AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

Bronchiolitis is an acute, infectious, inflammatory disease of the upper and lower respiratory tract that may result in obstruction of the small airways. Although it may occur in all age groups, the larger airways of older children and adults better accommodate mucosal edema; severe respiratory symptoms are usually limited to young infants.

Pathophysiology

Necrosis of the respiratory epithelium is one of the earliest lesions in bronchiolitis and occurs within 24 hours of the acquisition of infection.¹ Proliferation of goblet cells results in excessive mucus production, whereas epithelial regeneration with nonciliated cells impairs elimination of secretions. Lymphocytic infiltration may result in submucosal edema. Cytokines and chemokines, released by infected respiratory epithelial cells, amplify the immune response by increasing cellular recruitment into infected airways. Interferon and interleukin (IL)-4, IL-8, and IL-9 are found in high concentrations in respiratory secretions of infected patients.^{2, 3} 

In 2007, Johnson et al analyzed autopsy findings of children who died due to respiratory syncytial virus (RSV) from 1925-1959, before modern intensive care, and autopsy findings of a child with RSV bronchiolitis who died in a motor vehicle accident.⁴ They found that small bronchiole epithelium was circumferentially infected, but basal cells were spared. Both type 1 and type 2 alveolar pneumocytes were also infected. Airway obstruction was due to epithelial and inflammatory cell debris mixed with fibrin, mucus, and edema fluid but not bronchial smooth muscle constriction.⁴ Neutrophile inflammation, but not eosinophile inflammation, is related to the severity of a first infection in infants.⁵

The pathology results in obstruction of bronchioles from inflammation, edema, and debris, leading to hyperinflation, increased airway resistance, atelectasis, and ventilation-perfusion mismatching. Bronchoconstriction has not been described.

Infants are affected most often because of their small airways, high closing volumes, and insufficient collateral ventilation. Recovery begins with regeneration of bronchiolar epithelium after 3-4 days, but cilia do not appear for as long as 2 weeks. Macrophages remove mucus plugs. Risk factors include the following:^{6, 7, 8, 9}

• Low birth weight, particularly premature infants¹⁰
• Gestational age (independently associated with hospital resource use and outcome among infants hospitalized for RSV){Ref182}
• Lower socioeconomic group¹¹
• Crowded living conditions, daycare, or both
• Parental smoking¹²
• Chronic lung disease, particularly bronchopulmonary dysplasia
• Severe congenital or acquired neurologic disease
• Congenital heart disease (CHD) with pulmonary hypertension¹³ (Interestingly, French children with CHD did not show increased risk.¹⁴)
• Congenital or acquired immune deficiency diseases
• Age less than 3 months
• Airway anomalies

Virtually all children experience RSV infection within the first 3 years of life, but previous infection does not convey complete immunity. Reinfection is common, but significant antibody titers ameliorate severity of symptoms.¹⁵

Frequency

United States

Respiratory infection is observed in 25% of children younger than 12 months and 13% of children aged 1-2 years. Of these 25%, one-half have wheezing-associated respiratory disease. RSV can be cultured from one third of these outpatients and from 80% of hospitalized children younger than 6 months. Nearly 100% of children experience an RSV infection within 2 RSV seasons, and 1% are hospitalized. Among healthy full-term infants, 80% of hospitalizations occur in the first year, and 50% of hospitalizations occur in children aged 1-3 months.¹¹

From 1980-1995, admissions associated with bronchiolitis totalled 1.65 million. The hospitalization rate for children younger than 1 year doubled from 12.9 to 31.2 per 1000 population, and the number of hospitalized children diagnosed with bronchiolitis tripled from 5.4% to 16.4%.¹¹ From 2003-2004, the morbidity and mortality rates of bronchiolitis were unchanged. However, an estimated 51,000-82,000 patients were hospitalized annually for bronchiolitis. The increase in hospitalizations is not due to increased pediatrician risk aversion, but rather is attributable to physicians' desire to treat the condition with bronchodilators. The cost of hospitalization for bronchiolitis in children younger than 1 year is estimated to be more than $700 million per year.^{12, 15}

Fewer than 5% of hospitalizations occur in the first 30 days of life, presumably because of transplacental transfer of maternal antibody.

In the temperate climates of the northern hemisphere, RSV epidemics generally occur annually in winter and late spring, whereas Parainfluenzae outbreaks usually occur in the fall. Conversely, in the southern hemisphere, wintertime epidemics occur from May to September. Evidence indicates that RSV is endemic throughout the year in the subtropical areas of the southeastern United States, with peaks from October to February and subsidence only from March through July.¹⁶

Secondary infections occur in 46% of family members, 98% of other children in daycare, 42% of hospital staff, and 45% of previously uninfected hospitalized infants. Infection is spread through self-inoculation of fomites via direct contact and environmental surfaces to nasopharyngeal or ocular mucous membranes. RSV can survive for several hours on hands and surfaces; therefore, handwashing and using disposable gloves and gowns may reduce nosocomial spread.^{17, 18, 10, 1}

International

Bronchiolitis is a significant cause of respiratory disease worldwide. Its incidence in developed countries appears similar to that in the United States. Epidemiologic data from underdeveloped countries are incomplete. Worldwide, RSV is responsible for 3-5 million deaths annually.

Mortality/Morbidity

RSV bronchiolitis accounts for more than 90,000 pediatric hospitalizations and as many as 4,500 deaths annually. Overall, the mortality rate in children hospitalized for bronchiolitis in different series is 0.2-7%. This large variability is based on investigations of different cohorts with different risk factors and different points in time relative to modern intensive care. Recent studies in pediatric ICUs (PICUs) of children with RSV bronchiolitis without comorbidities show a 2-3% death rate, regardless of whether the children had CHD with pulmonary hypertension.⁸

Sex

Boys are affected 1.7 times more often than girls; the male-to-female ratio of hospitalization among these children is 1.5:1. Death is 1.5 times more likely in males.

Age

Although RSV bronchiolitis is clearly a significant disease of the young child, no lifelong immunity occurs; mildly symptomatic or asymptomatic adults can be infected and act as carriers. With the increasing use of treatment modalities that compromise cellular immunity, RSV infection may be life threatening to older children and adults undergoing organ and bone marrow transplantation.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

Because this disease primarily affects young infants, clinical manifestations are initially subtle. Infants may become increasingly fussy and have difficulty feeding during the 2-day to 5-day incubation period. A low-grade fever, usually less than 101.5°F, and increasing coryza and congestion usually follow the incubation period. Sixty percent of primary respiratory syncytial virus (RSV) infections are confined to the upper airway. During a period of 2-5 days, this may progress to lower respiratory tract involvement with the development of cough, dyspnea, wheezing, and feeding difficulties. When the patient is brought to medical attention, the fever has usually resolved. Infants younger than 1 month may present as hypothermic. Severe cases progress to respiratory distress with tachypnea, nasal flaring, retractions and irritability, and, possibly, cyanosis.

Physical

• Examination often reveals the following:
• • Otitis media
  • Tachypnea
  • Tachycardia
  • Fever (38-39ºC)
  • Retractions
  • Fine rales (47%)
  • Diffuse, fine wheezing
• Diagnosis is made based on age and seasonal occurrence, tachypnea, and the presence of profuse coryza and fine rales, wheezes, or both upon auscultation of the lungs.
• • Hypoxia is the best predictor of severe illness and correlates best with the degree of tachypnea (>50 breaths per min). The degree of wheezing or retractions correlates poorly with hypoxia.
  • First-time infections are usually most severe. Subsequent attacks are generally milder, particularly in older children.
  • Nonrespiratory manifestations of RSV infections include otitis media, myocarditis, supraventricular and ventricular dysrhythmias, and inappropriate secretion of antidiuretic hormone.
• In one study, apnea developed in 18-20% of young infants hospitalized with RSV bronchiolitis. Other studies have noted far lower rates of apnea. Frequency of apnea increases among premature infants whose gestation was less than 32 weeks, infants who have not yet reached age 44 weeks from conception, and especially among those who have neonatal apnea. Using the criteria of (1) full-term age less than 1 month, (2) preterm age less than 48 weeks, and (3) observed apnea Willwerth et al found the incidence of in-hospital apnea was only 2.7%.¹⁹
• • Apnea occurs early in the course of the disease and may be the presenting symptom.
  • Nonobstructive central apnea occurs during quiet sleep and is associated with increases in the apnea index (percentage of time the baby spends apneic), apnea attack rate (the number of episodes of apnea per unit time), and apnea percentage (the distribution of episodes of apnea while in a given sleep state).
  • Apnea rarely lasts longer than a few days; however, approximately 10% of these patients require intubation and mechanical ventilation. Because very few cases of sudden infant death syndrome are attributable to bronchiolitis, most infants with apnea apparently self stimulate and recover spontaneously. Mild RSV disease in young infants is not an indication for hospitalization to observe for apnea.

Causes

RSV is the most commonly isolated agent in 75% of children younger than 2 years who are hospitalized for bronchiolitis. RSV is an enveloped RNA virus that belongs to the Paramyxoviridae family within the Pneumovirus genus.

• Agents that cause wheezing-associated respiratory infections include the following:
• • RSV causes 20-40% of all cases and 44% of cases that involve children younger than 2 years.
  • • Two RSV subtypes, A and B, have been identified based on the structural variations in the G protein. Subtype A causes the most severe infections. One subtype usually predominates during a given season; thus, RSV disease has "good" and "bad" years.
    • The disease is highly contagious. Viral shedding in nasal secretions continues for 6-21 days after symptoms develop. The incubation period is 2-5 days.²⁰
  • Parainfluenza virus causes 10-30% of all bronchiolitis cases.
  • Adenovirus accounts for 5-10% of bronchiolitis cases.
  • Influenza virus accounts for 10-20% of bronchiolitis cases.
  • Mycoplasma pneumoniae infection accounts for 5-15% of bronchiolitis cases, particularly among older children and adults.
  • A newly discovered virus, human metapneumovirus (hMPV), has been increasingly implicated as an etiologic agent in bronchiolitis. First identified in Holland in 2001, it is a paramyxovirus.
  • • Serologic studies indicated that, by age 5 years, all Dutch children had seroconverted and that the virus had been prevalent in the population for at least 50 years.
    • In a retrospective examination of nasal washings obtained between 1976 and 2001 from 2009 children with acute respiratory tract illness, 248 had identifiable viruses. Of these, 20% were identified as hMPV, accounting for 12% of all viral lower respiratory illness in children younger than 2 years.
    • The mean age in the hMPV group was 11.6 months, with a male-to-female ratio of 1.8:1. They most often had illnesses between December and April, and 2% were hospitalized. The virus was associated with bronchiolitis in 59% of patients.
    • Subsequent studies have shown that hMPV accounts for 5-50% of bronchiolitis cases, seems to occur later in the bronchiolitis season, occurs with higher fevers, affects somewhat older children, and causes more wheezing but less oxygen requirement (possibly because the children are older and have less atelectasis).
    • Recent observations note that dual infections with both hMPV and RSV are strongly associated with severe bronchiolitis, with a 10-fold increase in PICU admission.
  • Human bocavirus (HBoV) was discovered in 2005 and causes both upper and lower respiratory infections. It has been implicated in both pertussis and bronchiolitislike syndromes. Arnold demonstrated that 5.6% of 1474 nasal scrapings collected over a 20-month period at San Diego Children's Hospital tested positive for HBoV, mostly in the months of March through May.²¹
• Abundant evidence reveals that complex immunologic mechanisms play a role in the pathogenesis of RSV bronchiolitis. Type I allergic reactions mediated by the immunoglobulin E (IgE) antibody may account for clinically significant bronchiolitis. Breastfed babies, who receive colostrum rich in immunoglobulin A (IgA), appear relatively protected from bronchiolitis.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Foreign body aspiration
Congenital structural anomaly
Bronchomalacia
Congenital lobar emphysema
Tracheal ring
Bronchial cleft cyst
Sepsis
Congenital heart disease

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• Few laboratory studies are necessary when age, season, and physical examination are consistent with the expected diagnosis.
• • Some authors suggest that a dry nose excludes respiratory syncytial virus (RSV) infection.
  • WBC counts are usually 8000-15,000/mL and may be left-shifted due to stress.  Elevated WBC counts do not predict serious bacterial infection in children hospitalized with RSV bronchiolitis. Children with RSV infections have shown a lower risk of serious bacterial infections or secondary bacterial superinfection than controls (0 vs 2.7% for bacteremia and 2% vs 14% for urinary tract infection [UTI]).
  • Confine etiologic testing to more severely affected patients, such as children with comorbidities and those who are hospitalized, to determine appropriate isolation measures. Because no definitive treatment for the specific virus exists, therapy is directed toward symptomatic relief and maintenance of hydration and oxygenation. Viral testing only adds to cost and mistakenly leads to hospitalization. Etiologic testing may allow in-patient cohorting or diminish the use of antibiotics. Severely ill children may have dual viral infections.
• Although viral culture for RSV is available and must be considered the criterion standard in making a definitive diagnosis, several immunologic tests are more convenient, more rapid, and less costly.
• • Commercially available tests detect the RSV antigen in epithelial cells from nasopharyngeal secretions, bronchoalveolar lavage, or lung tissue. These tests are performed using either direct immunofluorescent antibody (IFA) staining or an enzyme-linked immunosorbent assay (ELISA).
  • Reliability of the tests highly depends on sampling techniques. The antigen is attached to mucosal epithelial cells. Simply sampling the mucus from a nasal swab is clearly less traumatic but not nearly as reliable as a swab of the nasopharyngeal area or, preferably, a nasal washing. One third of nasal swab sample results are negative compared with results obtained with more aggressive techniques.
  • Although ELISA is somewhat quicker and easier to interpret because of a more objective endpoint, the IFA technique may be preferable because the number of epithelial cells recovered can be determined, thus verifying the adequacy of the sample.
  • With adequate sampling, IFA requires 2-6 hours for processing and is 90% sensitive and specific.
  • ELISA requires 30 minutes for processing and is 85-90% sensitive compared with viral culture.
  • Reliability of rapid diagnostic tests in adults is questionable.

Imaging Studies

• Chest radiography is most useful in excluding unexpected congenital anomalies or other conditions. Chest radiography usually reveals hyperinflation, and 20-30% show lobar infiltrates, atelectasis, or both.
• Confine neck radiography or contrast studies to children whose diagnosis is unclear or who have histories consistent with structural anomalies.
• Atelectasis is common and contributes to arterial desaturation. Because ciliated bronchial epithelium does not regenerate for 9-15 days, atelectasis may be persistent and shifting. 
• Only 2 of 265 infants were found to have radiography findings inconsistent with simple bronchiolitis. Risk of airspace disease was particularly low in children with saturation higher than 92% and mild-to-moderate respiratory distress.
• Opacities on radiographs do not suggest bacterial pneumonia and incorrectly lead to inappropriate treatment with antibiotics.

Other Tests

• Measurement of transcutaneous oxygen saturation is a good indicator of severity. It correlates best with tachypnea; however, it correlates poorly with wheezing and retractions. Patients with persistent resting oxygen saturations in room air below 92% require a period of observation and possible hospitalization. Because of atelectasis, administration of beta-agonist aerosol may increase heart rate and thus cardiac output without improving ventilation, causing relative desaturation (ventilation-perfusion mismatch).
• Reserve ECG studies or echocardiography for those few children who display arrhythmias or cardiomegaly.

Procedures

• In rare situations, such as severe immunodeficiency or a strong history of possible foreign body aspiration, bronchoscopy may be indicated for diagnostic bronchoalveolar lavage or actual foreign body removal.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

Despite the prominent role that inflammation plays in the pathogenesis of airway obstruction, corticosteroids have not proven beneficial in improving clinical status in a large, controlled multi-institutional study. Beta-agonists and ipratropium bromide, an aerosolized anticholinergic agent, have not shown effectiveness in the management of infants with respiratory syncytial virus (RSV) and wheezing.

Although numerous medications and interventions have been used to treat bronchiolitis, at present, only oxygen appreciably improves the condition of young children with bronchiolitis. Medical therapies used to treat bronchiolitis in infants and young children are controversial. Efficacy in infants is difficult to determine because it can be a function of the pharmacologic agent, the route of administration, the clinical status of the patient, or the adequacy of the outcome measure used to demonstrate an effect. Recombinant human DNAse also had no clinical effects in infants who were not receiving ventilation. Newer immunotherapies are being introduced to both treat the acute disease and prevent sequelae.

Bronchodilators

A meta-analysis reviewed 15 randomized placebo-controlled trials of inhaled albuterol treatment in bronchiolitis.²² It concluded that albuterol produces only modest short-term improvement in clinical features of mild or moderately severe bronchiolitis, primarily through making the child more alert.

A more recent meta-analysis of 9 clinical trials noted that conclusive analysis for the efficacy of beta2-agonist therapy for bronchiolitis remains unavailable, and that the routine use of beta2-agonist therapy for bronchiolitis is not supported.²³

One study compared nebulized albuterol with normal saline in an age-matched and severity-matched trial of 52 infants over 72 hours of treatment.²⁴ Nebulized albuterol did not improve recovery or attenuate severity, as indicated by improvement in oxygen saturation, length of stay, or clinical score. Two randomized studies using albuterol, ipratropium, and both medications combined versus normal saline found no improvement with medications.^{25, 26}

Only a single nonrandomized study of 25 ventilated young infants (13 of whom had preexisting cardiopulmonary disease) with RSV bronchiolitis demonstrated a statistically significant increase in maximum volume functional residual capacity (Vmax FRC); however, in 3 of these infants, respiratory function worsened.

Although initial evidence suggested that nebulized racemic epinephrine reduced symptoms and length of hospital stay,²⁷ subsequent studies have not supported the use of aerosol epinephrine.²⁸ A randomized, double-blind, placebo-controlled study of 62 somewhat older children (aged 6 wk to 2 y, mean age 6.4 mo) compared aerosolized racemic epinephrine with salbutamol. Racemic epinephrine resulted in significant improvement in wheezing and respiratory distress score on day 2 but did not shorten hospitalization or total duration of illness. However, in a randomized placebo-controlled trial of albuterol and epinephrine in equipotent doses, neither drug reduced the need for oxygen nor reduced length of stay.²⁹  Additionally, neither drug reduced the quantity of oxygen required nor reduced clinical respiratory scores.

In an editorial, Wohl and Chernick, both highly respected experts on bronchiolitis, speculated that inhaled epinephrine may relieve symptoms by acting as a nasal decongestant, and similar nose drops may help to relieve symptoms.³⁰ A follow-up letter to the editor asks for a controlled study to end the speculation. Multiple authors have recommended instillation of saline nose drops prior to feeding. Instillation of the lowest concentration of nasal decongestant drops 2-3 times a day for no more than 3 days in hospitalized infants could be evaluated for its benefits.

Because using bronchodilators in bronchiolitis lacks efficacy, administering a beta-agonist on a trial basis to older patients with bronchiolitis and a personal or family history of asthma and assessing the clinical response in 10-15 minutes is reasonable. If improvement in retractions, respiratory rate, and wheezing is noted, scheduled aerosol treatments may be continued, with additional treatments administered as needed. If little or no sustained response is noted, cease bronchodilator therapy because it contributes to agitation and ventilation-perfusion ratio mismatching.

Anti-inflammatory agents

The belief that corticosteroids can prevent or reduce the major pathology of inflammation and edema of the bronchiolar mucosa is tempting. However, 13 trials of 1198 children aged 0-30 months failed to demonstrate improvement in length of stay, clinical score, hospital admission rates, or readmission rates for either systemic or inhaled corticosteroids administered in hospital or in the emergency department. Despite these findings Weinberger refers to several small studies that suggest that high-dose systemic steroids early in the course of bronchiolitis may be effective in preventing the progression of inflammation or, at least, in modifying the course.³¹

Similarly, the mast cell inhibitor cromoglycate had no beneficial effects. One study suggested that montelukast, a Cys-LT receptor antagonist, may reduce postbronchiolitis reactive airway disease, but this intervention cannot be recommended at this time.³²

Chest physiotherapy

Medicinal therapy seems to be disappointing for bronchiolitis, but chest physiotherapy cannot be recommended either. Three clinical trials of unventilated hospitalized infants compared vibration and percussion techniques in postural drainage positions with no intervention.³³ No differences were reported in length of hospital stay, oxygen requirements, or improvement in the severity of clinical score in infants with bronchiolitis.

Given the lack of evidence-based support for medicinal interventions for the treatment of bronchiolitis, admission rates and the treatment of bronchiolitis widely varies, particularly in emergency departments. In a Canadian study, children evaluated in general emergency departments were admitted twice as often as those observed in pediatric emergency departments, controlling for age, gender, estimated family income, medical comorbidity, and clinical severity.³⁴

A survey of members of the Emergency Medicine section of the American Academy of Pediatrics (AAP) found that 96% recommended bronchodilators and 8% recommended steroids.³⁵ Twice as many pediatric emergency physicians would admit a child with an oxygen saturation of 92% versus 94%, as measured with pulse oximetry (SpO₂), although a respiratory rate of 50 breaths per minute versus 65 breaths per minute made little difference in admission rate. A study of 30 large children's hospitals in the United States found that 45% of patients received steroids and 25% received systemic antibiotics. Factors that contributed to longer stays included use of antibiotics, steroids, and bronchodilators. Undergoing chest radiography was a significant predictor of antibiotic administration.

These differences from recommendations and between practices have led to a call for national guidelines for the treatment of bronchiolitis. In 2006, the AAP, in conjunction with the American Academy of Family Physicians, the American College of Chest Physicians, and the American Thoracic Society, published recommendations.³⁵ These recommendations were as follows:

• Diagnosis and severity should be based on history and physical findings and not on laboratory and radiologic findings. Risk factors should be assessed when making decisions about evaluation and management.
• Bronchodilators should not be routinely used. If a trial of an alpha-adrenergic or beta-adrenergic medication is an option, they should be continued only if a positive (and continued) response is documented.
• Corticosteroids should not routinely be used.
• Ribavirin should not be used.
• Antibacterials should be used only upon proven coexistence of bacterial infection.
• Assess hydration and the ability to take oral fluids.
• Supplemental oxygen should be supplied for SpO₂ less than 90%; saturation measurement is otherwise unnecessary.
• Palivizumab prophylaxis should be administered to selective children.
• Hand decontamination prevents nosocomial spread.
• Infants should not be exposed to secondary smoking, and breastfeeding is recommended.
• Clinicians should inquire about use of complementary and alternative medicine (CAM) therapies.

Cincinnati Children's Hospital found that bronchiolitis admissions were increasing so that patients could receive bronchodilator therapy. In 1997, the hospital instituted evidence-based point-of-care algorithms and rules based on guideline recommendations on the overuse of therapies for bronchiolitis and reviewed them in 2001 and 2002. Their guidelines discouraged etiologic testing because the treatment is directed at the syndrome rather than the etiologic cause, reduced the use of chest radiography (because opacities [atelectasis] are unlikely to change for 7-9 d and are not influenced by antibiotics or chest physiotherapy), and discouraged the use of steroids and bronchodilators unless clear and sustained improvement was noted 20 minutes after aerosol administration.

After introduction of the guidelines, decreases were seen in admissions (29%), length of stay (17%), nasopharyngeal washings for RSV antigen (52%), chest radiography (20%), all respiratory therapies (30%), beta-agonist administrations (51%), cost of all services (37%), and cost of respiratory therapy services (77%). Research shows these changes continued in the 3-year and 4-year follow-up investigations.

Hospital care

Indications for hospital admission include the following:^{6, 8}

• Persistent resting SpO₂ below 92% in room air prior to beta-agonist trial (Increased reliance on pulse oximetry has contributed to an increase in hospitalizations for bronchiolitis over the past 2 decades.)
• Inability to maintain oral hydration in patients younger than 6 months
• Markedly elevated respiratory rate (>70 breaths per min)
• History of chronic cardiorespiratory disease including significant asthma
• Dyspnea and intercostal retractions, indicating respiratory distress
• Desaturation in 40% oxygen (3-4 L/min oxygen), cyanosis
• Extra pulmonary symptoms
• Parent unable to care for child at home
• Apnea and acidosis are indicators for pediatric ICU (PICU) referral.

Administer supplemental humidified oxygen to maintain transcutaneous saturation above 92%. Unger and Cunningham found that oxygen supplementation is the prime determinant of length of hospitalization.³⁶

These infants are mildly dehydrated because of decreased fluid intake and increased fluid losses from fever and tachypnea. The goal of fluid therapy is to replace deficits and to provide maintenance requirements. Avoid excessive fluid administration because this may promote interstitial edema formation, particularly if a component of inappropriate antidiuretic hormone release is present. Oral therapy is preferred.

Administer saline nose drops and perform nasal and oral suctioning. Carefully monitor the patient for apnea. Pay attention to temperature regulation in small infants.

Infants with bronchiolitis and recurrent apnea or increased work of breathing with respiratory failure occasionally require mechanical ventilation. Treat these patients supportively, providing adequate oxygen, ventilation, and hydration. Continuous positive airway pressure (CPAP) and intermittent mandatory ventilation (IMV) with positive end-expiratory pressure (PEEP) have been used to successfully treat these infants. Negative pressure ventilation has been used successfully, with reduced need for endotracheal intubation and shortened lengths of stay. The typical approach in patients who require ventilation using IMV and PEEP is to ventilate at rates slow enough to allow adequate emptying during exhalation.

In addition, a short inspiratory time optimizes ventilation to more compliant lung units without overdistending more obstructed ones. Aggressive weaning over the first 2 or 3 days is not warranted and is usually unsuccessful. Once the illness subsides, weaning can proceed quickly. Infants with progressive hypoxemia unresponsive to conventional ventilation may respond to high-frequency ventilation or extracorporeal membrane oxygenation.

Current experimental therapies for infants with pulmonary insufficiency caused by bronchiolitis include surfactant and nitric oxide. Heliox is a mixture of oxygen (20-30%) and helium (70-80%) that has lower viscosity than air. It has been used successfully in cases of airway obstruction, croup, airway surgery, and asthma to reduce respiratory effort during the period of airway compromise. Its use in bronchiolitis has had mixed results. A meta-analysis of several small studies suggests that surfactant therapy may shorten the duration of ICU stay in children ventilated for bronchiolitis. A multicenter trial evaluated administration of normal saline and 3% saline with or without bronchodilators. Combined results suggested a shortened length of stay but there were too few patients in each arm of the study to reach statistical significance.^{37, 38}

Discharge criteria primarily rests with (1) the ability of the caretaker to manage the infant's nasal congestion, (2) improvement in respiratory distress as evidenced by respiratory rate less than 60-70 breaths per minute and resting oxygen saturation above 92% without supplemental oxygen, (3) adequate oral intake, and (4) education and confidence of the caretaker.

Consultations

When a healthy infant presents with a history, physical examination findings, and course consistent with uncomplicated bronchiolitis, no consultations are necessary; however, refer infants with comorbidities, atypical histories, or critical conditions to a pediatrician, preferably at a center that can provide a spectrum of pediatric subspecialists in critical care, pulmonology, and infectious disease.

Diet

Although young infants have the unique ability to breathe and swallow simultaneously, risk of aspiration is significant when the respiratory rate is above 60 breaths per minute. Fever and hyperpnea may contribute to excessive fluid losses. For these reasons, infants who are hospitalized with bronchiolitis require careful fluid monitoring and provision of nasogastric or intravenous fluids when hyperpnea precludes safe oral feeding.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Drug Category: Oxygen

Oxygen decreases the work of breathing, thus delaying the onset of respiratory muscle fatigue, allowing other therapies to work.

Drug Category: Bronchodilators

These agents act by decreasing muscle tone in both small and large airways in the lungs, thus increasing ventilation.

Drug Category: Immunoglobulins

Specific immunoglobulin products with anti-RSV activity have been developed for prophylaxis of high-risk patients against RSV infection.

Drug Category: Antibiotics

Viruses are the primary etiologic agents in bronchiolitis; therefore, routine administration of antibiotics has not been shown to influence the course of this disease. Although rapid diagnostic techniques are available to identify RSV as a causative agent in bronchiolitis, they are not readily available for other viruses. In small, acutely ill infants, clinically excluding the existence of secondary bacterial invasion may be difficult. Administration of broad-spectrum antibiotics in critically ill infants is often justified until culture results prove to be negative.

At least 2 prospective studies of 1680 previously healthy febrile infants found lower rates of serious bacterial infections in those with bronchiolitis than in matched controls.

A positive test result for RSV does not exclude co-infection with other respiratory pathogens. Co-infection with parainfluenza, influenza, measles, adenovirus, hMPV, pertussis, Legionella, and Pneumocystis are all possible. Severe cases and those that do not follow typical courses for RSV bronchiolitis may benefit from investigation for co-infections.

Drug Category: Antiviral agents

Ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a synthetic nucleoside analog that resembles guanosine and inosine. It appears to interfere with the expression of messenger RNA and inhibit viral protein synthesis. Ribavirin has a broad spectrum of antiviral activity in vitro, inhibiting replication of RSV, influenza, parainfluenza, adenovirus, measles, Lassa fever, and Hantaan viruses. In adults, ribavirin can be used for the treatment of other infections, including hepatitis C.³⁹

Drug Category: Decongestant, Nasal

No controlled studies on the use of nasal decongestants in bronchiolitis have been performed. Supposition suggests that aerosol racemic epinephrine is primarily beneficial as a nasal decongestant.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Further Inpatient Care

• A systemic review of 3 randomized clinical trials concluded that chest physiotherapy does not improve clinical score, oxygen requirements, or hospital length of stay and may increase distress and irritability in infants.³³
• For patients who are hospitalized, follow-up appointment with a primary care physician 1-2 days after discharge is indicated to recheck room air saturation and for parental reassurance.
• No further laboratory testing is necessary unless the patient must test respiratory syncytial virus (RSV) negative for return to an environment where high-risk patients are present, such as at medical daycare centers or group homes. Secretions may remain positive for RSV for as long as 21 days after the onset of symptoms.²⁰

In/Out Patient Meds

• For children who required inpatient antibiotics for intercurrent infections, continue the same antibiotics to complete the suggested course.
• An older child with reactive airway disease may require continued treatment with bronchodilators.

Transfer

• Transfer to a facility that has an intensivist-managed critical care unit is indicated for patients with the following characteristics:
• • High risk
  • Requiring more than 40% oxygen
  • Extrapulmonary symptoms
  • Acidosis
  • Apnea
  • Unclear etiology of their symptoms

Deterrence/Prevention

• RSV is transmitted via direct contact with secretions of infected patients. Droplets and fomites do not play as important a role. Meticulous attention to handwashing between patient contacts should reduce the likelihood of hospital staff acquiring RSV infection from patients and of spreading infection by carrying RSV on their hands. Morbidity and death from RSV predominately occur in children younger than 2 years. Other high-risk infants and children include premature infants younger than 6 months, infants and children with underlying pulmonary or cardiac disease, and those with immunodeficiencies.
• Attempts to develop a safe and effective RSV vaccine have thus far been unsuccessful. A 1967 study of a formalin-inactivated RSV vaccine resulted in a 15-fold increase in hospitalization and mortality when immunized patients were subsequently reinfected. An adequate explanation for this exaggerated pulmonary response has not been elucidated. Active prophylaxis using RSV immunoglobulin intravenously (RSV-IGIV) at high doses (500-750 mg/kg) has been shown to prevent RSV in high-risk patients.
• The parenteral administration of human polyclonal RSV-specific immunoglobulin antibodies to infants has numerous disadvantages. These include intravenous administration monthly over 2-4 hours, the need to administer it in a clinic or hospital, and the potential for excessive fluid load. This therapy has been discontinued in favor of palivizumab.
• A more convenient RSV-specific monoclonal antibody preparation is available. Palivizumab (Synergis) can be administered intramuscularly at a dose of 15 mg/kg every 30 days from October through February or according to the local RSV season.^{40, 41}
• In a multi-institutional, randomized, placebo-controlled study of 1502 high-risk, preterm infants in 139 centers in the United States and Canada during the 1996-1997 RSV season, hospitalizations were decreased by 55%.^{42, 43, 44, 45, 46} Hospital length of stay, days on oxygen, and ICU admissions were all reduced. Adverse effects were uncommon Romero summarized 4 outcome studies encompassing over 16000 children after the use of palivizumab.⁴⁷ All showed high effectiveness in reducing RSV admissions.
• A 2005 study of pediatric ICU (PICU) admissions for bronchiolitis did not demonstrate a decrease in admissions or need for ventilation before and after palivizumab was licensed. Eighty-three percent of the infants admitted to the PICU did not meet criteria of the AAP for RSV prophylaxis.⁴⁰ Horn and Smout determined that the highest resource use was in infants born at 33-35 weeks' gestation and their outcome was worse than infants born at less than 32 weeks' gestation. Stevens and Hall summarized the controversies regarding the use of palivizumab for children born at 32-35 weeks' gestation. They concluded that infants born at 32-35 weeks' gestation without chronic lung disease who are less than 6 months old at the start of the RSV season may benefit from RSV prophylaxis if at least 2 of the following are observed: daycare attendance, school-aged siblings, passive smoke exposure, airway abnormalities, or neuromuscular disease.⁴⁸
• Prevention of serious RSV infections using palivizumab may reduce the incidence of subsequent wheezing.^{49, 50}
• Unfortunately, although possibly cost-effective, per-patient cost is approximately $5000, restricting availability to only high-risk patients.^{51, 52, 53, 54}
• Several studies have demonstrated a beneficial effect of breastfeeding, particularly prolonged nursing, to prevent or lesson the severity of RSV bronchiolitis.^{55, 56}

Complications

• As with any disease, complications are possible, including those caused by therapy. In most cases, the disease is mild and self-limiting. In infants who are immunosuppressed and those with preexisting heart or lung disease, RSV bronchiolitis can result in any of the following:
• • Acute respiratory distress syndrome (ARDS)
  • Bronchiolitis obliterans
  • Congestive heart failure
  • Secondary infection
  • Myocarditis
  • Arrhythmias
  • Chronic lung disease
• Complications of therapy include the following:⁵⁷
• • Ventilator-induced barotrauma
  • Nosocomial infection
  • Beta-agonist–induced arrhythmias
  • Nutritional and metabolic abnormalities
• Strict attention to fluid and nutritional therapy, avoidance of unnecessary invasive monitoring, infection control, and judicious ventilator management (including the use of high-frequency oscillatory ventilation to avoid volutrauma, barotrauma, or both), may preclude many of these complications.
• A possible association with asthma has been reported.^{58, 59}
• • RSV infections have been associated with the development of asthma, with an odds ratio of 4.3 in children aged 11 years or younger. However, because virtually all children encounter an RSV infection during the first 2-3 years of life, this association may reflect a multifactorial etiology or genetic predisposition.
  • Genetic variation in the interleukin-8 promotor region has been associated with susceptibility to severe bronchiolitis. Family-based association revealed that the interleukin-8 variant was transmitted significantly more often than expected in children who wheezed after the episode of bronchiolitis. This effect was not observed in a group of children who had bronchiolitis but did not develop wheezing. This association was significantly more frequent in patients with postbronchiolitis wheeze than in the general population. Thus, a genetic predisposition to wheeze following severe RSV bronchiolitis is suggested.^{2, 60} Some studies suggest that human metapneumovirus (hMPV) or coinfection with RSV and hMPV contribute to the likelihood of asthma in later years.⁶¹
• As many as 1% of previously healthy children and 3% of developmentally impaired children with bronchiolitis experience neurologic complications. These include seizures, encephalopathy with hypotonia, irritability, and abnormal tone. The long-term prognosis for these children is still unknown.

Prognosis

• RSV does evoke immunoglobulin E (IgE) elaboration.⁶² Recent studies suggest that IgE levels can be used as a marker of acute disease severity.
• Multiple small studies suggest that children who have been hospitalized with RSV bronchiolitis have a higher incidence of reactive airway disease and more abnormalities in pulmonary function than children never hospitalized for RSV.^{60, 63} These abnormalities may persist for as long as 5 years, eventually normalizing.
• Conflicting small studies have failed to prove whether early treatment of acute RSV bronchiolitis with ribavirin reduces the persistence of pulmonary dysfunction.⁶⁴

Patient Education

• Importance of RSV prophylaxis for high-risk patients
• Importance of avoiding RSV exposure in the first 2-3 months of life
• Natural history of bronchiolitis

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• Failure to recognize severity based on tachypnea and desaturation
• Failure to recognize apnea in young infants with bronchiolitis
• Failure to recognize myocarditis
• Over treatment with beta-agonists

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The author gratefully acknowledges Michael Gayle, MBBS, FRCPC, FAAP, FCCM, for his participation in the original production of this review in 2001.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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