some evidence that infants handled less get better quicker, 87 and the use of additional therapies should be considered with that in mind. There is widespread variation across hospitals and countries in the management and treatment of bronchiolitis reflecting local custom and individual clinician practice. 88 Reducing variation and associated health care costs is a key aim of bronchiolitis management presented through guidelines. Guidelines for the care of infants with bronchiolitis based on systematic review and published in English are available from the United Kingdom (2015), 89 92 and South Africa (2010), 76 which has been updated as a critical review 2016. 93 No therapies receive support across all guidelines for use with the exception of supplemental oxygen. Chest physiotherapy does not speed recovery. Antibiotics, though still widely used, are of no benefit in bronchiolitis. 79 In addition, bronchodilators are less likely to be recommended in more recent guidelines, and the theory that they may be of greater benefit in infants more likely to develop asthma has been refuted. 94 Nebulized hypertonic saline has been of benefit in cystic fibrosis and in early trials in bronchiolitis, 95 but larger well-designed trials have not demonstrated a persuasive benefit. [96] [97] [98] [99] [100] Recent years have seen the increasing use of HFNC oxygen in acute bronchiolitis. 101 Though clinical trials have not yet demonstrated important clinical or physiological benefits, 102 large well-designed trials are in progress and are beginning to report. 102a,103 CPAP has some benefit in bronchiolitis, and may prevent deterioration when used early. 104 As with all management in bronchiolitis, the use of HFNC oxygen, CPAP, and intubation varies across sites irrespective of disease severity, 105 and better understanding of the risks and benefits of these interventions is required. 106 There are no current effective pharmacological treatments for RSV. While ribavirin was previously used as an antiviral treatment for RSV, it is now considered ineffective. 107 Novel treatments for acute infection are in development: antivirals and nebulized immunoglobulin. In this rapidly moving field, it seems probable that a treatment for RSV will become available in the next 5 years. 108 Reduction in viral load has been demonstrated in adult challenge models of RSV treated with the antivirals ALS-8176 109 and GS-5806 110 Prevention of spread of RSV depends on good hygiene, in particular, hand washing, as RSV may survive for up to 6 hours on surfaces contaminated by droplets. 111 Similar precautions are appropriate for other respiratory virus infections associated with bronchiolitis. Many hospitals use PoC testing for RSV to determine cohorting of infants as inpatients. 107 While this is still common, the practice is called into question by the range of coinfection with other respiratory viruses revealed by PCR panel testing; up to 62% of children with viral respiratory tract infection have more than one virus detected. 112 Prevention of RSV (as the most common cause of bronchiolitis) has been a long-term goal. Early formalin inactivated There are no trials of outcome for antibiotic use in children with bronchiolitis receiving intensive care. Though uncommon, congenital lesions may masquerade as bronchiolitis, and this should be borne in mind for children with atypical clinical features or those slow to recover. Congenital heart disease may present as bronchiolitis when pulmonary vascular resistance falls increasing left to right shunt. More difficult to differentiate are children with congenital (or less commonly acquired) pulmonary malformations. Fixed focal wheeze may be a sign of tracheomalacia or bronchomalacia, stenosis, or compression from lobar emphysema or a bronchogenic cyst and would warrant a chest radiograph. A slow recovering course with persistent chest signs could be an infected congenital pulmonary malformation (such as a congenital cystic adenomatoid malformation [CCAM] or sequestration). Children with persistent fine crackles, tachypnea, and low (often borderline) oxygen saturation may have an interstitial lung disease, particularly neuroendocrine cell hyperplasia (NEHI) presenting as recurrent "bronchiolitis." Young children with persistent, sometimes focal, crackles postadenovirus (though may also be other respiratory viruses and mycoplasma pneumonia) should be evaluated for postinfectious bronchiolitis obliterans (PIBO); see section 6 of the book. Management of bronchiolitis is supportive, assisting hydration and hypoxemia until improvement. With increased respiratory rate and nasal secretions, oral feeding is challenged, and those with severe disease require assistance with feeding by enteral or parenteral means. The threshold for supporting hydration is typically when an infant's intake is reduced to 50% to 75% of usual volume. The chosen percentage of intake depends on the child's status: an expreterm 10-week-old infant on day 3 of illness may be supported at 75% understanding that they most likely will deteriorate, whereas a robust 8-month-old term infant may be able to tolerate 50% feed volume for a couple of days until disease resolution. Nasogastric feeding is easier to administer than intravenous fluids but has no advantage in recovery from acute disease. 83 Oxygen may be used to treat hypoxemia. The threshold oxygen saturation at which to use supplemental oxygen varies across guidelines and is typically set between 90% and 94% at sea level. In children admitted to hospital with bronchiolitis, management at a threshold of 90% SpO 2 is safe and as clinically effective as a 94% target. 84 The threshold oxygen saturation for admission to hospital is often 92%, as some data suggest that infants have a higher risk of desaturating further at this oxygen saturation. 85 Oxygen desaturation may however have a disproportionate influence on decisions to admit children to the hospital, 68 and much like hydration status (previously mentioned), the context of the measurement should be considered. Many infants discharged home from ED with bronchiolitis experience desaturation events subsequently that are not associated with clinical deterioration. 67 In hospitals, the use of intermittent oxygen saturation monitoring is much discussed, and though the benefit below 90% SpO 2 is not established, once stable above 90% SpO 2 , oxygen saturation monitoring should be stopped. 86 Use of bronchiolitis occurs in 62% of those who are RSV positive and 32% of those who are RSV negative. 120 Recurrent postinfectious wheeze is not reduced by montelukast 121 or inhaled corticosteroids, 122, 123 but there is good evidence of benefit from Palivizumab, 124 and potentially azithromycin, 125 though the latter requires further study. In the longer term, there is good evidence that children who have had an admission to the hospital for RSV bronchiolitis are 3 times more likely to have a diagnosis of asthma and lower lung function at age 6 years 23 and a higher incidence of asthma at age 13 126 and 18 127 years. The question remains whether such children are predisposed to bronchiolitis because of premorbid anatomy 119 and the consequent interrelationship between host and virus specific effects on the development of asthma. vaccines were associated with more severe enhanced RSV disease and deaths, possibly resulting from inadequate T cell priming. 113 Subsequent vaccine development has been cautious in view of this experience. In the 1990s, RSV intravenous immunoglobulin was developed 114, 115 but was rapidly superseded by palivizumab, a monoclonal antibody delivered by monthly intramuscular injection. When administered over the RSV season, it reduces hospital admission in high-risk infants. 116 Palivizumab's monthly injections and limited efficacy have prompted the development of extended life monoclonal antibodies that are undergoing licensing trials in preterm infants. 117 They will hopefully be evaluated in the future for high-risk infants born at term. RSV vaccine development has gained significant impetus over the last 15 years with a wide range of candidate vaccines in development both for pediatric and maternal use; maternal immunization could provide passive transplacental protection to infants in the first 3 to 6 months of life (http:// www.path.org). A Phase III trial of maternal immunization by Novovax is expected to conclude in 2020. For most children, bronchiolitis is a self-limiting disease, with cough as the most persistent symptom resolving at a median of 12 to 15 days. 84, 118 Many children, however, develop recurrent respiratory symptoms. In the first few months following illness, this is considered in part to result from loss of cilia from the airway epithelial surfaces during the acute illness. 40 For those who experience chronic symptoms, the debate continues on whether children with more severe bronchiolitis and recurrent postinfectious wheezing have premorbid susceptibility, with some evidence suggesting poorer preexisting lung function. 119 Recurrent wheeze in the year following Oxygen saturation targets in infants with bronchiolitis (BIDS): a double-blind, randomised, equivalence trial SABRE: a multicentre randomised control trial of nebulised hypertonic saline in infants hospitalised with acute bronchiolitis Nebulized hypertonic saline for bronchiolitis in the emergency department: a randomized clinical trial 7% Hypertonic saline in acute bronchiolitis: a randomized controlled trial 3% hypertonic saline versus normal saline in inpatient bronchiolitis: a randomized controlled trial The effect of 3% and 6% hypertonic saline in viral bronchiolitis: a randomised controlled trial Nebulized hypertonic saline for bronchiolitis: a randomized clinical trial Risk factors for bronchiolitis, recurrent wheezing, and related hospitalization in preterm infants during the first year of life Chronic diseases, chromosomal abnormalities, and congenital malformations as risk factors for respiratory syncytial virus hospitalization: a population-based cohort study Bronchiolitis: diagnosis and management in children Prospective study of healthcare utilisation and respiratory morbidity due to RSV infection in prematurely born infants Trends in respiratory syncytial virus and bronchiolitis hospitalization rates in high-risk infants in a United States Nationally Representative Database Respiratory syncytial virus hospitalization trends in infants with chronic lung disease of infancy Viral etiologies of infant bronchiolitis, croup and upper respiratory illness during 4 consecutive years Viral etiology of bronchiolitis among pediatric inpatients in northern Taiwan with emphasis on newly identified respiratory viruses Occurrence of groups A and B of respiratory syncytial virus over 15 years: associated epidemiologic and clinical characteristics in hospitalized and ambulatory children Severity of respiratory syncytial virus infection is related to virus strain Immunity to and frequency of reinfection with respiratory syncytial virus Association of rhinovirus infection with increased disease severity in acute bronchiolitis Community-acquired pneumonia requiring hospitalization among U.S. adults Aetiology of childhood pneumonia in a well vaccinated South African birth cohort: a nested casecontrol study of the Drakenstein Child Health Study Respiratory syncytial virus (RSV) and its propensity for causing bronchiolitis Pecularities of lesions in viral and mycoplasma infections of the respiratory tract Recovery of the ciliated epithelium following acute bronchiolitis in infancy Respiratory syncytial virus infections in infants: quantitation and duration of shedding Respiratory syncytial virus genomic load and disease severity among children hospitalized with bronchiolitis: multicenter cohort studies in the United States and Finland Respiratory syncytial virus load, viral dynamics, and disease severity in previously healthy naturally infected children Type 1 and type 2 cytokine imbalance in acute respiratory syncytial virus bronchiolitis Viral specific factors contribute to clinical respiratory syncytial virus disease severity differences in infants Respiratory syncytial virus disease is mediated by age-variable IL-33 Surfactant protein A2 polymorphisms and disease severity in a respiratory syncytial virus-infected population Latitudinal variations in seasonal activity of influenza and respiratory syncytial virus (RSV): a global comparative review Altitude and environmental climate effects on bronchiolitis severity among children presenting to the emergency department Environmental drivers of the spatiotemporal dynamics of respiratory syncytial virus in the United States Viral bronchiolitis in children Epidemiology of respiratory syncytial virus bronchiolitis in hospitalized infants in Greece Duration of illness in ambulatory children diagnosed with bronchiolitis Duration of illness in infants with bronchiolitis evaluated in the emergency department The clinical burden of respiratory syncytial virus (RSV) bronchiolitis among infants in the United Kingdom (UK) [PhD]: Imperial College Epidemiology of respiratory syncytial virus infection in Washington, DC. II. Infection and disease with respect to age, immunologic status, race and sex A comparison of the recording of 30 common childhood conditions in the Doctor's Independent Network and General Practice Research Databases Viral respiratory tract infections in the first six months of life Evaluation of hospitalized infants and young children with bronchiolitis-a multi centre study Trends in bronchiolitis hospitalizations in the United States Admission to hospital for bronchiolitis in England: trends over five decades, geographical variation and association with perinatal characteristics and subsequent asthma Risk factors for hospital admission with RSV bronchiolitis in England: a population-based birth cohort study International variation in the management of infants hospitalized with respiratory syncytial virus. International RSV Study Group The risk of mortality among young children hospitalized for severe respiratory syncytial virus infection Risk of primary infection and reinfection with respiratory syncytial virus Respiratory-syncytialvirus infections, reinfections and immunity. A prospective, longitudinal study in young children Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis The burden of respiratory syncytial virus infection in young children Hospitalizations associated with influenza and respiratory syncytial virus in the United States Increased risk of wheeze and decreased lung function after respiratory syncytial virus infection G489 blood gas analysis in acute bronchiolitis-who and when? A clustering approach to identify severe bronchiolitis profiles in children Deciphering clinical phenotypes in acute viral lower respiratory tract infection: bronchiolitis is not an island Variability in the diagnostic labeling of nonbacterial lower respiratory tract infections: a multicenter study of children who presented to the emergency department South African guideline for the diagnosis, management and prevention of acute viral bronchiolitis in children Rapid point of care diagnostic tests for viral and bacterial respiratory tract infections-needs, advances, and future prospects Co-infections in children hospitalised for bronchiolitis: role of roomsharing Antibiotics for bronchiolitis in children under two years of age High incidence of pulmonary bacterial co-infection in children with severe respiratory syncytial virus (RSV) bronchiolitis Pulmonary and systemic bacterial co-infections in severe RSV bronchiolitis Concurrent bacterial infection and prolonged mechanical ventilation in infants with respiratory syncytial virus lower respiratory tract disease Nasogastric hydration versus intravenous hydration for infants with bronchiolitis: a randomised trial Oxygen saturation targets in infants with bronchiolitis (BIDS): a double-blind, randomised, equivalence trial Predictors of major intervention in infants with bronchiolitis Intermittent monitoring of oxygen saturation in infants and children with acute bronchiolitis: peekaboo pediatrics or good clinical care? Racemic adrenaline and inhalation strategies in acute bronchiolitis Variability in inpatient management of children hospitalized with bronchiolitis Bronchiolitis in children: summary of NICE guidance Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis Clinical practice guideline on acute bronchiolitis. clinical practice guidelines in the Spanish National Healthcare System Finnish guidelines for the treatment of laryngitis, wheezing bronchitis and bronchiolitis in children Acute viral bronchiolitis in South Africa: strategies for management and prevention Allergic diseases and the effect of inhaled epinephrine in children with acute bronchiolitis: follow-up from the randomised, controlled, double-blind, Bronchiolitis ALL trial Nebulized hypertonic saline for acute bronchiolitis: a systematic review 3% Hypertonic saline versus normal saline in inpatient bronchiolitis: a randomized controlled trial Nasal lavage leukotrienes in infants with RSV bronchiolitis Serum cathelicidin level is associated with viral etiology and severity of bronchiolitis Lactate dehydrogenase and caspase activity in nasopharyngeal secretions are predictors of bronchiolitis severity. Influenza Other Respir Viruses Interleukin-15 is associated with disease severity in viral bronchiolitis A robust cytokine and chemokine response in nasopharyngeal secretions is associated with decreased severity in children with physician diagnosed bronchiolitis Nasopharyngeal bacterial burden and antibiotics: influence on inflammatory markers and disease severity in infants with respiratory syncytial virus bronchiolitis North Ryde: NSW Ministry of Health Virus type and genomic load in acute bronchiolitis: severity and treatment response with inhaled adrenaline The G glycoprotein of respiratory syncytial virus depresses respiratory rates through the CX3C motif and substance P Risk factors for requiring intensive care among children admitted to ward with bronchiolitis Effect of oxygen supplementation on length of stay for infants hospitalized with acute viral bronchiolitis Hospital course and discharge criteria for children hospitalized with bronchiolitis Inter-observer agreement between physicians, nurses, and respiratory therapists for respiratory clinical evaluation in bronchiolitis Bronchiolitis: recommendations for diagnosis, monitoring and management of children one to 24 months of age Is nasal suctioning warranted before measuring O2 saturation in infants with bronchiolitis? Wheezing in infants: the response to epinephrine Measuring clinical severity in infants with bronchiolitis Bacteremia in children hospitalized with respiratory syncytial virus infection WHO consultation on Respiratory Syncytial Virus Vaccine Development Report from a World Health Organization Meeting held on 23-24 Effect of oxygen desaturations on subsequent medical visits in infants discharged from the emergency department with bronchiolitis Effect of oximetry on hospitalization in bronchiolitis: a randomized clinical trial Variation in inpatient diagnostic testing and management of bronchiolitis Predictors of airspace disease on chest x-ray in emergency department patients with clinical bronchiolitis: a systematic review and meta-analysis Assessing the utility of urine testing in febrile infants aged 2 to 12 months with bronchiolitis Respiratory syncytial virus (RSV) immune globulin intravenous therapy for RSV lower respiratory tract infection in infants and young children at high risk for severe RSV infections: respiratory syncytial virus immune globulin study group Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants Lower respiratory tract infection caused by respiratory syncytial virus: current management and new therapeutics Epinephrine and dexamethasone in children with bronchiolitis Decreased lung function precedes severe respiratory syncytial virus infection and post-respiratory syncytial virus wheeze in term infants Clinical prediction rule for RSV bronchiolitis in healthy newborns: prognostic birth cohort study Study of montelukast for the treatment of respiratory symptoms of post-respiratory syncytial virus bronchiolitis in children Randomised placebo controlled trial of nebulised corticosteroids in acute respiratory syncytial viral bronchiolitis on behalf of the RSVCSG. Lack of long term effects of high dose inhaled beclomethasone for RSV bronchiolitis-a randomized placebo-controlled trial Respiratory syncytial virus and recurrent wheeze Randomized trial to evaluate azithromycin's effects on serum and upper airway IL-8 levels and recurrent wheezing in infants with respiratory syncytial virus bronchiolitis Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13 Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life Nebulized hypertonic saline for bronchiolitis: a randomized clinical trial The effect of 3% and 6% hypertonic saline in viral bronchiolitis: a randomised controlled trial 7% Hypertonic saline in acute bronchiolitis: a randomized controlled trial SABRE: a multicentre randomised control trial of nebulised hypertonic saline in infants hospitalised with acute bronchiolitis High-flow nasal cannula oxygen for bronchiolitis in a pediatric ward: a pilot study CPAP and high-flow nasal cannula oxygen in bronchiolitis High-flow warm humidified oxygen versus low-flow nasal cannula oxygen for moderate bronchiolitis (HFWHO RCT): an open, phase 4, randomised controlled trial Early high flow nasal cannula therapy in bronchiolitis, a prospective randomised control trial (protocol): a paediatric acute respiratory intervention study (PARIS) Improved clinical and economic outcomes in severe bronchiolitis with pre-emptive nCPAP ventilatory strategy Variability of intensive care management for children with bronchiolitis Mechanical ventilation drives inflammation in severe viral bronchiolitis Bronchiolitis in Children (SIGN 91). NHS Quality Improvement: Scotland Respiratory syncytial virus, an ongoing medical dilemma: an expert commentary on respiratory syncytial virus prophylactic and therapeutic pharmaceuticals currently in clinical trials. Influenza Other Respir Viruses Activity of oral ALS-008176 in a respiratory syncytial virus challenge study Oral GS-5806 activity in a respiratory syncytial virus challenge study Possible transmission by fomites of respiratory syncytial virus Viral coinfection in childhood respiratory tract infections Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine