Bronchiolitis: Diagnosis and Treatment of an Increasingly Common Seasonal Presentation

Authors: L. Lorraine Basnight, MD, Associate Professor of Pediatrics, Brody School of Medicine at East Carolina University, Greenville, NC; and Ronald M. Perkin, MD, MA, Professor and Chairman, Department of Pediatrics, Brody School of Medicine at East Carolina University, Greenville, NC.

Peer Reviewer: Alfred Sacchetti, MD, FACEP, Chief of Emergency Services, Our Lady of Lourdes Medical Center, Camden, New Jersey, Clinical Assistant Professor, Emergency Medicine, Thomas Jefferson University, Philadelphia, PA.

Bronchiolitis is the most common lower respiratory tract disease in infants, and respiratory syncytial virus (RSV) bronchiolitis is the leading cause of hospitalization in infants.1 More than 700,000 patients sought care in the emergency department (ED) for lower respiratory infections during the RSV seasons between 1997 and 2000. Almost one-third of these patients were admitted. Total hospital charges for RSV-coded primary diagnoses during this time period were more than $2.6 billion.1 This article reviews the current status of bronchiolitis diagnosis and management.

— The Editor

Introduction

The American Academy of Pediatrics defines bronchiolitis as a disorder in infants that is usually caused by viral lower respiratory tract infection and results in inflammation, edema, and necrosis of the epithelial cells lining the small airways, causing increased mucus production and bronchospasm.2 Most infants with bronchiolitis will exhibit rhinorrhea, cough, tachypnea, and may demonstrate nasal flaring and use of accessory respiratory muscles. Some infants will have sequelae of respiratory distress such as decreased oral intake and dehydration. Severe disease may present with apnea, respiratory failure, or sepsis syndrome.

Bronchiolitis is a common presenting complaint during the typical "season"3 (December to March in the United States) and an occasional presenting complaint at other times of the year. While most children recover from the illness without serious problems, bronchiolitis due to RSV infection is the leading cause of hospitalization in children younger than age 1 year.4 Providers of primary and urgent/emergent care to children should be able to accurately diagnose bronchiolitis and treat or support children during the course of the illness.

Thorough reviews of the literature on bronchiolitis were performed by the Agency for Healthcare Research and Quality (AHRQ) in 2003 and the American Academy of Pediatrics (AAP) in 2006.2,5 The AAP review resulted in the publication of Clinical Practice Guideline: Diagnosis and Management of Bronchiolitis.2 Both the AAP and the AHRQ documents are excellent resources for an in-depth review of the topic.

Epidemiology

RSV is the most frequently identified cause of bronchiolitis. While RSV has most closely been associated with bronchiolitis, a growing body of literature implicates rhinovirus as an important etiology of the clinical syndrome — one that may have an even greater association with asthma in later life.6 A number of other viruses also cause the clinical syndrome, including human metapneumovirus, influenza, adenovirus, enteroviruses, and parainfluenza.7 All of these viruses may be spread by aerosolized droplets and small particles. Clinicians should note that though the clinical course of these viruses in infants may include lower respiratory tract symptoms, sick contacts may be described only as having a "common cold."

RSV will infect 90% of children by 2 years of life. Almost half will have lower respiratory tract symptoms with the infection.2 Of the children hospitalized with RSV bronchiolitis, about 30% will have recurrent wheezing in subsequent years.8 Reinfection with RSV can occur throughout life.9 RSV is seasonal, with a preponderance of cases occurring between December and March. The incubation period ranges from 2 to 8 days.9 Viral shedding from an infected source occurs for 3 to 8 days, though young infants and those who are immunosuppressed may shed the virus for 3-4 weeks.

RSV is highly transmissible and epidemics are common. In addition to the usual respiratory transmission of virus, RSV is easily spread by fomites, which may remain infectious for many hours. The Red Book notes that RSV can persist on hands for half an hour and that infection of healthcare personnel and others can occur by self-inoculation.9 Hall has noted that "more than 50% of staff members on pediatric wards have been shown to become infected with RSV during periods when RSV is prevalent in the community."10 Standard and contact precautions are recommended during RSV outbreaks, though Hall notes that "good handwashing is probably the single most important procedure."10 See Table 1 for specific recommendations.11

Pathophysiology of Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) is a member of the Paramyxoviridae family of RNA viruses in the genus Pneumovirus. The viral envelope has 12 to 15 nm spikes composed of F (fusion) and G (attachment) glycoproteins located on the outer surface at regular intervals. The virus attaches to the host cell by the G protein, the larger of the two glycoproteins. The F protein provides the means for the viral genome to penetrate into the host cell and mediates cell-to-cell spread, leading to the characteristic syncytial formation in tissue culture. Both F and G glycoproteins have the capacity to induce the formation of antibodies that can neutralize RSV. The antibodies induced by the F glycoprotein are the more highly productive ones and are the only antibodies that completely neutralize RSV and inhibit syncytial formation in vitro. These observations have led to the development of monoclonal antibodies against the F glycoprotein.12

The virus infects the ciliate epithelial cells that line the airways. The first step in viral replication is attachment of the viral particle to the host cell, generally in the nasal epithelium. The viral RNA then enters the cell, along with the viral enzymes that direct production of new viral RNA and proteins. Multiple new viruses are assembled within the cell, and the cell is ultimately destroyed.13 The rapid destruction of ciliated epithelial cells lining the airways ultimately causes the symptoms that are characteristic of the infection.

Glycoprotein F causes fusion of infected cells with adjacent uninfected cells. This results in merging of membranes from infected cells, allowing for cell-to-cell transmission of the replicated viral RNA. This results in the appearance of epithelial cell syncytia, formations that appear to be large, multinucleated cells, which gives the virus its name.13 This mode of transmission from cell-to-cell also allows the virus to spread without coming into contact with antibodies in the nasal secretions.

Once an RSV infection has begun, extensive destruction of epithelial cells lining the respiratory tract occurs. Necrosis of the respiratory epithelium is one of the earliest occurring lesions in bronchiolitis.14 Proliferation of goblet cells results in excessive mucus production, while epithelial regeneration with nonciliated cells impairs elimination of secretions.15 It should be emphasized that ciliated epithelial cells rarely reappear before two weeks. Complete restoration of ciliated epithelial cells requires four to eight weeks, in correlation with the common clinical findings of prolonged cough, wheezing, and altered pulmonary function.16 In addition, lymphocytic infiltration in the area between epithelial cells may result in submucosal edema. These factors result in dense plugs of alveolar debris, with edema and excessive secretions partially or fully obstructing bronchioles. (See Table 2.)

The major physiologic consequences of these events are lung hyperinflation, increased airway resistance, atelectasis, and mismatching of ventilation and perfusion.17 Anatomical factors that also may contribute to the severity of disease in infants include narrow peripheral airways and deficient numbers of collateral channels for ventilation.14,18 These factors increase the likelihood of small-airway obstruction and reduce the adequacy of ventilation.

As epithelial cells are destroyed, they release a number of pro-inflammatory mediator substances, including cytokines (e.g., histamine and interleukin 1 and 6), which cause increased capillary permeability and elevated secretion production, and chemokines that attract additional pro-inflammatory cells such as macrophages, neutrophils, eosinophils, and natural killer cells to the site of infection.19 Increased capillary permeability results in leakage of plasma proteins into interstitial areas, small airways, and alveoli. This causes generalized interstitial swelling and also appears to inhibit pulmonary surfactant function.20 In addition, some of the pro-inflammatory mediator substances (specifically leukotrienes C4 and D4), which are known to be potent bronchoconstrictors, have been isolated from secretions of individuals with severe lower respiratory tract infections.13 The combination of increased secretion production, decreased secretion clearance due to compromised mucociliary elevator function, and ineffective surfactant function results in small airways filling with secretions and debris from destroyed cells. The release of bronchoconstrictor substances may cause small airways to narrow even further, resulting in increased airway resistance, air trapping, and wheezing, which are characteristic of severe lower respiratory tract RSV infection (See Table 2).19

Clinical Features

The diagnosis of bronchiolitis should be considered in infants and young children who present with lower respiratory tract symptoms following an upper respiratory tract infection. Commonly, patient history will reveal that the sick infant was exposed to an older child or adult with mild upper respiratory infection symptoms or had contact with a child at daycare with upper or lower respiratory symptoms. Usually, the patient will have had several days of clear rhinorrhea and low-grade fever (up to 38.9°C) prior to the onset of tachypnea, wheezing, and cough. Occasionally, bronchiolitis will be associated with a fever >40ºC. Concomitant otitis media frequently is found in patients with high fever. Premature or very young infants (first weeks of life), may present with little or no respiratory symptoms.9,21 RSV infection is associated with a number of extrapulmonary manifestations, including a sepsis-like syndrome characterized by any combination of hypothermia, fever, hypovolemia, and myocardial dysfunction.22 In some cases, inotropic or vasopressor support may be required.22,23 Poor feeding may result from difficulty coordinating suck and swallow, particularly in individuals who are younger than age 1 year. Other symptoms, such as vomiting and diarrhea, usually are absent. (See Table 3.)

RSV-associated apnea may be the presenting symptom in some infants.24 Infants at greatest risk for respiratory virus-associated apnea are those infants who are younger, have a history of prematurity, a history of apnea of prematurity, and those whose duration of illness is shorter.25 It also is of concern in infants who are nicotine or alcohol exposed, and in infants who sleep prone.

Unrecognized, respiratory virus-induced apnea may result in death. Particularly challenging to the pediatrician and the emergency medicine physician is the clinical conundrum of the young infant with a respiratory illness who is at risk of respiratory virus-associated apnea, but in whom no events have yet occurred. Recently, Willwerth and colleagues retrospectively applied a series of risk criteria to a set of infants younger than age 6 months who were hospitalized for respiratory disease.26 Infants were considered high risk if they fit any of the following criteria: 1) full term and younger than 1 month; 2) premature (37 weeks) and postgestational age less than 48 weeks; or 3) presented with apnea. These criteria identified all infants who had subsequent apnea during the hospitalization. It is not known if these criteria can be used to determine safe disposition from the ED of young infants who would not otherwise be hospitalized for their respiratory disease.25

In addition to the symptoms of bronchiolitis, the history should include a search for risk factors for severe disease. Risk of severe or fatal disease is increased in patients with a history of prematurity, chronic lung disease, congenital heart disease, immunodeficiency, or other causes of immunosuppression.9 Infants with diseases that increase the difficulty clearing the lower respiratory tract of secretions and debris, or that impair oxygenation, are at greater risk of severe disease. Individuals with a history of wheezing may be at increased risk of lower respiratory tract symptoms.

Holman and coworkers identified several factors associated with increased infant death from bronchiolitis.27 Very low birth weight infants (<1500gm) were 25 times more likely than infants of normal weight to die from bronchiolitis, and low birth weight infants (1500-2499gm) were 5 times more likely to die from bronchiolitis than normal weight infants. Clinicians should note that even though the risk of death in the study population increased significantly with low birth weight, the majority of bronchiolitis deaths were among infants of normal birth weights. Other risk factors for death included African American race, shorter gestational age, a low 5-minute Apgar score, plural birth, and a high birth order. Significant maternal characteristics included late, scant, or no prenatal care; unmarried; age younger than 25 years; tobacco use during pregnancy; and a lower educational level.27

Physical Examination

The most common physical exam findings are: rhinorrhea, tachypnea, wheezing, cough, crackles, use of accessory muscles, and/or nasal flaring.5 Assessment of adequate movement of air during respiration should be made. Tachypnea greater than 45 and often greater than 60 is noted, and is best assessed by counting for a minute, as infants with copious nasal secretions may not have a uniform respiratory rate over shorter periods of time. Apnea may be noted in very young infants without other respiratory symptoms. Oxygen saturation may be normal or low. The liver occasionally will be felt displaced downward by the hyperinflated chest. Hydration status should be assessed, including capillary refill and status of mucus membranes. Vital signs should be assessed, with clinicians reviewing for fever or hypothermia, tachycardia, and tachypnea. Respiratory rate during the first year of life is controversial, but an acceptable rate for safe discharge home is less than 70 breaths per minute when there is no clinical evidence of increased work of breathing.28

Hypothermia, poor feeding, tachypnea, or gasping may indicate the infant is seriously ill, and should prompt expedited assessment and supportive treatment.

Differential Diagnosis

Other causes of wheezing and cough should be considered, such as heart failure, asthma, bacterial pneumonia, and foreign body. A careful history will point to the diagnosis of bronchiolitis. Wheezing without URI symptoms or an enlarged liver should prompt a search for problems other than bronchiolitis.

Diagnostic Studies

As bronchiolitis is a clinical diagnosis, there are no studies that make the definitive diagnosis. In selected cases, viral testing, chest radiograph, and lab work may be appropriate.

Identification of the Specific Virus. Identification of the specific virus causing bronchiolitis may be useful to: 1) reassure the physician of the diagnosis so as to avoid further invasive work up in the febrile infant; 2) cohort patients admitted for supportive care; and 3) to determine if RSV is in the community for epidemiologic purposes.29 Viral cultures or specific viral antigen tests are available, yet they do not generally contribute to the treatment of bronchiolitis and are not routinely recommended. Testing may be beneficial to the patient if results are used to reduce radiation exposure or to limit other blood tests.2,5 Typically, viral antigen results will be more reliable if the test is done on nasal washings rather than nasal swab. Contact the lab performing the test for the appropriate specimen and collection process.

Radiographs. Radiographs may be indicated if the clinical course does not improve as expected, or if the diagnosis is in doubt. The chest X-ray (CXR) of the patient with bronchiolitis may show hyperinflation, atelectasis, focal consolidation, or widespread changes. One-third of patients will have scattered areas of consolidation on CXR representing atelectasis secondary to obstruction or patches of focal alveolar inflammation.30 Bordley et al reviewed numerous studies assessing the use of CXR in the diagnosis and treatment of bronchiolitis, and found that data for the utility of CXR in the setting of bronchiolitis is lacking.29 While CXR often is performed looking for focal disease, bacterial pneumonia is rare in the setting of bronchiolitis and the use of CXR is associated with overuse of antibiotics in patients with bronchiolitis.31,32 The utility of CXR to predict more severe disease is controversial. While some studies suggest that widespread disease on CXR may predict the patients most likely to have a severe course, meta-analysis has not proven the utility of this test for this purpose. CXR is not indicated for the routine workup of the infant with bronchiolitis.2,5

Blood, Urine, and Cerebrospinal Fluid Cultures. The utility of cultures of blood, urine, and cerebrospinal fluid has been studied by multiple authors.33,34 Melendez and Harper performed a review of febrile infants younger than 90 days of age who had clinical bronchiolitis to determine if cultures of blood, urine, and cerebrospinal fluid revealed serious bacterial illness in addition to the viral illness.33 None of their patients had bacteremia or meningitis. Two percent of the urine cultures were positive.33 In a recent study by Bilavsky et al, the only serious bacterial infection found in patients with bronchiolitis was, again, urinary tract infection (UTI) in girls. The rates for patients with UTI in RSV-positive bronchiolitis and bronchiolitis from all causes were 2.4% and 2.2%, respectively.34 The AAP Clinical Practice Guideline does not recommend the routine use of cultures in patients with bronchiolitis.2 However, in a commentary on the Bilavsky article, Pate notes that there is a paucity of data on SBI (serious bacterial illness) in febrile infants with RSV-negative bronchiolitis and on SBI in febrile infants with bronchiolitis who are younger than 4 weeks of age. Caution should be used in these patients when considering whether there may be a concurrent bacterial infection.35

Other Studies. Pulse oximetry or arterial blood gas may be useful in patients who are distressed or who have an increased work of breathing. Blood glucose should be obtained for patients with a decreased level of consciousness. If a patient has significant dehydration, labs to assist in the treatment of the dehydration may be indicated. Complete blood count and electrolytes have not been shown to be helpful in the diagnosis or treatment of bronchiolitis.5,36

Management

There is significant variation among institutions and clinicians in the treatment of patients with bronchiolitis. Much of this variation is due to the lack of consistent efficacy of medical therapy and the desire to improve the clinical status of the patient. Management of the patient with bronchiolitis should focus on supportive care, including respiratory and circulatory support. Assessment of the severity of illness will assist with the plan of care. Patients with mild or uncomplicated bronchiolitis will not need specific therapy.2,5 Parental monitoring of adequacy of feeding and worsening disease may be sufficient. Patients with more complicated disease may benefit from hospitalization and specific treatment, including oxygen therapy, ventilation support, and IV hydration.

Manage the Airway. The first step in the management of the patient with bronchiolitis is to assure that the airway is patent. Patients with RSV bronchiolitis often have copious mucous production; secretions may obstruct the upper airway, and especially the nares. Saline suctioning may decrease the work of breathing, increase the movement of air, decrease respiratory rate, and improve the respiratory status of the patient. Lower airway obstruction by bronchoconstriction, atelectasis, debris, and mucous leading to significant ventilation-perfusion mismatch may warrant intubation and mechanical ventilation.

Assure Oxygenation. The level of oxygen saturation demanding supplemental oxygen is controversial, but many clinicians will provide supplemental oxygen if the saturation is between 92% and 94%.37 If the oxygen saturation is < 91%, supplemental oxygen should be provided.28 Supplemental oxygen also should be given to patients with wheezing and respiratory distress, even if the oxygen saturation is normal.38

Medications in the Acute Care Setting

A number of medications have been used in patients with bronchiolitis, but none have been shown to be uniformly effective, and none are recommended for routine therapy.2,5,39 However, some patients will be ill enough to prompt the clinician to try a variety of therapies in an attempt to improve the clinical course of the disease. See Table 4 for recommended doses of medications.40,41

Bronchodilators. Albuterol and epinephrine have been used in patients with wheezing due to bronchiolitis, though randomized controlled trials assessing their effectiveness have failed to show consistent benefit of either alpha- or beta-adrenergic agents. Meta-analyses of these studies confirm that none are routinely effective.2,5

The failure to demonstrate a consistent response to bronchodilators should not be surprising considering the varied causes of small airway obstruction in RSV bronchiolitis. (See Table 2.) Epinephrine, because of its alpha-adrenergic agonist activity, is more effective at decreasing interstitial and mucosal edema; therefore, it may be more effective for opening small airways than a beta-adrenergic bronchodilator.

A review of specific trials of bronchodilators reveals that aerosolized epinephrine has been shown to decrease work of breathing at one hour post treatment and may reassure the clinician in the emergency setting to discharge a patient to home, but does not appear to have any effect on the overall course of the disease.42 When used in the inpatient setting, aerosolized epinephrine does not shorten the length of hospital stay over patients given aerosolized saline.43 Aerosolized albuterol produces small, short-term improvement in clinical scores, but has not been shown to produce any significant improvement over placebo in patients with typical bronchiolitis.2,5,44,45 It may be that a subset of patients with a history of wheezing or a strong family history of asthma will show some clinical improvement when other patients do not, but a study with sufficient power to confirm this has not been done. Aerosolized albuterol or epinephrine may be of benefit in this subset of patients, and clinicians may provide a trial of bronchodilator therapy with close observation of the patient before and after therapy. These medications may cause increased heart rate and agitation. Infants with RSV may be susceptible to tachycardia from beta-agonists and the side effects often outweigh the benefits of the therapy.46 If no improvement is found, the therapy should be discontinued.2,40 Preliminary data showed that the combined use of epinephrine and dexamethasone lowered hospitalization rates by 30% in comparison to epinephrine/placebo, dexamethasone/placebo, or placebo/placebo,47 but final data concerning this combined treatment is pending. Oral albuterol does not result in a significant clinical improvement, and is not recommended for wheezing in previously well infants with bronchiolitis.48

Steroids. As with bronchodilators, studies of inhaled and systemic steroids in the treatment of patients with bronchiolitis have had conflicting results. Clinical status of patients given steroids has trended toward improvement, but has not reached statistical significance.49,50 Neither inhaled nor systemic steroids have been shown to be uniformly effective in the treatment of bronchiolitis.51,52 Meta-analysis has confirmed this finding.39,45,51,53,54 Steroids are not recommended for routine use in patients with bronchiolitis.2,5 It has been suggested that early dosing of steroids may confer clinical improvement, but that clinical trials to date have not sufficiently accounted for the timing of treatment with steroids. Data are not available to support this hypothesis.

Antibiotics. Bronchiolitis is caused by viral infection, and antibiotics are not effective in treating this disease. Some patients will have concomitant bacterial infections (most commonly otitis media), and those patients should be treated with the appropriate antibiotic.40 Approximately 2% of infants with fever and bronchiolitis also will have UTI.33,34 In patients with risk factors (abnormal urinary tract or indwelling catheter), or when the urinalysis is abnormal, urine culture should be performed and antibiotics started pending culture results. Patients who appear septic should have the appropriate cultures done and treatment for presumptive sepsis begun.

Other. Nebulized Hypertonic Saline. A recent study of nebulized hypertonic saline (3%) versus normal saline (0.9%) showed a 26% reduction in the length of hospitalization in those patients who received the hypertonic saline.55 However, a significant number of the study patients received a variety of other therapies as well, reducing the power of the study to routinely support this therapy. A well designed and controlled trial of nebulized hypertonic saline is warranted.

Chest Physiotherapy. Review of randomized controlled trials shows that the use of percussion or vibration chest physiotherapy in patients with bronchiolitis does not reduce length of hospitalization, oxygen requirement, or improve the patient's clinical status.56

Helium-oxygen Mixtures. Helium-oxygen (Heliox) mixtures of 70% helium and 30% oxygen may enhance clinical respiratory status in infants with moderate-to-severe RSV bronchiolitis.27,57 The beneficial response characterized by improved clinical respiratory scores and reduction in tachycardia and tachypnea is seen within the first hour of administration by non-rebreather reservoir face mask.57

Disposition

Disposition of the patient with bronchiolitis will depend on the severity of the illness, the risk for severe disease or outcome, the family's ability to care for the patient or return for follow-up, and the clinician's comfort with the status of the infant and disposition plan.

Attempts have been made to develop risk assessment models to assist the clinician in predicting the need for hospitalization, respiratory failure, or long-term outcome.36,37,58 There is a need for further study of such models. The study published by Mansbach in 2008 identifies predictors for safe discharge from the emergency department. These include age older than 2 months, a history of no intubation, and the child having eczema (eczema appears to be protective from severe disease). Clinical parameters for safe discharge included respiratory rate lower than upper end of normal for age, no more than mild retractions, and oxygen saturation > 94%. Factors requiring clinical judgment were adequate oral intake and administration of nebulized albuterol or epinephrine in the first hour (patients who did not receive albuterol or epinephrine in the first hour were more likely to be discharged home safely, perhaps a marker for infants with illness of less severity).37

The current disparity among physicians and between institutions contributes to the difficulty in studying the most effective treatment options for patients with bronchiolitis, and may preclude the delivery of the most effective care for patients. In light of this, several institutions have implemented practice algorithms for their clinicians caring for the patient acutely ill with bronchiolitis.28,59,60 Tachypnea with increased work of breathing and low O2 saturation (<95%) are commonly accepted indicators for admission and supportive care (at a minimum, close outpatient follow-up). Patients with respiratory failure should be intubated and ventilated in the intensive care setting. Dehydrated patients should receive hydration support.

An algorithm for medical management of bronchiolitis in infants less than 1 year of age presenting with a first time episode is shown in Figure 1.28 Table 5 shows discharge criteria.28

Summary

Bronchiolitis is a common presenting complaint to the emergency setting. Most children will have mild disease and can be safely cared for at home with close outpatient follow-up. Otherwise healthy infants with first-time wheezing with bronchiolitis should be cared for in a supportive fashion, keeping oxygen saturation >95% and maintaining hydration.

Patients with increased work of breathing, or low oxygen saturation may be given a trial of nebulized epinephrine or albuterol in a closely observed outpatient setting. Epinephrine may be more likely to result in a brief improvement of clinical status than albuterol in most patients, but albuterol may be more effective in patients with a strong family history of wheezing. Nebulized epinephrine should not be continued for patients discharged home. Patients who improve with a trial of albuterol may be discharged home, with additional albuterol treatments given either by nebulizer or metered dose inhaler with spacer.

Steroids should be avoided. Antibiotics should not be used unless a concurrent bacterial infection is diagnosed. Infants with high fever who are younger than age 3 months may have an occult bacterial infection, and should be evaluated and treated appropriately for that risk.

Close outpatient follow-up with attention to respiratory and hydration status should be assured if the patient is discharged from the emergency department.

Patients with persistent hypoxia, risk of respiratory failure, or increased risk of severe disease should be admitted to the hospital.

Clinicians play an important role in the spread of viruses causing bronchiolitis and should use precautions to prevent the nosocomial spread of disease, particularly meticulous handwashing.

References

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