Key points

Introduction

Bronchiolitis is the most common lower respiratory tract infection to affect infants and toddlers. Bronchiolitis was originally described in 1901 by Wilhelm Lange, and is familiar to nearly every pediatrician and emergency physician. An abundance of new research has emerged over the last decade, changing some existing knowledge regarding bronchiolitis. Most of the research is stimulated by the increasing number of bronchiolitis-related primary care, Emergency Department (ED) visits, and hospital admissions in the United States. Physician, nursing, and financial resources used annually are higher than previously assumed, and rival those of influenza epidemics. A vast majority of bronchiolitis illness is attributed to respiratory syncytial virus (RSV), although new knowledge has highlighted 2 additional viral agents. The paradigm of treatment with bronchodilators and steroids has drastically changed. Novel therapies such as hypertonic saline nebulized therapy, helium/oxygen mixtures (heliox), and high-flow nasal cannula (HFNC) therapies are currently being investigated.

Introduction

Bronchiolitis is the most common lower respiratory tract infection to affect infants and toddlers. Bronchiolitis was originally described in 1901 by Wilhelm Lange, and is familiar to nearly every pediatrician and emergency physician. An abundance of new research has emerged over the last decade, changing some existing knowledge regarding bronchiolitis. Most of the research is stimulated by the increasing number of bronchiolitis-related primary care, Emergency Department (ED) visits, and hospital admissions in the United States. Physician, nursing, and financial resources used annually are higher than previously assumed, and rival those of influenza epidemics. A vast majority of bronchiolitis illness is attributed to respiratory syncytial virus (RSV), although new knowledge has highlighted 2 additional viral agents. The paradigm of treatment with bronchodilators and steroids has drastically changed. Novel therapies such as hypertonic saline nebulized therapy, helium/oxygen mixtures (heliox), and high-flow nasal cannula (HFNC) therapies are currently being investigated.

Public health burden

Bronchiolitis hospitalizations have been increasing over the last 20 years. An estimated 132,000 to 172,000 RSV-associated hospitalizations occur annually in children younger than 5 years. Hospital costs are estimated at US$700 million annually. Experts have postulated that the increase in hospitalization is multifactorial, and includes increased survival of preterm infants, increased use of pulse oximetry, changes in admission criteria, and even increased attendance in day care. Fortunately, the number of deaths from bronchiolitis has decreased significantly to fewer than 500 annually in the United States, partially attributable to effective use of RSV immune globulin and RSV monoclonal antibody for high-risk infants.

Hall and colleagues demonstrated an expanded burden of RSV bronchiolitis by examining a cohort of children up to 5 years of age. The extrapolated data suggest that 2.1 million children under the age of 5 would require treatment each year, 25% or 500,000 of whom would seek treatment in the ED, with 57,000 hospitalizations each year. This burden equals that of influenza for ages 2 to 5 years. For infants aged less than 6 months, the burden of bronchiolitis exceeds that of influenza. Risk factors for RSV bronchiolitis requiring hospitalization were similar to those previously reported, and include male sex, chronic illness, lower socioeconomic status, smoke exposure, and contact with other children. Independent risks factors for severe illness were young age and prematurity.

Pathogenesis

Bronchiolitis is characterized by bronchiole obstruction with edema, cellular debris, and mucus, resulting in symptoms of wheezing. Bronchiolitis takes place in the small thin-walled conducting passages of the lung of less than 2 mm in diameter. In addition to size, bronchioles differ from the larger bronchi in that they are absent of cartilage, goblet cells, or glands.

Small-bronchiole epithelium is circumferentially infected, but basal cells are spared. Both type 1 and 2 alveolar pneumocytes are also infected. Inflammatory infiltrates are centered on bronchial and pulmonary arterioles and consist of primarily CD69+ monocytes, CD3+ double-negative T cells, CD8+ T cells, and neutrophils. The neutrophil distribution is predominantly between arterioles and airways, whereas the mononuclear cell distributions are in both airways and lung parenchyma. Most inflammatory cells are concentrated submuscular to the airway, but many cells traverse the smooth muscle into the airway epithelium and lumen. Airway obstruction is a prominent feature attributed to epithelial and inflammatory cell debris mixed with fibrin, mucus, and edema, and compounded by compression from hyperplasic lymphoid follicles. These findings are important to our understanding of RSV pathogenesis, and may facilitate the development of new approaches to prevention and treatment.

There are 2 main patterns of disease: acute bronchiolitis and interstitial pneumonia. In acute bronchiolitis, the main lesion is epithelial necrosis, which occurs when a dense plug is formed in the bronchiolar lumen, leading to air trapping air and other mechanical interference with ventilation. In interstitial pneumonia, there is widespread inflammation and necrosis of lung parenchyma with severe lesions of the bronchial and bronchiolar mucosa.

Bronchioles make little contribution to airflow resistance in the healthy lung. However, in the setting of inflammation or obstruction, the bronchioles can produce significant impairment of lung function. In the pediatric population, bronchiolitis is nearly exclusively the result of viral infection, specifically RSV. Similar abnormality is also seen in adults with inhalation injury, postinfectious conditions, complications of lung or stem cell transplant, collagen vascular disease, and idiopathic causes.

Etiology

The proportion of disease caused by specific viruses varies depending on the season and the year; RSV is the most common, followed by rhinovirus. Parainfluenza, adenovirus, and Mycoplasma also produce similar bronchiolitis illness. Recent evidence has also shown that metapneumovirus and human bocavirus have also caused bronchiolitis alone or as a coinfection with RSV.

RSV is an enveloped, nonsegmented, negative-strand RNA virus of the family Paramyxoviridae. Humans are the only source of infection. Infection is via close or direct contact with contaminated secretions. RSV can persist on hands and surfaces for 30 minutes or more. RSV typically is seen in epidemics in North America between November and March. The incubation period is between 2 and 8 days. Infected hosts can shed the disease typically from 3 to 8 days, but immune-compromised hosts or infants can shed for as long as 4 weeks.

Rhinovirus has long been known as an etiologic agent of the common cold; it can also cause bronchiolitis and infects the lower respiratory tract, and triggers asthma exacerbations in children, highlighting that this viral pathogen causes greater morbidity than previously recognized.

Metapneumovirus was discovered in 2001 and is also of the Paramyxoviridae family. It causes upper respiratory infections in children of all ages and adults. In addition, it can cause asthma exacerbations, pneumonia, croup, and otitis media as well as bronchiolitis. Infections are generally from November to March, as for RSV. Recent studies link metapneumovirus with approximately 7% of bronchiolitis infections. Likewise, Human bocavirus, of the family Parvoviridae, was recently identified in 2005 as a source of upper respiratory infection in children. Bocavirus is identified as a coinfection in bronchiolitis 80% of the time. The pathogenesis of bocavirus is still being investigated.

Clinical features

Bronchiolitis generally is a self-limited illness resulting in cough, fever, and rhinorrhea and lasting between 7 and 10 days. RSV is ubiquitous, with estimates of 90% of children infected with RSV in the first 2 years of life. Nevertheless, RSV and non-RSV bronchiolitis can produce severe respiratory symptoms resulting in respiratory failure and even death.

Bronchiolitis is typically preceded by a 1- to 3-day history of upper respiratory tract symptoms, such as nasal congestion and/or discharge, cough, and low-grade fever followed by wheezing, and symptoms of respiratory distress including increased work of breathing with retractions.

Compared with other viruses that cause bronchiolitis, fever tends to be lower with RSV and higher with adenovirus.

Characteristic findings include tachypnea, mild intercostal and subcostal retractions, and expiratory wheezing. Additional auscultatory findings may include prolonged expiratory phase and coarse or fine crackles (rales). The chest may appear hyperexpanded with increased anteroposterior diameter, and may be hyperresonant to percussion. Hypoxemia (oxygen saturation <93%) commonly is detected by pulse oximetry.

Severity of illness and/or the need for hospitalization is determined by assessment of hydration status (eg, fluid intake, urine output), symptoms of respiratory distress (tachypnea, nasal flaring, retractions, grunting), presence of cyanosis, episodes of restlessness or lethargy, and history of apnea.

Children with severe illness have increased work of breathing (subcostal, intercostal, and supraclavicular retractions; nasal flaring; and expiratory grunting); they may appear cyanotic and have poor peripheral perfusion. Wheezing may not be audible if the airways are profoundly narrowed or when increased work of breathing results in exhaustion or respiratory failure.

Bronchiolitis usually is self-limited. Most children do not require hospitalization and recover within 28 days. In a cohort of 181 children, the median duration of illness (calculated as the reported duration of symptoms before initial hospital visit plus the time from first consultation to recovery) was 12 days. After 21 days, 18% were still ill and after 28 days, 9% were still ill. There was no association of duration of illness with age, sex, weight, age, or respiratory rate.

In previously healthy infants older than 6 months who require hospitalization, the average length of hospitalization is 3 to 4 days, although it may be longer in children with bronchiolitis resulting from rhinovirus.

Differential diagnosis

Bronchiolitis should be differentiated form other causes of wheezing in children, such as viral-induced wheezing and asthma exacerbation, foreign-body aspiration, pneumonia, and congestive heart failure. Most can be distinguished by a through history and physical examination. Few might require radiologic studies.

Assessment and risk stratification

In the ED, evaluation of infants with symptoms concerning for bronchiolitis relies mainly on determining the risk of severe disease. High-risk populations include infants younger than 3 months; premature infants; and children with immunodeficiency, cystic fibrosis, cardiopulmonary, or neuromuscular disease. High-risk infants are susceptible to apneic episodes, severe respiratory distress, and respiratory failure ( Table 1 ). Holman and colleagues found that from 1996 to 1998, 55% of infant deaths from bronchiolitis were between the ages of 1 and 3 months. Very low body weight in premature infants was also an independent risk factor, with 30% mortality. The introduction of palivizumab has likely reduced the overall mortality. As a general consensus, RSV-positive infants younger than 2 months should be admitted for observation.

Diagnosis

The diagnosis of bronchiolitis should be assessed based on the clinical presentation, including history, physical findings, and season. Severity should be likewise assessed by these clinical characteristics and age at presentation. The American Academy of Pediatrics (AAP) defines severe disease by persistent increased respiratory effort, apnea, or the need for intravenous hydration, supplemental oxygen, or mechanical ventilation. Patients at increased risk for a severe illness include infants of premature birth (<37 weeks’ gestation) and young age (<12 weeks) ; and patients with underlying medical conditions such as chronic lung disease (bronchopulmonary dysplasia, cystic fibrosis, congenital anomaly), hemodynamically significant congenital heart disease, and the presence of an immunocompromised state.

Several scoring instruments have been developed to assess the clinical severity of bronchiolitis. The lack of uniformity of clinical scoring systems in severity assessment of bronchiolitis, even among observers, makes its application limited in clinical practice. The most widely used clinical score, the Respiratory Distress Assessment Instrument, is reliable with respect to scoring but has not been validated for clinical predictive value in bronchiolitis. Few studies have shown the effectiveness of pulse oximetry in predicting clinical outcomes. Among hospitalized patients, the need for supplemental oxygen based on pulse oximetry has been associated with higher risk of prolonged hospitalizations, admission to the intensive care unit (ICU), and mechanical ventilation. The concentration of lactate dehydrogenase (LDH), a marker of cell damage and inflammation in nasal-wash fluid, may provide an objective measure of disease severity in children with bronchiolitis. In one study, increased nasal-wash LDH was suggestive of robust antiviral response and was associated with decreased hospitalizations.

Diagnostic laboratory tests are not routinely indicated in the evaluation of infants and children with bronchiolitis. The complete blood count is sometimes used to evaluate for the possibility of coexistent bacterial infection in children with suspected bronchiolitis and fever. However, the risk of serious bacterial infection is low except for urinary tract infection (UTI) in infants older than 1 month. Infants younger than 28 days with fever and symptoms/signs of bronchiolitis have the same risk for serious bacterial infection (SBI) as infants without bronchiolitis. Levine and colleagues found the rate of SBI in febrile infants younger than 60 days with confirmed RSV to be 7.0%, compared with 12.5% for infants without RSV. Although the risk is less, it is not negligible.

Current evidence also does not support routine chest radiography in children with bronchiolitis. Chest radiography often does not change clinical decisions or predict disease progression. Radiographs may be useful when hospitalized children do not improve at the expected rate, if the severity of disease requires further evaluation, or if another diagnosis is suspected.

Routine testing for specific viral agents do not alter the management or outcome of the illness and is not needed, especially in outpatient setting. However, the identification of a viral etiologic agent during ED evaluation or in hospitalized patients has been associated with a decreased use of antibiotic treatment.

In hospitalized patients, determination of a responsible virus may help to avoid nosocomial transmission by permitting isolation of patients. Identifying an etiologic agent may also be useful, if specific antiviral therapy is considered.

When the etiologic diagnosis is necessary, nasal aspirates can be used to diagnose RSV infection. Rapid antigen tests are available for RSV, parainfluenza, adenovirus, and influenza virus. Immunofluorescence tests are also available for these viruses that cause bronchiolitis. Viral culture and polymerase chain reaction (PCR) are additional methods that can be used in identifying an etiologic agent. Antigen-detection tests and culture are generally reliable in younger children. The rapid tests vary in terms of sensitivity and specificity when compared with viral culture or PCR.

The sensitivity for RSV rapid tests generally ranges from 80% to 90%. The sensitivity is approximately 50% to 70%, and the specificity is 90% to 95% for influenza. The interpretation of positive results should take into account the clinical characteristics of the case. If an important clinical decision is affected by the test result, the rapid test result should be confirmed by another test, such as viral culture or PCR.