Bronchiolitis: A Systematic Approach to Evaluation, Treatment, and Prevention

Author: Stephen R. Luber, MD, FAAP, Pediatrician, Rockwood Clinic, Spokane, WA; Clinical Faculty, University of Washington Medical School.

Peer Reviewers: Sharon E. Mace, MD, FACEP, FAAP, Associate Professor, School of Medicine, Ohio State University; Director, Pediatric Education/Quality Improvement, Cleveland Clinic Foundation; Director, Observation Unit, Cleveland Clinic Foundation; and Steven M. Winograd, MD, FACEP, Attending Physician, Department of Emergency Medicine, St. Joseph Hospital, Reading, PA.

Bronchiolitis begins with symptoms of a mild upper respiratory infection, but it rapidly may develop into a critical, life-threatening event for the at-risk infant. The hypoxic child experiences increased work of breathing, and respiratory failure may develop with startling rapidity. Bronchiolitis remains the most common admission to a pediatric service, with more than 125,000 admissions per year in the United States.1 Eleven to 15 percent of children will see their physician on an outpatient basis for this common infectious pulmonary event.2

During the winter respiratory care season, the evaluation and treatment of this viral infectious disease syndrome is an everyday event for the primary care, emergency, and urgent care physicians, as well as hospitalists and intensivists. There is, however, little consensus on many aspects of the diagnostic workup and subsequent treatment of bronchiolitis. There are questions concerning the utility of radiographs, viral assays and cultures, and common blood tests. Significant controversy exists concerning the use of commonly employed aerosolized bronchodilators, systemic steroids, and antibiotics. Not only do the published studies often contradict each other, they often are contrary to established community standards of therapy. Criteria for hospital admission vary within institutions and across geographical regions. The variation in approach has been shown to drive increasing admission rates and the wide disparity in resource utilization without discernible clinical benefits.3,4

Several studies have illustrated successful utilization of practice guidelines based on consensus best practice for inpatient care. Despite clearly derived benefits in cost control, quality of care, and family satisfaction, these guidelines have not been widely implemented.5,6 Clinicians practicing in the outpatient setting find the majority of clinical studies directed at infants in the inpatient setting. Despite numerous articles published on the individual components of outpatient management of bronchiolitis, a similar systematic implementation of outpatient practice guidelines with effective analysis of clinical, economic, and family satisfaction outcomes has not been performed.

No universal consensus will come of any review of the current literature concerning the diagnosis and treatment of bronchiolitis. Therefore, it is important to look behind these studies and examine their results in light of their methodology and interaction with the underlying pathophysiology of bronchiolitis. This monograph recognizes these necessities and reviews the literature in light of current controversies to extract pertinent information for the emergency department (ED) and urgent care specialist to employ in their management of these potentially ill infants.—The Editor


Introduction

The signs and symptoms of respiratory infection are the most common cause of acute childhood illness visits to the primary care physician.2 These infections also frequently are seen in busy EDs and urgent care centers during the winter cold season. Practitioners in these settings have a unique opportunity to effectively intervene in the evaluation and treatment of these patients. Acute bronchiolitis is the most common lower respiratory tract infection (LRTI) seen in the general pediatric population.7 Effective outpatient evaluation and management of this entity can reduce hospital admissions while directing intensive therapy to those truly in need. The admission rate for bronchiolitis doubled between 1988 and 1996.1 The diagnosis of bronchiolitis led to 47% of all childhood lower respiratory tract hospitalizations in 1996 and fully 16% of all pediatric admissions in the same year.1 It results in an economic burden of more than $300 million annually.8

Bronchiolitis is defined pathologically as inflammation of the terminal bronchioles in infants and young children, usually as the result of viral infection. The inflammation leads to airway obstruction as a result of edema and accumulation of mucus and cellular debris within the small airways. The obstructive pulmonary disease may lead to air trapping and hyperinflation while work of breathing is increased by dramatic narrowing of the airways.9 Hypoxemia occurs early in the process, with respiratory failure and hypercapnia being rare and late events.9 The mechanism of illness drives traditional approaches to therapy. The fundamental role of inflammation leads to consideration of anti-inflammatory therapy with steroids. The role of smooth muscle contraction and bronchoconstriction is controversial and leads to debate over the well-established use of bronchodilators. Viral infection triggers lead one to consider antiviral agents.

Respiratory syncytial virus (RSV) infection is the leading cause of acute bronchiolitis. Overall prevalence is estimated at 43-74% of cases of bronchiolitis throughout the year, with a dramatic increase during winter months.1 During these annual winter epidemics, it may account for 90% of cases.10 The season is relatively long (12-16 weeks), with poorly defined boundaries in contrast to the brief, intense, sharply defined influenza season. The overwhelming importance of RSV infection has led to the erroneous synonymous use of RSV infection and bronchiolitis, and many clinical trials restrict inclusion criteria to confirmed RSV inflection. Other agents may cause bronchiolitis. Parainfluenza virus 3, adenovirus, and rhinovirus can provoke the same inflammatory response and account for year-round presentation of children with bronchiolitis.11,12 Influenza virus, Mycoplasma pneumoniae, and Chlamydia trachomatis are important causes of infant interstitial pneumonias which may present with virtually identical signs and symptoms in the infant. Coinfection of these agents with RSV in up to 10% of cases has been cited.13,14

Human metapneumovirus recently has been identified as a serious pathogen causing viral respiratory tract infections. It apparently has a similar epidemiologic picture to RSV but the clinical syndrome generally milder. It may cause severe illness in younger at-risk infants.15

RSV infection occurs in 50% of children in the first year of life, with the remainder seroconverting by age 3.16 Natural immunity is short-lived, and reinfection occurs throughout life with most illness relatively mild beyond the first two years. Eleven to 15 percent of children are brought to the attention of their physicians for RSV LRTI in the first year of life. Ten percent of these children will require admission.1 More than 80% with severe illness will be between 6 weeks and 6 months of age. Boys are represented nearly 2:1 among serious cases, and lower socioeconomic classes are disproportionately represented.8,9,12

There are an estimated 5000 deaths per year due to RSV infection in the United States.17 Case fatality rates for hospitalized children may be up to 10-15% in children with multiple risk factors, 3-4% with underlying cardiac and pulmonary disease, and between 1% and 2% for all hospitalized children.18,19 While children with risk factors represent a higher risk for serious disease and subsequent hospitalization, the vast majority—80%—of admissions occur in healthy children without antecedent illness or risk factors.

Historically, management of bronchiolitis has been limited to supportive measures with the inherent course of illness dictating hospital admission and utilization of medical resources. Despite the vast number of children with acute bronchiolitis and intense interest in diagnosis and treatment, there had been little consensus on the most appropriate treatment and vast differences in approaches to management within individual medical centers. Recent meta-analyses of treatment options and institution of consensus guidelines have served to reinforce the role of supportive therapy as the critical basis of care despite widespread use of bronchodilators, systemic steroids, and antibiotics in the outpatient setting by experienced, responsible practitioners.

Some of this dichotomy comes from practice setting. Most reported therapeutic trials have centered on the moderately to severely ill hospitalized patient representing one in 10 affected children. Recent trials centered on the clinical approach to the acutely infected child in the outpatient setting present strong evidence for guided use of systemic steroids and sympathomimetic aerosols in bronchiolitis. These therapies effectively may reduce hospital admissions and provide symptomatic relief for ill children.

It long has been observed that infants who recover from acute bronchiolitis have an increased frequency of recurrent wheezing. The reported variance is high, from 29% to 83%.20 The relationship between recurrent infant wheezing with later development of asthma and of early viral infection is the subject of intense scrutiny. Two theories have emerged and represent alternative ways of accounting for long-term sequelea. The first approach postulates direct damage to the respiratory epithelium by the infecting virus. The second states that the symptoms are a result of a predisposed host with an exaggerated response to the viral infection through either decreased pulmonary function or tendency to atopic disease. The relationship between infant viral infections, wheezing, and the subsequent development of asthma continually is evolving and is beyond the scope of this article.

An examination of the Tucson Children’s Respiratory Study data may shed some light on the interaction between host characteristics and the inciting virus.21 In doing so, one may begin to discern how reputable practitioners observing individual patients may come to different conclusions from studies assuming the homogenous nature of children with the diagnosis of bronchiolitis or those studies dependent on meta-analysis.

In a prospective study of nearly 20 years, more than 800 children were followed for incidence of lower respiratory disease with wheezing. Four groups evolved:

1) Those who never wheezed;

2) Those who wheezed late in childhood but not before age 3;

3) Those who wheezed early in life but did not wheeze after age 6 (early wheezers); and

4) Those who wheezed early and persisted (persistent wheezers).

The latter two groups are of interest. They present in the first year of life with wheezing and commonly are diagnosed as having bronchiolitis. Several important characteristics differentiate the two groups. Early wheezers had impaired pulmonary function tests by squeeze technique in infancy, indicating smaller airways. Viral infection producing airways edema had a more significant effect on work of breathing in these infants compared to normal infants with larger airways. While recurrence of wheezing occurred, the infants were well between events and the process resolved as the children grew. They had relatively smaller airways than normal at 6 years but did not develop classic asthma. There were 113 infants in this category.21-23

Persistent wheezers had normal pulmonary functions as infants but had an increased IgE level at 9 months, increased occurrence of atopy by skin test and occurrence of eczema, and were more likely to have a maternal history of asthma. Exacerbations of wheezing in the first years were triggered by viral infection, but they wheezed and required more therapy between acute events. Pulmonary functions had deteriorated by age 6. They may be interpreted as early presentation of (ongoing) asthma. There were 164 infants in this category.22,23 (See Table 1.)

Infants in the first group had wheezing secondary to airway edema and narrowing and would not be expected to respond to classic beta-adrenergic medication. Infants in the second group with early asthma may be expected to benefit from classic asthma therapy. The practicing physician has no reliable way to identify these patient groups with first occurrence of wheezing illness. They all will be diagnosed as having bronchiolitis. Any study cohort of first-episode wheezers will have the two groups represented. One group may respond significantly to a specified therapy with the effect diluted with inclusion of the second group. The clinical trial will show no significant therapeutic effect even though there was a salutary effect on one of the two groups. In contrast, the caring, observing practitioner would see and record the significant effect on the individual patient. The practitioner will elect to employ the therapy widely, despite the clinical trial suggesting little efficacy for the treatment modality.

The long-term relationship between early infection with RSV and asthma will be the subject of debate for the foreseeable future. One recent study of mild RSV bronchiolitis indicates no increased risk for airway hyper-reactivity with observable pulmonary function abnormalities resolved by age 8-12 years.24 Other studies on long-term implications of bronchiolitis frequently are confounded by inclusion of the two distinct groups identified in the Tucson study.

Readers should bear in mind these two groups when discussion of diagnosis and treatment ensues. The focus will be on the child with first episode of wheezing without strong indication of atopy. Children with recurrent wheezing, evidence of atopy, and strong familial history of allergy and/or asthma potentially represent early manifestation of classic asthma with chronic airways inflammation and secondary bronchospasm as opposed to the infectious acute airway inflammation and edema of bronchiolitis.

Clinical Presentation

The viral infections leading to bronchiolitis present in a protean fashion. For most children, the infection with RSV, adenovirus, or parainfluenza virus appears as a mild to moderate upper respiratory infection requiring little more than parental concern and support.9 The infection typically begins with 1-3 days of clear rhinorrhea and upper respiratory congestion. A low-grade fever may be present, and the child may appear ill, with decreased appetite. The clinical course generally peaks by day 4 and rapidly resolves without sequelea. Physician or parental preference may dictate over-the-counter symptomatic relief. There is no evidence that antihistamine/decongestant therapy either affects the course of the illness or appreciably reduces upper respiratory symptoms.25 While there is wide regional variation in use of these agents, many physicians discourage their use in routine viral infections, particularly in patients younger than 6 months.

The onset of significant cough, typically worse at night, indicates progression to more serious lower respiratory involvement. Wheezing is a clinical signature of bronchiolitis. It erroneously has been ascribed to bronchospasm, but the origin generally is attributed to airway narrowing from inflammation and edema.2 Hypoxemia develops with more serious disease, and accessory muscles of ventilation become involved with prolonged expiratory phase and signs of obstructive lung disease. Pulmonary infiltrates may be seen on x-ray, leading to the diagnosis of viral pneumonia as an alternative or in addition to bronchiolitis. The primary infectious and pathophysiologic process is the same and the distinction is one of nomenclature and often is arbitrary.9 The therapeutic approach is similar and the appearance of infiltrates does not necessarily indicate the presence of bacterial pneumonia and is not an indication for the use of antibiotics. As the illness progresses, the child may show obvious signs of respiratory distress, with carbon dioxide retention leading to frank respiratory failure.2,9,10

Young infants may present with apnea as the sole manifestation.26 They often have a history of premature birth with an elevated incidence of pulmonary complications. It is uncertain whether the apnea is central or peripheral, and treatment is supportive with mechanical ventilation occasionally required. Central stimulants are not employed, as the apnea resolves promptly as the viral infection clears.

Secondary otitis media is not uncommon in bronchiolitis, approaching an incidence of 15-30%,2 and a dramatic increase in fever, irritability, or perceived pain should initiate a diligent examination of the tympanic membrane. The observed high frequency of otitis raised the question of whether RSV itself was a primary pathogen in otitis media. One study examined 42 successive children with bronchiolitis in the ED of the University of Pittsburgh with performance of tympanocentesis. Sixty-two percent had acute otitis media on presentation. They found only 14% of the children remained free of bacterial otitis during the course of their illness with the usual spectrum and frequency of bacterial pathogens. They concluded that RSV was not the primary pathogen in the development of the otitis, and bacterial otitis media should be treated with antibiotics.27

Clinical Evaluation

The physician in the acute care setting is charged with evaluating infants with acute respiratory infection and determining who has serious illness and needs intervention with pharmacologic and/or hospital support. The classic medical paradigm of a good history and thorough, directed physical examination supplemented by limited laboratory and radiological support is the approach of choice. The diagnosis of bronchiolitis is clinical by nature.

The advent of effective, though costly, prophylaxis for RSV has led to the identification of a high-risk group of infants who tend to have a more serious clinical course. These infants have inherent compromise to the cardio-respiratory system. They include children with congenital heart disease and cystic fibrosis, and premature infants with chronic lung disease. Children with compromised immune systems and uncomplicated premature infants younger than 6 months of age also are at risk.28 (See Table 2.) The attending physician is well advised to take a careful history looking for these risk factors. While these children bear a disproportionate burden of disease, it always should be remembered that the vast majority of serious outcomes with bronchiolitis occur in previously healthy children without identifiable risk factors.

Table 2. Risk Factors for Severe RSV Disease

The physical examination is directed to evaluation of the respiratory status of the infant as well as general physical well-being. The experienced clinician’s judgment of toxicity is invaluable. An estimation of dehydration helps to determine the general health of the infant. The infant using his strength for air exchange may not have the reserve or desire to maintain hydration with the work of feeding. The classic physical findings of tachypnea, cyanosis, fine crackles, and inspiratory and expiratory wheezing may be difficult to appreciate in an irritable, fearful child. The clinician must develop a feeling for air exchange in these children, looking for physical evidence of distress such as retractions, flare, and audible grunting, as well as recording the auscultatory findings. Often the chest is quiet, as the minimal air exchange cannot produce the classic wheezing of the bronchiolitic infant.28

Recognizing the difficult task of evaluating sick infants, one study prospectively evaluated more than 200 infants presenting for ED evaluation. They isolated six variables associated with serious illness requiring admission that have met with wide acceptance.29 (See Table 3.) The time course of clinical symptoms is important. The severity of RSV bronchiolitis reaches a peak in 48-72 hours. An otherwise healthy infant seen after that time period is unlikely to develop more severe disease.2

Table 3. Predictors of Severe
RSV Disease in Otherwise Normal Infants

Oxygen saturation by pulse oximeter in a quiet, feeding baby was the most important objective measure predictive of severe illness and need for hospitalization. It also is useful for objectively measuring response to either bronchodilator or oxygen therapy. An infant will defend oxygen saturation late into respiratory failure.22 An arterial blood gas determination of rising pCO2 may be necessary to assess impending respiratory failure in a toxic, tired infant. As with older children with asthma, tachypnea should drive down the pCO2, and a normal pCO2 may indicate severe respiratory distress. The risk of significant hypoxemia and CO2 retention generally begins with a respiratory rate greater than 60, and persistent tachypnea alerts one to the possibility of respiratory failure.2

Routine laboratory evaluation of complete blood count, metabolic panel, and urinalysis seldom add to the evaluation and are not recommended.30 The nasopharyngeal swab for RSV assay has come into wide acceptance, with sensitivities approaching 90%.31 Use of the test in selected sick infants with clinical bronchiolitis has several potential clinical benefits. Children with bronchiolitis appear to be at low risk for serious, invasive bacterial infection.32 One study examined 211 infants younger than 3 months of age with bronchiolitis and found no evidence of bacteremia, meningitis, or urinary tract infection.33 A positive assay, therefore, may be used to postpone a sepsis workup in a sick infant. RSV bronchiolitis will have associated serious bacterial illness by sepsis workup in fewer than 2% of cases.34 Algorithms for institution of sepsis evaluation and institution of systemic antibiotics are keyed to the febrile child without identifiable focus of infection. The use of antibiotics for presumed sepsis has been reported to be associated with an increased frequency of subsequent bacterial infection and emergence of resistant organisms.35 The individual practitioner may elect to perform a septic workup for serious bacterial illness on a young toxic infant, but the diagnosis of RSV bronchiolitis predicts a very low yield. Confirming this viewpoint is a recent study looking at the use of intravenous broad-spectrum antibiotics in all children admitted for documented RSV bronchiolitis/pneumonia with classical symptoms and physical findings. A study reviewed 2396 children retrospectively who represented seven years’ worth of admissions for RSV bronchiolitis in a Texas children’s hospital. Broad-spectrum IV antibiotics were initiated in 70.5% of the patients and continued to discharge in 97% of these children. Performance of septic workup was at the discretion of the attending physicians. Unfortunately, data are not available on the number of septic workups performed. Twelve children had positive blood cultures all deemed skin contaminates. There were no positive cerebrospinal fluid (CSF) cultures.32 The 27 positive urine cultures—1.1%—is comparable to published series of asymptomatic bacteruria.36 Hoberman reported incidence of urinary tract infection of 3.5% in febrile infants with an identifiable source of fever (i.e., bronchiolitis, otitis media [OM], etc.).37 The authors concluded that asymptomatic bacteruria could not account for all the positive urine cultures and some must represent serious bacterial infection. There was no evidence of missed sepsis or meningitis in the hospitalized infants.

A negative RSV assay may suggest evaluation for influenza that typically runs concurrently with the RSV season. Influenza produces an interstitial pneumonia difficult to distinguish on clinical grounds from bronchiolitis in the infant and is a potentially treatable viral illness of significant mortality in a vulnerable infant. Recent studies of epidemiology of influenza have highlighted the importance of this respiratory pathogen with seasonal hospitalization rates comparable to those of RSV infections.38 Studies in Japan have registered higher rates of influenza hospitalization during epidemic years.39 Rapid laboratory diagnosis of influenza with good sensitivity and specificity is available on a Clinical Laboratories Improvement Act (CLIA) waived basis.40 Treatment using traditional amantadine antiviral agents and the neuraminidase inhibitors is effective with prompt diagnosis.41 When confirmed influenza is in the community, there is an increasing premium on consideration of specific viral etiologic diagnosis. A negative RSV assay of an ill child with LRTI should trigger consideration of influenza and appropriate diagnosis and treatment.42

The identification of specific viral etiology is a topic that will continue to interest clinicians as progress in diagnostic technology improves turnaround time while reducing costs, and specific antiviral therapies come to market. The use of a rapid direct fluorescent antibody (DFA) screen for respiratory virus pathogens was examined during a two-year period at the University of Utah. DFA-positive patients received fewer days of intravenous antibiotics, fewer days of oral antibiotics, and fewer discharge prescriptions of outpatient follow up antibiotics. As the staff became more comfortable with specific viral diagnosis fewer DFA-positive patients had intravenous antibiotics initiated during the second winter season than the first (26% vs 44%).43 Multiplex polymerase chain reaction (PCR) also was evaluated at the same institution, with excellent clinical correlation with viral shell cultures.44 While clinically useful on an individual basis, routine use of RSV assay has not been included in recent guideline implementation with significant monetary savings and little negative clinical impact.5

Chest x-ray findings in bronchiolitis are relatively nonspecific. Hyperinflation, peribronchial cuffing, atelectasis, and diffuse interstitial disease often are seen.45 (See Figure 1.

Figure 1. Chest X-ray of Typical
Infant with Bronchiolitis

Many films are read as normal, and the radiologic findings do not correlate with disease severity. The most compelling reason to order a film with the first episode of wheezing is to rule out confounding diagnoses that may present with the same picture of respiratory distress.46 Congenital heart disease with failure, cystic fibrosis, foreign body aspiration, and pneumonia from other infectious agents all may present similarly. Recent practice guidelines discourage routine utilization of the chest film without clinical repercussion.5 The emergency medicine literature has contributed to advocating decreased use of routine chest films in first episodes of bronchiolitis.47 In a survey of 140 infants with clinical bronchiolitis in Atlanta and Knoxville, 17 had abnormal films that led to three interventions with additional therapy. These were opacities leading to use of antibiotics for pneumonia possibly of bacterial origin. The one case of congestive heart failure visualized was predicted by physical examination. The authors conclude that routine first-time x-ray is not warranted, but commentary suggests the practice will not be abandoned soon.47

Treatment and Controversy

Recommended treatment of bronchiolitis has focused on supportive care of the patient ensuring adequate oxygenation and hydration as the viral illness runs its course.28 Fever with increased respiratory rate increases fluid requirements while oral intake declines with the general malaise of illness. The difficulty of suckling with tachypnea and hyperpnea also reduces the ability to maintain fluid balance. Hypoxemia is managed with supplementary oxygen to maintain oxygen saturations greater than 92%. The transition from outpatient to inpatient management often hinges on the ability of the infant to maintain adequate fluid intake and oxygenation.

In the hospital, care is directed at fluid support with restriction of oral intake, with respiratory rates greater than 60-80 to prevent aspiration.48,49 Evaluation for syndrome of inappropriate secretion of antidiuretic hormone (SIADH) proceeds as clinical condition warrants. Warm, humidified oxygen is administered with cannula, mask, or tent as tolerated by the infant. More intensive observation for apnea is warranted in the very young infant, particularly those with premature birth and subsequent lung disease. Intensive care with intubation and mechanical ventilation is indicated for respiratory failure. Respiratory failure may be defined by clinical observation with retained CO2 and inability to maintain oxygen saturation greater than 92-95% with inspired oxygen of 50% as laboratory support for more intensive treatment.50

Clinicians have long recognized many similarities in clinical presentation of infants with acute bronchiolitis and older children with acute asthma. The infants wheeze with prolonged expiratory phase and decreased air exchange. Searching for active intervention in the disease process, physicians have tended to treat bronchiolitis in a fashion resembling therapy of older children with the bronchospasm and airway inflammation of asthma. Supportive care has been augmented by the use of corticosteroids, aerosolized bronchodilators, antiviral agents, chest physiotherapy, and antibiotics.4 Recent surveys of common clinical practice reveal this approach, yet compendiums of best clinical practice, hospital guideline publications, and most meta-analyses of individual components51,52 recommend limited utilization of these therapies.5,6,53 They correctly point out the pathologic basis of respiratory distress in bronchiolitis is small airways edema and inflammation from acute viral infection, not the bronchospasm of acute asthma.54

This widespread disparity of treatment in the light of inconclusive studies highlights the dilemma for the practitioner. The treating physician must examine each component of care in light of his or her own clinical observation and experience and take into account the presentation of each individual patient to implement a reasonable evidence-based plan of care.

Bronchodilators. There have been many studies attempting to determine efficacy of bronchodilator treatment in acute bronchiolitis. Many early studies have been faulted for small sample sizes, use of sedated convalescent infants, and use of subjective clinical scoring systems. They have been performed on sick inpatients. Individually, these studies failed to show a convincing evidence for use of nebulized beta-adrenergic medication in bronchiolitis.55-58 Meta-analysis is a critical reappraisal of prior clinical studies and has been used draw further conclusions from these studies. Data are pooled, and statistically significant conclusions may be reached if study design parameters are appropriately matched. In 1996, one study examined the effect of all bronchodilators on bronchiolitis and found a significant, though mild, effect on clinical scoring. The researchers did not find a change in admission rate.51 The study often is faulted for inclusion of all bronchodilators, including anticholinergics. When limited to only beta-adrenergic medication, the results remain the same. While this study and others have demonstrated modest improvement in clinical scoring from beta-adrenergic medications, the relative benefits and lack of effect on critically relevant parameters such as admission rate, length of stay, and oxygen utilization have led consensus reports to discourage the routine use of albuterol aerosol in routine bronchiolitis.5,6,53

The potential for the potent alpha adrenergic effect of epinephrine to relieve airway edema has led to reconsideration for the treatment of bronchiolitis. Early work published by Kristjansson suggested a positive effect on clinical scores and oxygen saturation with use of aerosolized epinephrine vs. saline.59 Further studies on sedated inpatients showed clear preference for epinephrine vs. albuterol in clinical score and pulmonary mechanics.60 Reijonen demonstrated epinephrine as a safe medication with more rapid improvement in clinical score (Respiratory distress Assessment Instrument-RDAI) compared to albuterol.61 In 1995, the Journal of Pediatrics published a study of 42 infants younger than 12 months with first-time wheezing in the ED. L-epinephrine was compared with albuterol. The control group had greater length of stay in the ED, greater need for ongoing nebulization with albuterol, and decreased clinical scores relative to the epinephrine. Furthermore, 81% of the albuterol group required admission vs. 33% of the L-epinephrine group.62

The use of epinephrine in hospitalized infants with bronchiolitis was investigated in a placebo controlled multi-center trial in Australia. It was reported in the New England Journal of Medicine in July 2003. There was no difference in length of stay, vital signs, or respiratory effort.63 The accompanying editorial by highlights the uncertainty in the medical community over the use of aerosolized bronchodilators in bronchiolitis. They acknowledged that neither epinephrine nor albuterol routinely can be recommended for the treatment of infant bronchiolitis, but stated there is some evidence epinephrine reduces airway resistance and increases clinical scores compared to albuterol.64

There have been no studies published showing a clear clinical role for the use of anti-cholinergic medications either alone or in conjunction with other bronchodilators for the treatment of acute bronchiolitis.65

Emergency Department and Outpatient Issues

It may be concluded that epinephrine is safe and effective for the treatment of acute bronchiolitis in the ED. It would appear to offer significant clinical advantage over albuterol. It also would be prudent to insist on formal clinical assessment of the patient before and after treatment before routine use of any bronchodilator is prescribed and restrict utilization to those who show a clear clinical benefit. If there is no ascertainable improvement in clinical score, vital signs, or sense of well-being, it is sensible to discontinue the use of aerosol bronchodilators rather than increase the frequency of a demonstrably ineffective therapy.

Glucocorticoids. Bronchial inflammation is the fundamental pathophysiologic event in bronchiolitis. The presence of this inflammation with clinical similarity to asthma has led to widespread interest in the use of anti-inflammatory systemic cortico-steroids in acute bronchiolitis. Up to 60% of children with bronchiolitis will receive systemic steroids.53 Despite the teleological attractiveness of this hypothesis, early studies have failed to show clinical benefit. A study published in Pediatrics in 1983 did suggest the use of albuterol with dexamethasone was superior to placebo or either albuterol or dexamethasone alone in acutely wheezing infants. The broad entry criteria limit its usefulness in application to uncomplicated bronchiolitis.66 In a 1991 study of 29 previously healthy infants admitted for bronchiolitis, dexa-methasone or placebo was added to standardized therapy of oxygen fluids, albuterol, and ipraprotium aerosols. No difference in oxygen saturation, clinical score, or pulmonary function was noted on day 3.67

Randomized controlled trials published in Lancet in 1997 failed to show benefit from either oral or intramuscular dexamethasone in acute bronchiolitis.68 In 1997, a controlled study examined the addition of dexamethasone to albuterol in hospitalized children with bronchiolitis. Seventy-two infants were enrolled, and no differences were detected in length of stay, clinical scores, or need for further intervention.69 As a result, recent compendiums of clinical guidelines published in Clinical Evidence as well as guidelines used in clinical studies of hospitalized patients have all recommend against routine use of steroids in bronchiolitis.5,6,53

A meta-analysis published in Pediatrics in 2000 reviewed six randomized, controlled trials. The analysis attempted to ask two significant questions:

1) Is systemic steroid therapy associated with a decreased length of hospital stay?

2) Does such therapy provide symptomatic improvement?

Differences in rating scales, endpoints, dosing, and starting points led to difficulty with selection of papers to review. All subjects were younger than 24 months. Exclusion criteria included previous wheezing and chronic cardio-respiratory disease. Two studies limited patients to positive RSV laboratory tests. Corticosteroid use was oral, intramuscular, or intravenous. Compounds used included dexamethasone, prednisone, prednisolone, and hydrocortisone. None of the studies reported adverse effects of the use of the steroids, and meta-analysis showed the use of corticosteroids in the treatment of bronchiolitis in infants may be more effective than previously acknowledged. There were differences in symptom scores within 24 hours of treatment. As symptom reduction is associated with discharge from the hospital, the length of stay differential was 0.43 days per patient in favor of treatment. The authors were careful to recommend further study and suggested a research design to resolve the question over a broad range of disease severity. They did comment on the long history of safe and effective steroid therapy in asthma and concluded systemic steroids should be considered in the therapy of infants with bronchiolitis.52

Confirming the ongoing controversy within academic pediatrics concerning steroid use in inpatients with bronchiolitis, the September 2002 issue of The Pediatric Infectious Disease Journal offers a review of the literature from researchers at Turku University of Finland. They conclude that current evidence does not support the use of systemic steroids in wheezing children with primary bronchiolitis younger than 2 years.70

Attempts to explain study conclusion differences based on dosing, outcome measures selected, selection of steroid used, route of administration, inpatient vs. outpatient setting, and stage of illness at time of intervention are useful speculations for future trials, provide substrate for academic musings and ferment, and will alter structure of future meta-analysis, but cannot be used to draw firm conclusions concerning general use of steroids in uncomplicated bronchiolitis.

Emergency Department and Outpatient Issues

The majority of patients with bronchiolitis are not admitted to the hospital and are treated as outpatients by parents, primary care physicians, and ED physicians. These practitioners often use oral corticosteroids in bronchiolitis. Most studies of steroids in bronchiolitis have been performed on inpatients. Early in 2002, the Hospital for Sick Children in Toronto published a study of ED utilization of dexamethasone. The objective was to investigate use of a single dose of oral dexamethasone (1.0 mg/kg) in children younger than 2 years of age. Seventy children were enrolled in the study. They were given medication or placebo and observed for four hours in the ED. At four hours, the decision to admit or discharge was made. Outpatients were continued on a daily dose of dexamethasone 0.6 mg/kg with albuterol by small volume nebulizer (SVN). The treatment group had significantly fewer admissions—17% vs. 41%—and fewer children with a poor clinical response over four hours measured by a Respiratory Assessment Change Score (RACS). There was no difference in hospitalization following discharge from the ED, and clinical scores were similar seven days following ED visit.71

The authors were conservative in their conclusions, suggesting further research. An editorial by Dr. John T. McBride in the same issue of The Journal of Pediatrics, while complementing the authors on their study, offered alternative explanation for the results and urged caution before implementing the protocol in clinical practice.72 However, the study is straightforward and directed at answering a specific clinical question of great importance, and the data are compelling.

Further evidence supportive of routine corticosteroids in children with mild to moderate bronchiolitis was published in 2002, following a study of outpatients with clinically defined first episode of bronchiolitis seen in the ED of the University of South Alabama. Subjects were randomized to either prednisolone (2 mg/kg/day divided bid ´ 5 days) with aerosol or oral albuterol or albuterol alone. Fifty-one subjects were enrolled and followed with a clinical bronchiolitis score. There were early significant differences favoring the treatment group. No difference in hospitalization was noted.73

Physicians in the outpatient setting are well-advised to read the articles and associated editorial and apply the evidence to their clinical practice as their experience dictates.

Long-term Considerations of Corticosteroid Use. The association between infant bronchiolitis and subsequent wheezing long has been observed. It would be attractive to intervene early to prevent subsequent episodes of bronchospasm. Investigators have looked at this issue in several controlled studies. Van Woensel and colleagues treated hospitalized infants with either prednisolone 1 mg/kg/day for seven days or placebo. There was no difference in respiratory symptoms recorded by telephone interviews during the next three years.74 There was no difference in nocturnal cough, daily respiratory symptoms, or pulmonary functions in infants younger than 12 months of age who were administered inhaled fluticasone vs. placebo administered for three months following hospital discharge.75 With a first-time bronchiolitis admission, nebulized budesonide was given for 14 days after discharge. No difference between treatment and control groups in need for respiratory medication, physician visits, or re-hospitalization was found for nine months.76 While there may be short-term benefits with the use of steroids in bronchiolitis, studies do not support the idea that they prevent further episodes of wheezing.

Antibiotics. The syndrome of bronchiolitis is a consequence of an acute viral infection. Other than the recognized and relatively common occurrence of bacterial otitis media, super-infection with bacteria causing systemic infection is uncommon.30,34 Some authors suggest the use of RSV assay may eliminate the need for a sepsis workup in a young infant with clinical bronchiolitis. Incidence of serious bacterial infection is fewer than 2% in an infant younger than 2 months of age with a positive RSV assay. A positive RSV immunoassay associated with signs and symptoms of clinical bronchiolitis was considered evidence of RSV infection.34 In recent series evaluating evidence-based guidelines, more than 50% of infants admitted for bronchiolitis received antibiotics.5 Antibiotics are indicated for documented bacterial infection and the comorbid otitis media common in RSV infections. Routine coverage for possible bacterial infection in the lungs and upper airway is not indicated or necessary.30

Antiviral Therapy. An effective antiviral agent theoretically would be of benefit in the treatment of acute viral bronchioles. Ribavirin is a synthetic nucleoside virostatic agent that inhibits messenger RNA and prevents replication of many viruses, including RSV.77 It has been promoted heavily for the treatment of seriously ill infants with RSV infection. Following early studies indicating clinical improvement but no effect on length of stay in non-ventilated patients, a 1991 clinical trial was published of ventilated patients indicating reduced time of mechanical ventilation, decreased length of stay, and decreased mortality.78 The American Academy of Pediatrics (AAP) recommended use in high-risk infants with serious RSV infection.76 A multi-center trial published in The Journal of Pediatrics in 1996 showed no difference in length of ventilation or mortality.79 A subsequent review of 10 small trials failed to confirm early findings of efficacy.80 The questions of toxicity and possible teratogenetic effects to health care workers, significant expense, and questionable efficacy have led the AAP to modify its stance. Ribavirin is to be considered on a case-by-case basis for infants with immunosuppression or immunodeficiency. Infants with underlying chronic lung disease, congenital heart disease, and cystic fibrosis are candidates for treatment.81 A recent randomized trial in previously healthy infants with severe RSV bronchiolitis showed markedly fewer episodes of reactive airways disease and respiratory admissions in the year following the signal event.82 Enthusiasm for the treatment seems to center within specific institutions with common usage in certain centers and virtually no use in others. Its role remains controversial.

Studies of the use of RSV immunoglobulin and monoclonal antibody to RSV in sick children with RSV bronchiolitis have indicated rapid clearing of viral burden with active agent. However, the rapid clearing of virus from tracheal aspirates was not associated with change in clinical course.83 Once infection initiates a serious host inflammatory reaction, specific antiviral therapy has been of little benefit. Studies of antiviral therapy early in the course of illness have not been published.

Chest Physiotherapy. Despite widespread use of chest physiotherapy in the hospital treatment of bronchiolitis, there is very little evidence of efficacy. In a small inpatient study of infants with mild to moderate bronchiolitis, there was no difference in pulmonary compliance, resistance, or work breathing before and after chest physiotherapy.84 There virtually are no data on implementation with infants with demonstrated atelectasis or those intubated with mechanical ventilation.

Hospital Guidelines—The Cincinnati Experience

Physicians at the Children’s Hospital Medical Center in Cincinnati published their experience with hospital care guidelines for epidemic bronchiolitis in December 1999. Examination of hospital records between 1993 and 1997 had revealed a wide variation in criteria for admission and subsequent treatment. Admission rates had risen 15% per year during the period. The principal indication for admission appeared to be the physician decision to employ the use of beta-adrenergic inhalation therapy. A growing body of evidence had cited lack of efficacy for bronchodilator therapy. A study team of 12 participants, including pulmonologists, community physicians, hospital physicians, nurses, respiratory therapists, and members of the hospital division of Health Policy and Clinical Effectiveness, was formed in 1996 to study the problem.5

The committee was charged with development of clinical guidelines based on academically supported best practice. The population was limited to infants younger than 1 year of age with a first episode of classic bronchiolitis. The guidelines were implemented on a voluntary basis during the ensuing year with daily monitoring by the study coordinator, chief resident, and head nurse. Extensive physician detailing with presentation at grand rounds, meeting of community physicians, house staff training sessions, and nurse education forums supported the effort.

Table 4 highlights the basis of the guidelines and principles of therapy.

Table 4. Summary of Guidelines Principles

The data was analyzed following 1997. Thirteen hundred historical controls from the prior four-year period were compared with 229 infants admitted that winter season with classic initial bronchiolitis. Demographic characteristics of both groups were similar. Seventy-nine percent of admissions were admitted through the voluntary protocol. Admissions rate declined 29%, with length of stay decreasing from 2.9 to 2.4 days. Readmission rates remained constant at 3%, and patient satisfaction surveys showed 93% approval for those treated by guideline vs. 77% admitted off-guideline.5

Bronchodilator therapy utilization declined from 69% to 43% post implementation. Multiple doses fell from 57% to 28%. Curiously, neither nurses, respiratory therapists, nor house staff embraced the use of a formal scoring systems for post bronchodilator improvement. RSV assay utilization fell from 89% to 43%, and chest x-ray utilization fell from 70% to 56%. There was no change in the 6-8% use of blood gas determination or the 56-57% incidence of antibiotic usage.5

Extensive analysis was done to ensure hospitalization and utilization rates were not affected by a mild RSV season. Utilization of other hospitals and confounding admitting diagnosis by practitioners anxious to avoid the guidelines were not detected. Hospital costs per admission fell 37% during the study period, with a 77% decrease in respiratory therapy costs. There was no increase in morbidity and mortality with these savings. Parents were surveyed for satisfaction during the trial, and the guideline group was significantly more pleased with their experience than families treated outside the guidelines. A preference also was noted with comparison to existing historical hospital patient satisfaction surveys.5

Cincinnati Follow Up

The successful initiation of a clinical guideline program with the full backing of the hospital administration, academic medical departments, nursing and resident staff is a significant achievement. Maintaining utilization of the guidelines while letting them evolve to meet changing staff expectations while incorporating new clinical data is another and perhaps more difficult task. The group from Cincinnati reported their experience of three years following introduction of guidelines in October 2000.85

The guidelines had evolved, reflecting increasing evidence of the efficacy of epinephrine aerosol in the ED in preventing subsequent admission. This led to insertion of a somewhat ambiguous algorithm recommendation in 1998, which was interpreted by many practitioners as a direct endorsement of epinephrine aerosol for all patients. The evidence was left in the working documents, but implementation of the algorithm was removed in 1999.

Admission rates continued to drop through 1998 and 1999 at a rate of 21% and 23%, respectively, for a total reduction in three years of 56%. Length of stay continued to drop, reaching 2.1 days in 1999. Total reduction of hospital costs fell almost 15% from $3297 before implementation to $2825 following. Rates of ancillary service utilization remained low with continued broad support in the physician and parent community.85

Multisite Extension of Cincinnati Guidelines

The success of the Cincinnati Guidelines led to their implementation in the 11 Child Health Accountability Hospitals in the winter of 1998-1999. Infants younger than 1 year with first-episode bronchiolitis were included. Oxygen use, radiologic evaluation, and arterial blood gas (ABG) determinations showed insignificant declines. RSV assay utilization rose slightly. The number of children initially treated with bronchodilators fell 9%, with numbers of multiple treatments dropping from a median of eight doses to three doses post implementation. Ipraprotium use fell from 17% to 0.2%, while trials with epinephrine aerosol increased from 13% to 34% of patients. Systemic steroid used dropped 44%.86

It is notable with multiple contemporary publications citing lack of efficacy of aerosolized bronchodilators and significant protocol emphasis on objective limited use of said treatments that attending physicians continued to employ this therapy on a regular, consistent basis during the observed periods. Selection and duration of use showed significant learning experiences. The report’s conclusion cites the difficulties in implementing evidence-based medicine in multiple centers and highlights the necessity for effective local leadership and physician buy-in by department chairmen and local thought leaders. The difficulty in changing embedded practice is highlighted.86

Cleveland Clinic and Upstate Medical Center

Implementation of guidelines in the Cincinnati experiences was limited by design to infants with a first episode of clinical bronchiolitis. A later examination of a more heterogeneous group of children with documented RSV disease, including children with prior episodes of wheezing (30%) indicated a broader implementation of guidelines is both feasible and beneficial. The Upstate Medical Center in Syracuse, with Cleveland Clinic faculty input, implemented guidelines for RSV bronchiolitis through physician and ancillary detailing in November 1997. Based on the same body of evidential data, the guidelines were remarkably similar to those used in Cincinnati. Documentation of RSV was required in this case, and the use of nebulized albuterol was limited to patients with documented improvement in clinical status with trial nebulization or, less frequently, at the discretion of the treating physician. Results were compared with historical controls of the prior respiratory disease season.6

Children admitted after institution of the guidelines were less likely to receive supplemental oxygen or cardiac monitoring and were more likely to have a documented statement of efficacy of albuterol therapy. There was a trend to shortened stay on both the ward and pediatric intensive care unit (PICU) with a significant decrease in children sent home with SVN for nebulized albuterol. Utilization of ABGs and chest radiographs were unaffected but had been low before implementation. There was no change in morbidity or mortality.6

Discussion and Implications for Emergency Department Organization and Therapy

In 1999, a study of 804 children at 10 children’s hospitals identified significant variability in approach to treatment of RSV bronchiolitis. The variation in resources utilized was not explained by disease severity or practitioner specialty and experience had no effect on patient morbidity or mortality. It did account for the variation in length of stay and was the primary driver of hospital expense.4 It was postulated that a rationalized common approach to bronchiolitis could positively affect clinical outcome while directly reducing resource utilization without negatively affecting patient/parental satisfaction or professional values. The studies at Children’s Cincinnati and Upstate Medical Center in Syracuse would appear to confirm this hypothesis for inpatient treatment associated with admissions through community primary care practitioners.4,5

The ED is the medical system point of contact for many infants with bronchiolitis. Community practitioners will refer sick children to the ED for professional evaluation. Many families see the ED as their primary source of care for their ill children. The department staff initiates and dictates early evaluation and treatment of bronchiolitis, with the decision to admit resting in the hands of the emergency physician and staff. Curiously, representatives of the EDs were not listed on the committees that produced either of the cited protocols for bronchiolitis care.

Implementation of a coordinated guideline between inpatient hospitalists and the ED would appear to be a logical progression from the above trials. It is clear that standardized approaches to the treatment of bronchiolitis as inpatients may reduce admissions and resource utilization. Establishment of similar protocols for early intervention in the ED with common criteria for admission would appear to be a fruitful place for ongoing investigation. A recent survey of admission rates for bronchiolitis in a Canadian metropolitan area showed significantly different admission rates between the general EDs and the pediatric EDs. After controlling for age, clinical severity, socioeconomic status, and co-morbidity, admission rates were 24% for the dedicated pediatric ED vs. 43% for the general EDs.87 Coordination across multiple outpatient delivery sites also may be a useful tool for more efficient delivery of interventional care.

Prevention

The prevention of RSV infection would be the key to an effective public health program to reduce the burden of infant bronchiolitis. Early attempts to immunize with formalin inactivated whole virus vaccine failed to produce protection against infection.88 Moreover, vaccinated infants exposed to native virus showed increased morbidity and mortality. Attempts to produce an effective vaccine proceed with use of subunit, recombinant DNA, live attenuate, and peptide vaccine technology has failed to produce a safe and effective vaccine.88 Clinical trials continue.

The Pediatric Red Book on Infectious Diseases cites traditional nursing interventions of cohort segregation in the hospital, hand washing, and the use of gowns, masks, and gloves as useful for prevention of nosocomial spread of RSV infection in the hospital. Three studies found lower transmission with introduction of cohort segregation alone, hand washing alone, and goggles alone.89-91 Another found no significant difference with added gowns and masks.92

RSV Immune Globulin (RSVIG, Respigam) has been demonstrated to reduce hospital admissions in select high-risk populations.93 Monthly infusion during RSV season requires IV access, and volume can become an issue in at-risk infants with failure from congenital heart disease. Use of RSVIG has declined significantly with introduction of monoclonal antibody to RSV.

Palivizumab (Synagis), the humanized mouse antibody to RSV, is administered intramuscularly monthly during the RSV season. A controlled trial of more than 1500 infants with gestational age younger than 35 weeks or with diagnosed bronchopulmonary dysplasia (BPD) demonstrated decreased hospitalizations, hospital days, and ICU days as well as number of documented RSV infections. Admissions of children with BPD were reduced 38% and of premature infants by 78%. Based on the results of trials, the AAP has released recommendations for candidates for prophylaxis.94 (See Table 5.)

Table 5. Recommendations for Palivizumab
(Synagis) Prophylaxis Candidates

Summary

Bronchiolitis is an acute viral infection with respiratory distress based on airway edema in peripheral bronchioles. Traditional therapy has been supportive, with common use of beta-adrenergic bronchodilators and considered use of steroids without firm clinical trial basis for either therapy. Controlled implementation of evidence-based treatment has shown to be cost effective while increasing parent satisfaction and reducing morbidity. Recent publications have indicated early outpatient use of steroids and epinephrine sympathomimetic treatment have solid scientific basis for use in the ED and urgent care setting. (See Table 6.)

Table 6. Summary Recommendations
for Urgent Care and Emergency Practitioners

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