Authors: Jeffrey F. Linzer Sr., MD, MICP, FAAP, Assistant Professor of Pediatrics and Emergency Medicine, Emory University School of Medicine, and Emergency Pediatric Group, Children’s Healthcare of Atlanta at Egleston, Atlanta, GA; Cecilia C. Guthrie, MD, Assistant Professor of Pediatrics and Emergency Medicine, Emory University School of Medicine, and Emergency Pediatric Group, Children’s Healthcare of Atlanta at Egleston, Atlanta, GA.
Peer Reviewer: James E. Colletti, MD, Senior Associate Consultant, Department of Emergency Medicine, Department of Pediatrics, The Mayo Clinic, Rochester, MN.
Bronchiolitis causes significant morbidity in infants and young children.1-3 The significant number of hospitalizations each winter and the risk for subsequent wheezing and respiratory symptoms contribute to the importance of the disease.4-6 The treatment of bronchiolitis is mainly supportive with some additional controversial strategies demonstrating varied improvement in the patient’s clinical course.
The authors of this article review the pathophysiology and clinical presentation of this common winter illness. State-of-the-art management strategies are presented with the controversies surrounding individual therapies highlighted.—The Editor
Definition
Bronchiolitis is an acute lower respiratory tract infection caused by a virus, resulting in small airway obstruction. In research, the age range defined for bronchiolitis typically is children younger than 2 years, but further definition may vary, depending upon the author. Many authors define bronchiolitis as the first episode of lower respiratory tract symptoms during infancy, while other authors include subsequent episodes of wheezing in this definition. Although some classic symptoms—wheezing, hypoxia, and hyperinflation—typically are associated with bronchiolitis, many young infants may not have wheezing as part of their initial presentation.
Epidemiology
Bronchiolitis is a significant disease that is found throughout the world.7-11 Typically, bronchiolitis peaks during the winter months of a geographic area. Tropical climates have peaks during the rainy season. Table 1 lists the risk factors for bronchiolitis.7
Bronchiolitis is an important health issue in the United States. The large number of hospitalizations, high health care costs for these infants, and lost wages for caretakers impose a significant burden on society.1,12,13 Bronchiolitis hospitalization rates increased during the period from 1988 to 1996, as reported by Shay et al.1
Infants younger than 1 year of age accounted for 81% of the hospitalizations, and infants younger than 6 months of age accounted for 57% of hospitalizations during the study period.1 The number of bronchiolitis-associated deaths has remained stable over time, with 80% of deaths occurring in children younger than 1 year of age and a death median age of three months.2 Shay’s current estimation of 200-500 deaths per year of young children in the United States is lower than the estimate of 4500 made by the Institute of Medicine in 1985.2,14
Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract disease in infants and young children.15-19 During the winter, RSV accounts for 60-80% of bronchiolitis cases.18 Other causes of bronchiolitis include parainfluenza and influenza viruses.18,20 The majority of parainfluenza viruses account for bronchiolitis in the fall and spring, bracketing the RSV peak.20,21 By the age of 2 years, approximately 90% of children have had an RSV infection.20 Reinfection is common, although subsequent infection usually is less severe. Approximately 30-50% of patients who acquire a RSV infection in the first year of life develop a lower respiratory tract infection.12,13 Studies have shown that up to 50% of infants who have RSV bronchiolitis have subsequent wheezing episodes.6,22-24
Respiratory Syncytial Virus
RSV is a single-strand RNA virus in the family Paramyxoviridae. The genome is made up of 11 proteins, two of which are most clinically significant. These two glycoproteins are the G protein and the F protein. The G protein attaches the virus to the airway epithelium, while the F protein promotes infected airway epithelial cells to fuse to healthy cells with subsequent cell syncytium formation.20 The F protein genome is conserved, and current vaccine development targets this area. The G protein has variability and contributes to the antigenic variation between subgroups.
The major strains of RSV are A and B. Both concurrently circulate during RSV season, with one strain predominating, usually group A. A relationship between disease strain A and clinical severity has been proposed; however, conclusive correlations could not be made after several studies presented conflicting results.25-29
RSV Pathogenesis. RSV is transmitted through contact with respiratory secretions and a mucosal surface, typically the eye or nose. RSV can live on nonporous surfaces (countertops) for up to 30 hours and on porous surfaces (cloth) or hands for less than one hour.20 An incubation period of 2-8 days occurs after inoculation. Replication occurs in the nasopharyngeal epithelium. RSV may spread from the upper respiratory tract to the lower respiratory tract by direct extension. Lower respiratory tract infections also may occur through the movement of infected macrophages from the upper respiratory tract. Usually, lower respiratory tract symptoms develop 1-3 days following upper respiratory tract symptoms.21 Following infection, necrosis of the respiratory epithelium occurs. Mucosal inflammation with sloughing of the epithelium of the small airways, microvascular leak and edema, and increased mucus secretion contribute to the development of small airway obstruction. In autopsies of fatal cases of bronchiolitis, a predominantly peribronchial lymphocytic infiltration was found.20
Immunopathology. In addition to the direct injury of the respiratory epithelium, the host’s immune response to the viral infection plays an important role in the pathogenesis of the disease. The importance of understanding the immune response to RSV infection was discovered in the 1960s during an RSV vaccine trial. Children who received a formalin inactivated RSV vaccine were not protected from RSV infection and had an enhanced, exaggerated response to subsequent natural infection. Two deaths and a higher rate of hospitalization occurred in the vaccinated population. The inflammatory response, which was initiated in response to RSV antigenic recognition, persisted when an inadequate cytotoxic lymphocyte response and inactive neutralizing antibody were produced.30 The desire to understand what happened led research studies to further define the immune response of the immunized host to RSV infection. Investigators concluded that the enhanced response by the vaccine recipients occurred secondarily to production of RSV neutralizing antibody, which had decreased activity.30 Mouse studies have shown an imbalance of cell-mediated immune response to a natural RSV infection. Following a formalin inactivated vaccination, a high level of virus-specific memory T-lymphocytes was produced, but not RSV-specific cytotoxic T-lymphocytes.30
The immune response is a complex and interrelated process that involves not only antibody production, but also cytokine, chemokine, and soluble mediators of inflammation. Cytokines are a diverse group of intercellular proteins, which regulate local and systemic immune and inflammatory responses, among others. The cytokines produced against a natural viral infection are a Type-1 T-helper lymphocyte response, Th1 (IL-2 and Interferon-g [IFN-g]). While studying the production of IFN-g, IL-4, and IL-10 from nasal secretions in RSV-infected infants, Welliver documented a difference in the predominant cytokine present based on where the infection was located. Patients with upper respiratory tract infections produced predominantly IL-4 secretion, while patients with lower respiratory tract infections produced IFN-g.31 INF-g production was noted in direct correlation with RSV-specific CD8+ cytotoxic T lymphocyte levels in peripheral blood mononuclear cell culture studies.32 Studies suggest that naturally acquired RSV infection induces a predominantly Th1 response.31-33
The Type-2 T-helper lymphocyte cytokine response, Th2, (IL-4 and IL-5) is important in the pathogenesis of allergic asthma. In animal model studies, the formalin vaccinated population produced a Th2 response. In addition, the Th2 response to infection has been found to be more prone in infants.34 Specific IgE antibody production has been observed in the respiratory secretions of infants with RSV disease, which may add to a Th2 response.35
Both T-helper responses have been observed in vitro and in vivo.33,36-40 The specific sensitizing RSV antigen has been suggested to be a factor in inducing different T-cell helper responses.41 One research group demonstrated that a specific epitope on the G glycoprotein may elicit both Th1 and Th2 responses.42 A recent study of infants intubated for RSV bronchiolitis observed production of IL-4 or IFN-g or both with no association between age, RSV type, or concentration of the cytokines.43 Multiple factors contribute to the differentiation of the T cell response.
Chemokines may play a role in stimulation of IgE production and attraction and degranulation of eosinophils, which usually are seen in a Th2 response.
Viral-infected respiratory epithelium releases pro-inflammatory cytokines and chemokines. Chemokines, chemoattractant cytokines, attract different cell types to the injured area. These mediators have been documented in nasal secretions of infants infected with RSV.44-48 Although in autopsy a peribronchial lymphocytic infiltration was observed, tracheal aspirates and nasal secretion from RSV-infected infants produced predominantly neutrophils.48-50 Although eosinophils have not been documented in autopsy of RSV-infected lung tissue, eosinophil cationic protein and leukotriene C4 was demonstrated in the respiratory secretions of infants with RSV. This is indicative of eosinophilic degranulation, which has been observed in patients with asthma and represents a Th2 end-pathway component. This reinforces the complexity of the viral immune response to RSV.47,51 Monocyte interactions with RSV also contributes to production of the proinflammatory cytokines during the acute infection, with a possible impact on subsequent recurrent wheezing.52 The immunological response is complex with multiple factors contributing to the type of T helper cell response elicited.
Clinical Manifestations of Bronchiolitis and RSV Disease
RSV infection begins with rhinorrhea, nasal congestion, and cough, which can develop subsequently into signs of bronchiolitis. These signs include severe coughing, which may produce posttussive emesis, prolonged expiration, crackles, wheezing, tachypnea, retractions, difficulty feeding, and dyspnea.7 Apnea is a complication seen in approximately 20% of RSV-infected hospitalized infants with risk factors of prematurity, prior history of apnea of prematurity, and age at the time of infection younger than 2 months.20 Apnea may or may not be associated with other respiratory symptoms. A fever may occur for approximately 2-4 days and may become as high as 40°C when associated with otitis media.7,20 Otitis media is a common finding accompanying RSV infection, which may be due to RSV virus alone or concurrent bacterial infections.53-56
Although bronchiolitis is the most predominant lower respiratory form of RSV disease, other forms of infection include pneumonia, tracheobronchitis, or croup. The classic chest x-ray of bronchiolitis has hyperinflation, perihilar infiltrates, peribronchial wall thickening, and patchy atelectasis. (See Figures 1A-B and Figure 2.) Lobar, segmental, and subsegmental pneumonia also have been documented.20 (See Figure 3 and Figure 4.) High-risk groups for severe RSV disease are outlined in Table 2.7,20 Prematurity is the greatest risk factor identified.57 Predictors of disease severity in otherwise healthy infants are outlined in Table 3.58 Oxygen saturation as determined by pulse oximetry is the single best predictor of severe disease in normal children. Uncommon manifestations of RSV disease reported include meningitis, ataxia, myelitis, myocarditis, and complete heart block.20
Gastroesophageal reflux (GER) has been documented in RSV bronchiolitic patients without a previous history of feeding difficulties.59,60 In one series, nine of 15 patients had abnormal swallowing studies with thin barium.59 Of the nine patients with reflux, four patients had frank aspiration.59 A swallow study using thick barium was performed on infants with GER;59 eight out of the nine patients had a normal swallow study with thickened barium.59 The author recommended thickening of feeds for infants with RSV bronchiolitis.59,60
Review of Therapeutic Options
The treatment for bronchiolitis remains controversial. Because the disease generally presents as a bronchospastic respiratory illness, the approach of therapy has been similar to other bronchospastic conditions such as asthma. Bronchodilators and steroids have been used as the first line of care. Results of studies have varied widely in demonstrating the benefits from either bronchodilators or steroids.
The list of bronchodilators that have been evaluated is impressive: isoproterenol,61 ipratropium,62,63 fenoterol, aminophylline,64 and metaproterenol.65,66 Albuterol has been far and away the most studied bronchodilator. The results have been mixed and difficult to compare since they tend to have dissimilar endpoints. Studies by Schuh67 and Klassen68 have shown improvement in clinical outcome measures (e.g., respiratory rate, accessory muscle use), while those by Gadomski69 and Dobson70 did not. Even meta-analysis of essentially the same studies have drawn opposing conclusions as to the clinical effectiveness of albuterol.71,72 The review by Kellner71 looking at all bronchodilators (including beta [b]-agonists and epinephrine) concluded that bronchodilators provided short-term improvement in clinical scoring but did not affect hospitalization rates and that a trial of bronchodilator therapy is reasonable. However, Flores72 found no benefit from b-2 agonist therapy.
Besides supportive care, are there any therapeutic modalities that may be of benefit in bronchiolitis? It is important to understand that while the clinical presentation may be that of bronchospastic disease, the underlying pathophysiology is dissimilar enough to necessitate a different approach. As noted earlier, in bronchiolitis there is not a uniform bronchoconstriction of the airways. There is direct damage to the respiratory endothelium with subsequent microvascular leakage, increased mucous production, and collection of cellular debris in the respiratory lumen. While there is a release of inflammatory mediators similar to that seen in asthma, the inflammatory response may be more in line with other infectious-based inflammatory responses (e.g., septic shock), as opposed to that seen with atopy. This helps explain why b-2 agonists and systemic corticosteroids have shown little consistent clinical benefit.
Epinephrine has both alpha and beta activity. Its alpha activity may be responsible for the clinical advantage it has shown in the treatment of bronchiolitis.73-76 In addition to clinical symptoms, pulmonary function and oxygenation have been shown to significantly improve with nebulized epinephrine.77-79 Nebulized epinephrine has been shown to be of greater clinical benefit in bronchiolitis especially when compared to albuterol.80,81 Menon found patients who received two treatments with 3 mL of 1:1000 (3 mg) epinephrine 30 minutes apart in the ED had lower hospitalization rates and shorter ED visits when compared to the salbutamol group.82 Furthermore, the epinephrine group had a higher mean oxygen saturation at 60 minutes and a lower heart rate at 90 minutes. The rate of return to the ED was the same between the two groups. There have been no studies specifically looking at the need for an observation period following nebulized epinephrine treatment in the ED. A minimum two-hour observation has been used in upper airway conditions (i.e., croup), but there has been no documented necessity for observation periods for small airway obstruction.
There is no clinical advantage of racemic (1:1 mixture of D and L isomers) epinephrine over isomeric (L) epinephrine.83,84 Of note, the L isomer has greater biological activity, availability, and affordability. The average wholesale cost of a 30 mL multidose vial is $5.63 for L-epinephrine and $33 for racemic (DL) epinephrine.
In the United States, the currently available racemic epinephrine contains chlorobutanol, postassium and sodium metabisulfite, and propylene glycol, while the 1:1000 isomeric also contains sodium metabisulfite (and chlorobutanol in the multidose vial). While there have been concerns about potential allergic or irritant properties from metabisulfites, no problems have been documented with the use of nebulized epinephrine.82,83
There is less evidence supporting the use of systemic steroids in acute bronchiolitis. Few studies have shown any significant benefits. Tal showed earlier hospital discharge in patients who received intramuscular dexamethasone along with salbutamol (albuterol) treatments, but the study results were limited due to small sample size.85 Goebel demonstrated a transient improvement in clinical status on the second day of treatment with prednisolone and albuterol, but the effect was not detectable after that point.86 Hospitalization and length of stay rates were not evaluated. Additionally, a meta-analysis of six smaller studies implied that steroid use may improve clinical symptoms and decrease their duration as well as the length of hospitalization.87
Trials dating back to the 1960s have not demonstrated any benefit of steroids in acute bronchiolitis.88-90 More recent studies have had better design and incorporated bronchodilator therapy. While one study using high dose dexamethasone (1 mg/kg PO) in the ED showed clinical improvement within four hours of administration and decreased hospitalization,91 most have not shown any clinical benefit.92-96
While systemic steroids do not appear to be helpful in the acute setting, inhaled anti-inflammatories do appear to decrease post-bronchiolitis wheezing and the need for acute intervention. Several studies have looked at decreasing the number of wheezing episode in infants and young children with the use of beclomethasone,97 budesonide,98-100 and cromolyn,100-102 but only a few have directly examined the effect of these medications in post-bronchiolitis patients. Investigators found that nebulized beclomethasone improved lung function,103 and after eight weeks of use significantly decreased the number of obstructive respiratory symptoms in the year following treatment.104 Patients who had at least eight weeks of nebulized budesonide (500 mcg twice a day) during the acute phase of bronchiolitis had a reduction in the number of subsequent wheezing episodes and hospitalizations.100,105 Efficacy was not affected by a history or predisposition to atopy. Both method and length of administration of budesonide appear to be important. Fewer than eight weeks of therapy did not demonstrate a reduction in respiratory symptoms.106 Administration by metered-dose inhaler also was less effective.107
Since bronchiolitis is a viral disease, antibiotics are of no value in its treatment. The risk of bacterial co-infection or superinfection appears to be almost negligible, especially in otherwise healthy children.108-112 Chest x-rays in RSV infections may range from normal to significant infiltrates.113 The use of ribavirin is controversial.114,115 Currently, its use is restricted to hospitalized patients, particularly those with underlying cardiac or pulmonary disease, and would not be used in the ED.
Ancillary Testing
Routine use of laboratory tests and radiographs are not indicated in uncomplicated bronchiolitis. Children with fever who are younger than 3 months of age, who have significant past medical history (e.g., prematurity or exposure to group B Streptococcus) or significant co-existing medical condition (e.g., congenital heart disease or sickle cell disease), or who are toxic-appearing should be evaluated for a coexisting bacterial infection with a complete blood count, blood culture, urine analysis and urine culture (depending on the age and gender), chest x-ray, and lumbar puncture as clinically indicated. Radiographs also are indicated for patients with significant respiratory distress that has not responded to treatment and should be considered in children younger than 3 months of age with their first episode of wheezing. Use of other ancillary tests should be based on the patient’s history and clinical presentation.
While there has been a suggestion that routine RSV antigen testing may reduce the need for additional ancillary tests and decrease the unnecessary use of antibiotics,116 at this time it appears to be of most benefit for hospitalized patients, if needed, to determine patient cohorting or isolation status. In infants younger than 2 months of age who present with apnea during peak RSV season, a positive rapid antigen test may reduce the need for a more comprehensive evaluation.
Conclusion
Therapy is generally supportive, ensuring oxygenation (SpO2 > 95%) and hydration. (See Figure 5.) Nebulized epinephrine is indicated for those patients with significant increased work of breathing, tachypnea, wheezing and/or hypoxia. This may be repeated once in 30 minutes. Caution should be used in patients with underlying congenital cardiac disease, especially pulmonary hypertension; consultation with a pediatric cardiologist is advised. Patients should be watched for at least 90 minutes before the decision is made to discharge home. Prolonged observation or hospitalization should be considered for those who do not respond to epinephrine, are hypoxic, unable to maintain oral hydration or present with a significant clinical history or evaluation, such as apnea or cyanosis.
Patients discharged from the ED may be sent home on inhaled albuterol either by nebulizer or metered dose inhaler with spacer based on the response in the ED to a trial dose. While nebulized epinephrine has been shown to provide better relief of symptoms, there have been no studies looking at its safety and efficacy in the non-hospital setting. There appears to be a subset of patients who will have a good response to albuterol. There are no markers, however, identifying this group of patients.
Systemic corticosteroids should be avoided. Nebulized budesonide, 500 mcg twice daily for eight weeks, may be of benefit in reducing subsequent respiratory symptoms in hospitalized children.
Antibiotics are not indicated in the treatment of bronchiolitis. Patients presenting with temperatures of 40ºC or greater are likely to have an acute suppurative otitis media. Antibiotic use should be guided by community bacterial prevalence and sensitivities. Children younger than 3 months of age who present with a high fever in addition to respiratory symptoms may still be at risk for occult bacteremia. Treatment with antibiotics should be guided by appropriate clinical evaluation and ancillary tests.
Hospitalization is indicated for children who are hypoxic, at risk of respiratory failure, or have significant co-morbidities (e.g. immunodeficient, chronic lung, or cardiac disease). Children younger than 2 months of age have a risk for developing apnea,117 and the clinician should have a lower threshold for admission with this group. Consideration should be given if the child is dehydrated or unable to tolerate oral fluids. Persistent wheezing in a child with normal oxygen saturation who is tolerating liquids and has no underlying co-morbidity generally is not an indication for admission.
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Bronchiolitis is an acute lower respiratory tract infection caused by a virus, resulting in small airway obstruction. Although some classic symptomswheezing, hypoxia, and hyperinflationtypically are associated with bronchiolitis, many young infants may not have wheezing as part of their initial presentation.
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