548 SECTION V Pediatric Critical Care Pulmonary patients in the PICU without bronchiolitis have risk factors for severe disease; thus, preventing spread to these susceptible chil dren may help to impr[.]
548 S E C T I O N V Pediatric Critical Care: Pulmonary patients in the PICU without bronchiolitis have risk factors for severe disease; thus, preventing spread to these susceptible children may help to improve their outcomes.65 Hand disinfection, with either alcohol-based rubs or soap and water (if hands are visibly soiled), is recommended by the AAP before and after direct contact with patients, after contact with nearby inanimate objects, and after removing gloves.41 Use of gowns, gloves, and face protection also reduce transmission.66,67 Children at high risk for severe and life-threatening disease from RSV may be candidates for prophylactic passive immunization Palivizumab, a monoclonal antibody against the RSV F glycoprotein, reduces the rates of hospitalization and ICU admission by 50% in high-risk children.68 Local guidelines vary by region, but prophylaxis may be warranted in children born extremely premature and those with chronic lung disease, hemodynamically significant congenital heart disease, immunodeficiency, and other comorbidities.69 Palivizumab does not improve clinical outcomes when given during acute illness to lower risk children.70 Vaccines against RSV are under development.71 Treatment Multiple national organizations have published guidelines for the treatment of children with bronchiolitis; however, these are generally intended for non-ICU clinicians.41,72–74 Treatment for critical bronchiolitis is predominantly supportive, particularly for hypoxia, hypercarbia, dyspnea, and dehydration.75,76 Use of medications and respiratory support modalities vary widely by region and among institutions without clear benefits on clinical outcomes.75,77–80 Hypertonic Saline Hypertonic saline (HTS) may improve respiratory mechanics by increasing mucociliary clearance and reducing airway edema.81 HTS was prescribed to 13% of critical bronchiolitis subjects in one recent multicenter report and one-third of surveyed intensivists report prescribing HTS.82,83 In general, treatment guidelines not encourage its routine use in children hospitalized with bronchiolitis, though the AAP and Canadian Pediatric Society (CPS) suggest it may have some utility in inpatients.41,72,73 Two recent meta-analyses show that HTS may reduce hospital LOS, but results are nonsignificant if only studies with a very low risk of bias are included.81,84 One included randomized controlled trial had 10 PICU patients (out of 408 total), but critically ill children were excluded from the vast majority of trials to date.45 A single retrospective study of PICU patients showed no differences in PICU LOS or duration of respiratory support between 45 children who received HTS and 59 who did not.85 Thus, there are insufficient data to support or refute the use of HTS for critical bronchiolitis, and it is not a common part of our practice Inhaled Bronchodilators Inhaled racemic epinephrine may improve respiratory distress via activation of a-receptors (airway vasoconstriction and fluid resorption) and b-receptors (bronchodilation),86 though wheezing in bronchiolitis may be predominantly due to obstruction with debris and not bronchoconstriction.74 Meta-analysis of trials in children with bronchiolitis shows that inhaled epinephrine does not improve LOS among inpatients,87 and scheduled administration may actually prolong hospitalization.88 Small studies of mechanically ventilated children show that inhaled epinephrine modestly improves resistance of the respiratory system and peak inspiratory pressures.89,90 Albuterol, a b-agonist bronchodilator, was also tested in one of those studies and had similar effects.90 More recent studies show that albuterol improves respiratory resistance by more than 20% in approximately 40% of subjects, though clinicians’ ability to identify “responders” based on subjective clinical examinations was generally no better than a coin flip.91 Meta-analyzed data support that albuterol does not shorten hospital LOS.92 The AAP, Australasian guidelines, and United Kingdom’s National Institute for Health and Care Excellence (NICE) guidelines41,72,73 state that neither epinephrine nor al buterol should be used in inpatients, though the AAP points out that critically ill children are generally excluded from the trials supporting that recommendation Both the AAP and CPS suggest considering epinephrine specifically in select circumstances (e.g., “as a rescue agent in severe disease”).41,74 In three recent multicenter studies, each from a different continent, approximately 50% to 75% of PICU patients received inhaled bronchodilators, and most of the surveyed intensivists report prescribing them.75,82,83,93 While there is likely a role for bronchodilators, particularly epinephrine, in some children with critical bronchiolitis, objective ways to identify “responders” are needed to restrict use to only those children who actually benefit from them Until those are available, we suggest considering bronchodilators (preferentially epinephrine) in children with worsening respiratory failure, with continued use ideally based on objective improvement in respiratory mechanics Corticosteroids Inhaled and systemic corticosteroids reduce airway inflammation but have generally been shown to be ineffective in inpatients and outpatients with bronchiolitis.94 Thus, they are not recommended by national guidelines.41,72–74 Data suggest that corticosteroids are also ineffective in children with bronchiolitis who later develop asthma; their use is not recommended even in bronchodilator responders.73,95 Unlike many other therapies discussed in this chapter, corticosteroids have been prospectively studied versus placebo in critically ill children In a randomized controlled trial of prednisolone versus placebo, there was no statistically significant difference in duration of mechanical ventilation (4.7 1.1 vs 6.3 1.6 days, P 56) in the subgroup of mechanically ventilated children (n in each arm), but hospital LOS was significantly shorter (11.0 0.7 vs 17.0 2.0 days, P , 01).96 The same research group completed two subsequent multicenter studies that randomized a total of 171 mechanically ventilated children with RSV lower respiratory tract infections to either dexamethasone or placebo and found no significant difference in duration of mechanical ventilation.97,98 Results of another trial of dexamethasone similarly found no improvements in clinical outcomes.99 Recent data show that approximately 25% of contemporary PICU patients with bronchiolitis receive corticosteroids despite the absence of efficacy data.75,83,93 Unless supportive evidence becomes available, corticosteroids should not be used for children with critical bronchiolitis unless another indication exists concurrently Hydration and Nutritional Support Children with bronchiolitis may be dehydrated secondary to increased fluid losses from the respiratory tract and/or decreased fluid intake Furthermore, hospitalized patients may not be CHAPTER 49 Acute Viral Bronchiolitis allowed oral intake due to concerns about the increased risk of aspiration100,101 or progression to endotracheal intubation Targeting euvolemia is likely appropriate given the risks of both hypovolemia and fluid overload.102 The AAP, CPS, and Australasian guidelines recommend either nasogastric feeding or intravenous fluids to maintain hydration, while the NICE guidelines preferentially support nasogastric feeding.41,72–74 Both routes lead to similar outcomes, though there was more placement failure with peripheral intravenous lines than nasogastric tubes in one large randomized trial.103 For children with impending respiratory failure or those with significant hypovolemia, intravenous fluids are more appropriate Isotonic fluids are recommended by the AAP101 and CPS74 and may help reduce the risk of iatrogenic hyponatremia and unfavorable clinical outcomes.59 Enteral nutrition should be started as soon as the risk of intubation is sufficiently low or once clinically stable following intubation Children with bronchiolitis supported by high-flow nasal cannula (HFNC)104 and noninvasive positive pressure ventilation (NIPPV)105 can receive enteral nutrition, but there are insufficient data to state at what point in the disease course it is ideal to initiate feeds Our general practice is to initiate oral nutrition after the first successful wean of HFNC flow rate In sicker patients, we commence nasogastric feeds once the child is stabilized after endotracheal intubation Other Inhaled Therapies Mechanically ventilated children with RSV have reduced levels of surfactant.106 Three trials totaling 39 children performed before 2002 showed no statistically significant improvement in the duration of mechanical ventilation (MV) when metaanalyzed.107,108 However, two of those trials109,110 were “positive,” and meta-analyzed data did show that surfactant shortened PICU LOS A more recent trial of 165 children aged years or younger—72 of whom had bronchiolitis—showed improved oxygenation with surfactant but no change in the duration of MV.111 Despite the lack of proven efficacy, some providers continue to use surfactant in severe bronchiolitis.112 Ribavirin is an antiviral agent A meta-analysis of three older trials (1991–1999) showed that ribavirin decreases the duration of mechanical ventilation,113 but this may reflect the use of sterile water as the placebo in one of the three studies.76 Coupled with administration-related issues, ribavirin is rarely used in the current era and is not recommended by the AAP or CPS.41,74 Trials of ipratropium have also been negative; thus, its use is not recommended by the NICE guidelines.72,92 Other Systemic Therapies Bronchiolitis is caused by viruses, and rates of serious bacterial infections are low among non-ICU patients.58 Therefore, national guidelines not recommend routine use of antibiotics, though use “may be justified in some children with bronchiolitis who require intubation” per the AAP.41,72–74 Limited data suggest that rates of bacteremia and urinary tract infections are low among PICU patients with bronchiolitis,114 but that 20% to 40% of children with bronchiolitis requiring MV may have bacterial pneumonia.114,115 Provision of antibiotics for critical bronchiolitis patients requiring MV is a common practice among intensivists75,82,83,93,116 and may improve outcomes,116 but its efficacy has not been proven Some clinicians prescribe caffeine for bronchiolitis-associated apnea,79 though a recent placebocontrolled trial of 90 patients showed that a single dose of 549 caffeine did not impact the resolution of apnea nor the need for respiratory support.117 Respiratory Support Most patients with critical bronchiolitis receive respiratory support modalities such as HFNC, continuous positive airway pressure (CPAP), or invasive MV.78,83 High-Flow Nasal Cannula HFNC systems condition (i.e., heat and humidify) the inspiratory gas so that higher gas flows can be used compared to traditional “off-the-wall” nasal cannula systems without causing desiccation or discomfort.118 HFNC improves a patient’s respiratory status via several mechanisms, including reduced metabolic work of the nasopharyngeal tissues, improved mucociliary function, and reduced inspiratory resistance.118 Substantial effects of the use of HFNC are due to washout of the nasopharyngeal anatomic dead space, replacing the CO2-rich and O2-poor air that remains in the nasopharynx at the end of exhalation with CO2free and O2-rich gas, thereby improving CO2 removal and oxygenation.118 This may be particularly beneficial in young children, such as those with bronchiolitis, given the higher ratio of anatomic dead space to tidal volume in infants.119 HFNC is intended to be an open system, with the nares more than 50% unobstructed by the cannula to enable washout, thereby limiting the amount of positive airway pressure generated Nasopharyngeal pressures may reach to cm H2O, with flows up to 2.5 L/kg per minute; however, pressures depend heavily on flow rate and whether the child’s mouth is open or closed and vary widely between patients even if those factors are equivalent.120,121 How much of this pressure is transmitted to the alveoli is unclear In one study, esophageal pressures on HFNC at L/min were, on average, only cm H2O higher than pressures on a standard nasal cannula at L/min,122 though a recent bench study using a threedimensionally printed airway model reported simulated alveolar pressures up to 10 cm H2O in the term neonate and toddler models with flows of ,2 L/kg per minute.123 Regardless of the mechanisms, HFNC reduces the work of breathing in children with bronchiolitis,124,125 with maximal effects seen at 1.5 to 2.0 L/kg per minute,126 and its introduction into clinical practice has been associated with reduced rates of intubation for bronchiolitis.127,128 Still, approximately 10% of PICU patients with bronchiolitis who are initially supported with HFNC will require intubation,129 and the impending failure of HFNC may be identified by a lack of improvement in tachycardia/tachypnea within 60 minutes of HFNC initiation.118,128 In three interventional trials (n 1734) of children with bronchiolitis, an HFNC at to L/kg per minute has been shown to reduce the risk of treatment failure (generally defined as tachycardia, tachypnea, hypoxemia, and/or a clinical decision to escalate care) versus simple nasal cannula or facemask oxygen.130–132 In the two larger trials (n 1674),130,131 HFNC did not shorten the duration of oxygen therapy or hospital LOS More recent trials found equivalent outcomes when comparing versus L/kg per minute133 and versus L/kg per minute.134 Supported by its salutary effects on the work of breathing, modest side-effect profile, ease of setup, and tolerance by patients, HFNC use has increased for critical bronchiolitis to more than 60% to 70% of children in North America and Australasia.6,129 550 S E C T I O N V Pediatric Critical Care: Pulmonary Continuous Positive Airway Pressure CPAP is also commonly used for bronchiolitis, helping to maintain airway patency, increase functional residual capacity, and provide oxygen without entraining ambient air.135 Interventional trials show that CPAP can improve respiratory mechanics, the work of breathing, and ventilation,136–138 though some patients require sedation to tolerate the interface.139 Though none of those interventional trials found that CPAP improves clinical outcomes or reduces the need for invasive MV, introduction of NIPPV has been associated with reduced MV rates versus historical controls.140,141 Approximately 20% of bronchiolitis patients on CPAP or bilevel positive airway pressure (BiPAP) will require MV,141,142 even if first treated with HFNC.129 Two randomized trials have compared HFNC to CPAP in children with bronchiolitis The larger study (n 142) compared L/kg per minute of HFNC to cm H2O of CPAP and found more “failure” with HFNC, predominantly due to increases in either respiratory rate or work of breathing, though HFNC was better tolerated by the children.143 Interestingly, the rate of failure with CPAP in that study (31%) was similar to the failure rate with HFNC reported by the same research group in a subsequent study (39%),134 suggesting that the high failure rate with HFNC in the earlier study (51%) may have been related to clinician inexperience with HFNC.144 A smaller CPAP versus HFNC trial (n 31) found no differences in respiratory outcomes and reported that HFNC was better tolerated.145 A third, larger trial (n 225) found equivalent outcomes between HFNC and CPAP but also included older children (up to years old) and those with bacterial pneumonia.146 Intubation rates were approximately 6% to 10% in all three trials and did not differ significantly between HFNC and CPAP, though none of the trials were sufficiently powered for this outcome In a large database study (n 6496), intubation rates were higher following initial support with NIPPV versus HFNC (20% vs 11%, P , 001).129 Though this relationship was statistically significant even after adjusting for available confounders, the risk of treatment bias in this study limits application at the bedside In total, the available studies support that HFNC is more comfortable than CPAP, but there are insufficient data to state that HFNC or CPAP is superior as a first-line therapy for critical bronchiolitis Recent multicenter studies suggest that some PICUs are “CPAP units,” while others predominantly use HFNC.75,78 While our experience is that the vast majority of patients with critical bronchiolitis can be supported with HFNC alone, with rare need for either CPAP or invasive MV, clinicians should select the respiratory support modality based on local practice and patient-specific factors until a comparative trial powered to reduce need for MV and improve clinical outcomes becomes available Invasive Mechanical Ventilation Indications for intubation for children with bronchiolitis are similar to those for children with other causes of respiratory failure They include refractory hypoxemia/hypercarbia or intolerable dyspnea, though apnea76 is a somewhat unique indication in some children with bronchiolitis Physiologic studies have shown patterns of both obstructive disease and restrictive disease during MV; thus, ventilator settings must be selected and adjusted based on each patient’s respiratory mechanics.147,148 Use of MV has decreased in recent years as more children are supported noninvasively.6 Approximately 10% to 25% of PICU patients with bronchiolitis receive MV,4,6,75,83 though rates vary between centers and are influenced by each institution’s criteria for admission to the PICU versus general ward The median duration of MV is approximately days.83,116 Other Respiratory Support Several other respiratory support modalities are used by some intensivists for critical bronchiolitis These include negative pressure ventilation,149 nasal intermittent mandatory ventilation,150 and neutrally adjusted ventilation (invasively and noninvasively).82,151 Inhaled nitric oxide and extracorporeal membrane oxygenation are used rarely.4 The prone position has been suggested as beneficial for children with bronchiolitis.152 Further data describing these practices in critical bronchiolitis are needed Chest physiotherapy, while generally a low-risk therapy, has been shown to be unhelpful.153 Nasal suctioning may relieve obstruction, but “deep” nasopharyngeal suctioning has been associated with unfavorable outcomes.154 Some data suggest that heliox may improve respiratory distress but not necessarily clinical outcomes.76,155 Complications Most children with bronchiolitis recover fully, without any shortterm or long-term complications Mortality in the United States is less than 1%, but children from resource-limited countries die disproportionately.2 In high-resource countries, risk factors—including low birth weight, younger age, and comorbid conditions—are associated with mortality in bronchiolitis.156,157 Though mortality is rare, the associated morbidity remains high As one of the most common causes of hospitalization in pediatric patients, it remains a significant public health burden, with hospital charges exceeding $1.7 billion annually in the United States.3 Expenditures for outpatient-related care may be as high as one-third of direct healthcare costs.158 While most children hospitalized for bronchiolitis recover fully, hospital-associated complications are not uncommon Retrospective data from a multicenter study including over 600 infants showed that most (79%) had at least one complication and 24% had a severe complication, defined as respiratory failure, apnea, pneumothorax, sepsis, shock, cardiopulmonary resuscitation, or seizures.159 Like all PICU patients, children with critical bronchiolitis are at risk for neurofunctional morbidity that persists after PICU discharge (post–intensive care syndrome) In one single-center study, approximately 10% of 236 children with critical bronchiolitis had neurologic morbidity at the time of transfer to the general ward, including lethargy, abnormal tone, and feeding difficulty.160 In a long-term follow-up study from a different center, more than 25% of patients with bronchiolitis had a “fair” or worse quality of life months after PICU discharge, though it was unclear how directly attributable that was to the episode of critical bronchiolitis.161 More recently, a database study of 13,267 children without identifiable preexisting comorbidities reported a 13% incidence of post-ICU morbidity, such as the need for physical therapy or a feeding tube.162 Prospective studies that include assessment of preillness function are needed to better determine the rate of neurofunctional morbidity after critical bronchiolitis Observational studies show that children hospitalized with bronchiolitis have an approximately fourfold higher risk of having asthma and/or wheezing later in life, though this association becomes less pronounced after the first few years of life.163 Whether severe bronchiolitis causes subsequent respiratory morbidity, or if CHAPTER 49 Acute Viral Bronchiolitis children who are already predisposed to asthma are also predisposed to more severe bronchiolitis as infants is not fully known One interventional trial that randomized otherwise healthy preterm infants to palivizumab versus placebo may help to answer this question Palivizumab effectively decreased wheezing during the first year of life,164 suggesting that RSV may be causative However, at the age of years, palivizumab improved parentreported wheezing but not lung function (forced expiratory volume) or clinician-diagnosed asthma.165 This suggests that RSV is not causative but rather that severe bronchiolitis may be a marker for children already predisposed to pulmonary morbidity As is the case for most elements of critical bronchiolitis, further research is needed to better answer this question Key References American Academy of Pediatrics Committee on Infectious Diseases, American Academy of Pediatrics Bronchiolitis Guidelines Committee Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection Pediatrics 2014;134(2):415-420 Byington CL, Wilkes J, Korgenski K, Sheng X Respiratory syncytial virus-associated mortality in hospitalized infants and young children Pediatrics 2015;135(1):e24-e31 Davison C, Ventre KM, Luchetti M, Randolph AG Efficacy of interventions for bronchiolitis in critically ill infants: a systematic review and meta-analysis Pediatr Crit Care Med 2004;5(5):482-489 551 Franklin D, Babl FE, Schlapbach LJ, et al A Randomized trial of highflow oxygen therapy in infants with bronchiolitis N Engl J Med 2018;378(12):1121-1131 Hartling L, Bialy LM, Vandermeer B, et al Epinephrine for bronchiolitis Cochrane Database Syst Rev 2011;(6):CD003123 Hasegawa K, Pate BM, Mansbach JM, et al Risk factors for requiring intensive care among children admitted to ward with bronchiolitis Acad Pediatr 2015;15(1):77-81 Hasegawa K, Tsugawa Y, Brown DF, Mansbach JM, Camargo Jr CA Trends in bronchiolitis hospitalizations in the United States, 20002009 Pediatrics 2013;132(1):28-36 Jat KR, Chawla D Surfactant therapy for bronchiolitis in critically ill infants Cochrane Database Syst Rev 2015(8):CD009194 Jat KR, Mathew JL Continuous positive airway pressure (CPAP) for acute bronchiolitis in children Cochrane Database Syst Rev 2019;1:CD010473 Milesi C, Pierre AF, Deho A, et al A multicenter randomized controlled trial of a 3-L/kg/min versus 2-L/kg/min high-flow nasal cannula flow rate in young infants with severe viral bronchiolitis (TRAMONTANE 2) Intensive Care Med 2018;44(11):1870-1878 Pierce HC, Mansbach JM, Fisher ES, et al Variability of intensive care management for children with bronchiolitis Hosp Pediatr 2015;5(4):175-184 Shein SL, Kong M, McKee B, O’Riordan M, Toltzis P, Randolph AG Antibiotic prescription in young children with respiratory syncytial virus-associated respiratory failure and associated outcomes Pediatr Crit Care Med 2019;20(2):101-109 Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP Nebulised hypertonic saline solution for acute bronchiolitis in infants Cochrane Database Syst Rev 2017;12:CD006458 The full reference list for this chapter is available at ExpertConsult.com e1 References Global Burden of Disease Pediatrics Collaboration, Kyu HH, Pinho C, et al Global and National Burden of Diseases and Injuries Among Children and Adolescents Between 1990 and 2013: Findings From the Global Burden of Disease 2013 Study JAMA Pediatr 2016;170(3):267-287 Nair H, Nokes DJ, Gessner BD, et al Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis Lancet 2010; 375(9725):1545-1555 Hasegawa K, Tsugawa Y, Brown DF, Mansbach JM, Camargo Jr CA Trends in bronchiolitis hospitalizations in the United States, 20002009 Pediatrics 2013;132(1):28-36 Gupta P, Beam BW, Rettiganti M Temporal Trends of Respiratory Syncytial Virus-Associated Hospital and ICU Admissions Across the United States Pediatr Crit Care Med 2016;17(8):e343-e351 Green CA, Yeates D, Goldacre A, et al Admission to hospital for bronchiolitis in England: trends over five decades, geographical variation and association with perinatal characteristics and subsequent asthma Arch Dis Child 2016;101(2):140-146 Schlapbach LJ, Straney L, Gelbart B, et al Burden of disease and change in practice in critically ill infants with bronchiolitis Eur Respir J 2017;49(6):1601648 Huff N, Katherine S, Jason C, et al Trends in Epidemiology of Critically Ill Children in a Large National Database in the United States Poster presented at: 49th Critical Care Congress; February 2020; Orlando, FL Hall CB, Weinberg GA, Blumkin AK, et al Respiratory syncytial virus-associated hospitalizations among children less than 24 months of age Pediatrics 2013;132(2):e341-e348 Hall CB, Weinberg GA, Iwane MK, et al The burden of respiratory syncytial virus infection in young children N Engl J Med 2009; 360(6):588-598 10 Wright AL, Taussig LM, Ray CG, Harrison HR, Holberg CJ The Tucson Children’s Respiratory Study II Lower respiratory tract illness in the first year of life Am J Epidemiol 1989;129(6):1232-1246 11 Freymuth F, Vabret A, Cuvillon-Nimal D, et al Comparison of multiplex PCR assays and conventional techniques for the diagnostic of respiratory virus infections in children admitted to hospital with an acute respiratory illness J Med Virol 2006;78(11):1498-1504 12 Ong GM, Wyatt DE, O’Neill HJ, McCaughey C, Coyle PV A comparison of nested polymerase chain reaction and immunofluorescence for the diagnosis of respiratory infections in children with bronchiolitis, and the implications for a cohorting strategy J Hosp Infect 2001;49(2):122-128 13 Mansbach JM, Piedra PA, Teach SJ, et al Prospective multicenter study of viral etiology and hospital length of stay in children with severe bronchiolitis Arch Pediatr Adolesc Med 2012;166(8):700-706 14 Mansbach JM, McAdam AJ, Clark S, et al Prospective multicenter study of the viral etiology of bronchiolitis in the emergency department Acad Emerg Med 2008;15(2):111-118 15 Miller EK, Gebretsadik T, Carroll KN, et al Viral etiologies of infant bronchiolitis, croup and upper respiratory illness during consecutive years Pediatr Infect Dis J 2013;32(9):950-955 16 Calvo C, Pozo F, García-García ML, et al Detection of new respiratory viruses in hospitalized infants with bronchiolitis: a three-year prospective study Acta Paediatr 2010;99(6):883-887 17 Papadopoulos NG, Moustaki M, Tsolia M, et al Association of rhinovirus infection with increased disease severity in acute bronchiolitis Am J Respir Crit Care Med 2002;165(9):1285-1289 18 Chorazy ML, Lebeck MG, McCarthy TA, Richter SS, Torner JC, Gray GC Polymicrobial acute respiratory infections in a hospitalbased pediatric population Pediatr Infect Dis J 2013;32(5):460-466 19 Peng D, Zhao D, Liu J, et al Multipathogen infections in hospitalized children with acute respiratory infections Virol J 2009;6:155 20 Rose EB, Wheatley A, Langley G, Gerber S, Haynes A Respiratory Syncytial Virus Seasonality – United States, 2014-2017 MMWR Morb Mortal Wkly Rep 2018;67(2):71-76 21 Haynes AK, Manangan AP, Iwane MK, et al Respiratory syncytial virus circulation in seven countries with Global Disease Detection Regional Centers J Infect Dis 2013;208(suppl 3):S246-S254 22 Garcia CG, Bhore R, Soriano-Fallas A, et al Risk factors in children hospitalized with RSV bronchiolitis versus non-RSV bronchiolitis Pediatrics 2010;126(6):e1453-e1460 23 Alvarez AE, Marson FA, Bertuzzo CS, Arns CW, Ribeiro JD Epidemiological and genetic characteristics associated with the severity of acute viral bronchiolitis by respiratory syncytial virus J Pediatr (Rio J) 2013;89(6):531-543 24 Pignotti MS, Carmela Leo M, Pugi A, et al Consensus conference on the appropriateness of palivizumab prophylaxis in respiratory syncytial virus disease Pediatr Pulmonol 2016;51(10):1088-1096 25 Nascimento MS, Souza AV, Ferreira AV, Rodrigues JC, Abramovici S, Silva Filho LV High rate of viral identification and coinfections in infants with acute bronchiolitis Clinics (Sao Paulo) 2010;65(11): 1133-1137 26 Schuh S, Kwong JC, Holder L, Graves E, Macdonald EM, Finkelstein Y Predictors of critical care and mortality in bronchiolitis after emergency department discharge J Pediatr 2018;199:217-222.e1 27 Hasegawa K, Pate BM, Mansbach JM, et al Risk factors for requiring intensive care among children admitted to ward with bronchiolitis Acad Pediatr 2015;15(1):77-81 28 Damore D, Mansbach JM, Clark S, Ramundo M, Camargo Jr CA Prospective multicenter bronchiolitis study: predicting intensive care unit admissions Acad Emerg Med 2008;15(10):887-894 29 Jones LL, Hashim A, McKeever T, Cook DG, Britton J, LeonardiBee J Parental and household smoking and the increased risk of bronchitis, bronchiolitis and other lower respiratory infections in infancy: systematic review and meta-analysis Respir Res 2011;12:5 30 Koehoorn M, Karr CJ, Demers PA, Lencar C, Tamburic L, Brauer M Descriptive epidemiological features of bronchiolitis in a population-based cohort Pediatrics 2008;122(6):1196-1203 31 Zheng DX, Mitri EJ, Garg V, et al Socioeconomic status and bronchiolitis severity among hospitalized infants Acad Pediatr 2020;20(3):348-355 32 Slain KN, Shein SL, Stormorken AG, Broberg MCG, Rotta AT Outcomes of children with critical bronchiolitis living in poor communities Clin Pediatr (Phila), 2018;57(9):1027-1032 33 Aherne W, Bird T, Court SD, Gardner PS, McQuillin J Pathological changes in virus infections of the lower respiratory tract in children J Clin Pathol, 1970;23(1):7-18 34 Visscher DW, Myers JL Bronchiolitis: the pathologist’s perspective Proc Am Thorac Soc 2006;3(1):41-47 35 Camp JV, Jonsson CB A role for neutrophils in viral respiratory disease Front Immunol 2017;8:550 36 Welliver TP, Garofalo RP, Hosakote Y, et al Severe human lower respiratory tract illness caused by respiratory syncytial virus and influenza virus is characterized by the absence of pulmonary cytotoxic lymphocyte responses J Infect Dis 2007;195(8):1126-1136 37 Zinserling A Peculiarities of lesions in viral and mycoplasma infections of the respiratory tract Virchows Arch A Pathol Pathol Anat 1972;356(3):259-273 38 Johnson JE, Gonzales RA, Olson SJ, Wright PF, Graham BS The histopathology of fatal untreated human respiratory syncytial virus infection Mod Pathol 2007;20(1):108-119 39 Welliver TP, Reed JL, Welliver RC Sr Respiratory syncytial virus and influenza virus infections: observations from tissues of fatal infant cases Pediatr Infect Dis J 2008;27(suppl 10):S92-S96 40 Pickles RJ, DeVincenzo JP Respiratory syncytial virus (RSV) and its propensity for causing bronchiolitis J Pathol 2015;235(2):266-276 41 Ralston SL, Lieberthal AS, Meissner HC, et al Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis Pediatrics 2014;134(5):e1474-e1502 42 Schroeder AR, Mansbach JM, Stevenson M, et al Apnea in children hospitalized with bronchiolitis Pediatrics 2013;132(5):e1194-e1201 43 Kneyber MC, Brandenburg AH, Rothbarth PH, de Groot R, Ott A, van Steensel-Moll HA Relationship between clinical severity of respiratory syncytial virus infection and subtype Arch Dis Child 1996;75(2):137-140 ... sufficiently powered for this outcome In a large database study (n 6496), intubation rates were higher following initial support with NIPPV versus HFNC (20% vs 11%, P , 001).129 Though this relationship... end of exhalation with CO2free and O2-rich gas, thereby improving CO2 removal and oxygenation.118 This may be particularly beneficial in young children, such as those with bronchiolitis, given the... closed and vary widely between patients even if those factors are equivalent.120,121 How much of this pressure is transmitted to the alveoli is unclear In one study, esophageal pressures on HFNC