Bronchiolitis

(also see Synagis)

Background:

• acute, infectious, inflammatory disease of the upper and lower respiratory tract
• results in obstruction of the small airways.
• may occur in all age groups, but the larger airways of older children and adults better accommodate mucosal edema; severe respiratory symptoms usually are limited to young infants.
• two respiratory syncytial virus (RSV) subtypes, A and B, with subtype A causing most severe infections.
• one subtype usually predominates during a given season; thus, “good” years and “bad” years occur for RSV disease.
• the disease is highly contagious. Viral shedding in nasal secretions continues for 6-21 days after development of symptoms. The incubation period is 2-5 days.
• Human rhinoviruses are a major pathogen among children under age 2 and may be responsible for a significant proportion of wheezing in this population and may trigger asthma. These researchers write that hospitalization rates may be similar to RSV. (1)

Pathophysiology:

• Necrosis of the respiratory epithelium
  
• proliferation of goblet cells results in excessive mucus production
• epithelial regeneration with nonciliated cells impairs elimination of secretions.
• lymphocytic infiltration may result in submucosal edema.
• the pathology results in obstruction of bronchioles by inflammation, edema, and debris, leading to hyperinflation, increased airway resistance, atelectasis, and ventilation-perfusion mismatching.

Infants have small airways, high closing volumes, and insufficient collateral ventilation; thus, they are affected most often. Recovery begins with regeneration of bronchiolar epithelium after 3-4 days, but cilia do not appear for up to 2 weeks. Mucus plugs are removed by macrophages. Risk factors include the following:

• Low birth weight, particularly premature infants
• Lower socioeconomic group
• Crowded living conditions and/or daycare
• Parental smoking
• Chronic lung disease, particularly bronchopulmonary dysplasia
• Severe congenital or acquired neurologic disease
• Congenital heart disease with pulmonary hypertension
• Congenital or acquired immune deficiency diseases

Frequency:

• In the US: Twenty-five percent of children younger than 12 months and 13% of children aged 1-2 years have respiratory infections.
• Of these 25%, one half have a wheezing-associated respiratory disease.
• RSV can be cultured from one third of these outpatients and from 80% of hospitalized children younger than 6 months.
• Nearly 100% of children experience an RSV infection within 2 RSV seasons and 1% are hospitalized.
• Among healthy full-term infants, 80% of hospitalizations occur in the first year, and 50% of hospitalizations occur in children aged 1-3 months.
• Fewer than 5% of hospitalizations occur in the first 30 days of life, presumably due to transplacental transfer of maternal antibody.
• In temperate climates, RSV epidemics generally develop yearly in winter and late spring, while Parainfluenzae outbreaks usually occur in the fall.
• Evidence indicates that, in the subtropical areas of the southeastern US, RSV is endemic throughout the year, with peaks from October to February and subsidence only from March through July.
• Secondary infections occur in 46% of family members, 98% of other children in daycare, 42% of hospital staff, and 45% of previously uninfected hospitalized infants.
• Infection is spread by fomites via environmental surfaces. Hand washing and the use of disposable gloves and gowns may reduce nosocomial spread.

• Internationally: Bronchiolitis is a significant cause of respiratory disease worldwide. Its incidence in developed countries appears similar to the US. Epidemiologic data from underdeveloped countries are incomplete.

Mortality/Morbidity:

• RSV bronchiolitis accounts for more than 90,000 pediatric hospitalizations and up to 4,500 deaths annually.

• Overall, the mortality for children hospitalized for bronchiolitis in different series is 0.2-7%. This large variability is based on investigations of different cohorts with different risk factors and different points in time relative to modern intensive care.

• Very recent studies in pediatric intensive care units of children with RSV bronchiolitis and without comorbidities show a 2-3% death rate regardless of whether the children had congenital heart disease with pulmonary hypertension.

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

Age:

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

History:

• As this disease primarily affects young infants, the clinical manifestations initially are subtle.

• Infants may become increasingly fussy and have difficulty feeding during the 2- to 5-day incubation period. A low-grade fever, usually less than 101.5°F, and increasing coryza and congestion usually follow the incubation period.

• Sixty percent of primary RSV infections are confined to the upper airway.

• During a period of 2-5 days, this may progress to lower respiratory tract involvement with the development of cough, dyspnea, wheezing, and feeding difficulties.

• By the time the patient is brought to medical attention, the fever usually has resolved.

• Infants younger than 1 month may present as hypothermic.

• Severe cases progress to respiratory distress with tachypnea, nasal flaring, retractions and irritability, and, possibly, cyanosis.

Physical:

• Examination often reveals the following:

• Otitis media
• Tachypnea
• Tachycardia
• Fever (38-39°C)
• Retractions
• Fine rales
• Diffuse, fine wheezing

• Diagnosis is based on the age and seasonal occurrence, tachypnea, and the presence of profuse coryza and fine rales and/or wheezes on auscultation of the lungs.

• Hypoxia is the best predictor of severe illness and correlates best with the degree of tachypnea. The degree of wheezing or retractions correlates poorly with hypoxia.

• First-time infections usually are most severe. Subsequent attacks generally are milder, particularly in older children.

• Nonrespiratory manifestations of RSV infections include
  • otitis media
  • myocarditis
  • supraventricular and ventricular dysrhythmias
  • inappropriate secretion of antidiuretic hormone.

• Of infants hospitalized with RSV bronchiolitis, 18-20% develop apnea. Frequency of apnea increases among premature infants whose gestation was less than 32 weeks, infants who have not yet reached the age of 44 weeks from conception, and especially among those who have neonatal apnea.

• Apnea occurs early in the course of the disease and may be the presenting symptom.

• Nonobstructive central apnea occurs during quiet sleep and is associated with increases in the apnea index (percentage of time the baby spends apneic), apnea attack rate (the number of episodes of apnea per unit time), and apnea percentage (the distribution of episodes of apnea while in a given sleep state).

• Apnea rarely lasts longer than a few days; however, about 10% of these patients require intubation and mechanical ventilation to get through this period.

Causes: RSV is the most commonly isolated agent in 75% of children younger than 2 years and who are hospitalized for bronchiolitis.

• Agents that cause wheezing-associated respiratory infections include the following:
• Mnemonic: PM AIR

• Parainfluenza virus causes 10-30% of all bronchiolitis cases.
• Mycoplasma pneumoniae accounts for 5-15% of cases of bronchiolitis, particularly among older children and adults.
• Adenovirus accounts for 5-10% of cases of bronchiolitis.
• Influenza virus accounts for 10-20% of cases of bronchiolitis.
• RSV causes 20-40% of all cases and 44% of cases involving children younger than 2 years.
• Abundant evidence reveals that complex immunologic mechanisms play a role in the pathogenesis of RSV bronchiolitis. Type I allergic reactions mediated by the immunoglobulin E (IgE) antibody may account for clinically significant bronchiolitis. Babies who are nursed with colostrum rich in immunoglobulin A (IgA) appear relatively protected from bronchiolitis.

DDx

Asthma
Pertussis
Pneumonia

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

Medical Care:

Shown not to work in the management of the infant with RSV and wheezing. : corticosteroids , Ipratropium bromide (atrovent), an aerosolized anticholinergic agent

• Indications for hospital admission include the following:
  • Oxygen saturation monitored by pulse oximetry below 92% in room air
  • Younger than 6 months and unable to maintain oral hydration
  • Markedly elevated respiratory rate
  • History of chronic cardiorespiratory disease
  • Desaturation in 40% oxygen (3-4 L/min oxygen), cyanosis
  • Extra pulmonary symptoms
• Apnea and acidosis are indicators for pediatric intensive care referral.

Hospital care

• Administer supplemental humidified oxygen to maintain transcutaneous saturation above 92%.
• Fluid replacement: These infants are mildly dehydrated because of decreased fluid intake and increased fluid losses from fever and tachypnea. The goal of fluid therapy is to replace deficits and provide maintenance requirements. Avoid excessive fluid administration because this may promote interstitial edema formation, particularly if a component of inappropriate antidiuretic hormone release exists.
• Perform nasal and oral suctioning.
• Monitor patient carefully in order to detect apnea.
• Pay attention to temperature regulation in the very small infant.
• Mechanical ventilation: Infants with bronchiolitis occasionally require mechanical ventilation in cases of recurrent apnea or increased work of breathing with respiratory failure. The treatment of these patients is supportive, with provision of adequate oxygen, ventilation, and hydration. Continuous positive airway pressure (CPAP) and intermittent mandatory ventilation (IMV) with positive end-distending pressure (PEEP) have been used successfully in the treatment of these infants.
•  in patients requiring ventilation using IMV and PEEP
  • ventilate at rates slow enough to allow adequate emptying during exhalation.
  • short inspiratory time is used to optimize ventilation to more compliant lung units without overdistending more obstructed ones.
  • Aggressive weaning over the first 2 or 3 days is not warranted and usually is unsuccessful.
  • Once the illness subsides, weaning can proceed quickly.
  • Infants with progressive hypoxemia unresponsive to conventional ventilation may respond to high-frequency ventilation or extracorporeal membrane oxygenation. Current experimental therapies for infants with pulmonary insufficiency from bronchiolitis include surfactant and nitric oxide.

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

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

Medication

Although a number of medications and interventions have been used to treat bronchiolitis, at present, only oxygen and racemic epinephrine have been shown to affect the condition of the young child with bronchiolitis appreciably. Neither of these appreciably shortens the duration of the disease; however, each may prevent complications and improve comfort.

Therapeutic use to treat bronchiolitis in infants and young children has been controversial. Efficacy in infants is complex because it can be a function of the pharmacologic agent, the route of administration, the clinical status of the patient, or the adequacy of the outcome measure used to demonstrate an effect.

A meta-analysis reviewed 15 randomized placebo-controlled trials of bronchodilator treatment in bronchiolitis. It concluded that bronchodilators produce modest short-term improvement in clinical features of mild or moderately severe bronchiolitis.

A more recent meta-analysis of 8 clinical trials noted that conclusive analysis for the efficacy of beta2-agonist therapy for bronchiolitis remains unavailable and that the routine use of beta2-agonist therapy for bronchiolitis is not supported.

A recent study compared nebulized albuterol to normal saline in an age-matched and severity-matched trial of 52 infants over 72 hours of treatment. Nebulized albuterol did not improve recovery or attenuate severity, as indicated by improvement in oxygen saturation, length of stay, or clinical score.

Although evidence about the efficacy of bronchodilators in bronchiolitis is conflicting, administering a beta-agonist, such as albuterol (0.15 mg/kg/dose), on a trial basis to patients with bronchiolitis (particularly if a history of asthma exists) and assessing the clinical response in 10-15 minutes is reasonable. If improvement in retractions, respiratory rate, and wheezing is noted, scheduled aerosol treatments may be continued, with additional treatments administered as needed.

Ribavirin, a nucleotide analog, may have a role in certain unique situations.

Ribavirin treatment for RSV infections has been controversial because of the aerosol route of administration, the variable course of RSV infection, drug cost, toxicity, and adverse effects.

The current recommendations of the Academy of Pediatrics are that ribavirin aerosol therapy may be considered in selected infants and young children at high risk for serious RSV disease.

This includes patients with complicated congenital heart disease, including pulmonary hypertension; patients with bronchopulmonary dysplasia, cystic fibrosis, and other chronic lung disease; patients with underlying immunosuppressive disease; patients who are severely ill with or without mechanical ventilation; and hospitalized patients who are younger than 6 weeks or who have underlying conditions, such as multiple congenital anomalies or certain neurological and metabolic diseases.

The academy added, "More definitive answers to the questions of ribavirin efficacy and effectiveness require multi-institutional prospective randomized clinical trials. Recommendations may be modified as new information becomes available."

Subsequent studies have shown that ribavirin does not reduce mortality rate significantly or lower the probability of respiratory deterioration. Ribavirin treatment did not reduce the diagnosis of reactive airway disease, and pulmonary function test results did not show any differences when assessed 5-6 years after initial RSV infection.

Oxygen -- Decreases the work of breathing, hence, delaying the onset of respiratory muscle fatigue, allowing other therapies to work.

Bronchodilators -- Act by decreasing muscle tone in both the small and large airways in the lungs, thereby increasing ventilation.

Immunoglobulins -- Specific immunoglobulin products with anti-RSV activity have been developed for the prophylaxis of high-risk patients against RSV infection. Palivizumab (Synagis) -- Humanized monoclonal antibody directed against the F (fusion) protein of RSV. Given monthly through the RSV season, it has been demonstrated to decrease the chances of RSV hospitalization in premature babies who are at increased risk for severe RSV-related illness.

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

Nucleoside analogs -- Ribavirin (1-beta-D-ribafuranosyl-1,2,4-triazole-3-carboxamide) is a synthetic nucleoside analog that resembles guanosine and inosine. It appears to interfere with the expression of messenger RNA and inhibit viral protein synthesis. Ribavirin has a broad spectrum of antiviral activity in vitro, inhibiting replication of RSV, influenza, parainfluenza, adenovirus, measles, Lassa fever, and Hantaan viruses. Ribavirin (Virazole) -- Appears to be safe but expensive. Efficiency and effectiveness have not been demonstrated clearly in large, randomized, placebo-controlled trials. Routine use at this time cannot be recommended. In adults, ribavirin can be used for the treatment of other infections, including hepatitis C.

Followup

Further Inpatient Care:

• For patients who are hospitalized, a follow-up appointment with a primary care physician 1-2 days after discharge is indicated to recheck room air saturation and for parental reassurance.

• No further laboratory testing is necessary unless the patient must test RSV negative for return to an environment where high-risk patients are present, such as at medical daycare centers or group homes. Secretions may remain positive for RSV for as long as 21 days after the onset of symptoms.

In/Out Patient Meds:

• For children who required inpatient antibiotics for intercurrent infections, continue the same antibiotics to complete the suggested course.

• A child with reactive airway disease may require continued treatment with bronchodilators.

Transfer:

• Transfer to a facility that has an intensivist-managed critical care unit is indicated for patients with the following characteristics:

• High risk
• Requiring more than 40% oxygen
• Extrapulmonary symptoms
• Acidotic
• Apnea
• Unclear etiology of their symptoms

Deterrence/Prevention:

• Transmission of RSV probably occurs via contact with secretions of infected patients. Meticulous attention to hand washing between patient contacts should reduce the likelihood of hospital staff acquiring RSV infection from patients or of spreading infection by carrying RSV on their hands. Morbidity and death from RSV occurs predominately in children younger than 2 years. Other high-risk infants and children include premature infants younger than 6 months, infants and children with underlying pulmonary or cardiac disease, and those with immunodeficient states.

• Attempts to develop a safe and effective RSV vaccine thus far have been unsuccessful. A 1967 study of a formalin-inactivated RSV vaccine resulted in a 15–fold increase in hospitalization and mortality when immunized patients were subsequently reinfected. An adequate explanation for this exaggerated pulmonary response has not been elucidated. Active prophylaxis by the use of respiratory syncytial virus immunoglobulin intravenously (RSV-IGIV) at high doses (500-750 mg/kg) has been shown to prevent RSV in high-risk patients.

• Presently, a number of disadvantages to the parenteral administration of human polyclonal RSV-specific immunoglobulin antibodies to infants exist. These include intravenous administration monthly over 2-4 hours, the need to administer it in a clinic or hospital, and the potential for excessive fluid load.

• A more convenient RSV-specific monoclonal antibody preparation, Palivizumab, which can be administered as an intramuscular injection, is available. It is administered at a dose of 15 mg/kg every 30 days from October through February or according to the local RSV season (ie start in November). See Synagis.

• In a multi-institutional, randomized, placebo-controlled study of 1502 high-risk, preterm infants in 139 centers in the US and Canada during the 1996-1997 RSV season, hospitalizations were decreased by 55%. Hospital length of stay, days on oxygen, and intensive care unit admissions all were reduced. Adverse effects were uncommon. Unfortunately, while cost effective, per-patient cost is approximately $3000, thus restricting availability to only high-risk patients.

Complications:

• As with any disease, complications of the disease itself and complications of the therapy are present. In most cases, the disease is mild and self-limiting. In infants who are immunosuppressed and those with preexisting heart or lung disease, RSV bronchiolitis can result in any of the following:

• Acute respiratory distress syndrome (ARDS)
• Bronchiolitis obliterans
• Congestive heart failure
• Secondary infection
• Myocarditis
• Arrhythmias
• Chronic lung disease

• Complications of therapy include the following:

• Ventilator-induced barotrauma
• Nosocomial infection
• Beta-agonist–induced arrhythmias
• Nutritional and metabolic abnormalities

• Strict attention to fluid and nutritional therapy, avoidance of unnecessary invasive monitoring, infection control, and judicious ventilator management, including the use of high-frequency oscillatory ventilation to avoid volutrauma/barotrauma may preclude many of these complications.

Prognosis:

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

Patient Education:

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

Medical/Legal Pitfalls:

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

Bronchiolitis. Last Updated: July 17, 2003. http://www.emedicine.com/ped/topic287.htm
Other references
(1) Pediatr Inf Dis J. 2009;28:25-29