ETIOLOGY AND EPIDEMIOLOGY
Bronchiolitis is an acute lower respiratory tract infection that results in an inflammatory obstruction of the peripheral airways, usually in children younger than 2 years.1 Children with bronchiolitis commonly wheeze. Bronchiolitis frequently is the first episode of wheezing in a previously healthy child. Almost all cases are viral induced, with respiratory syncytial virus (RSV) most often implicated. Less frequent but other notable pathogens that may trigger bronchiolitis include parainfluenza, influenza, rhinovirus, adenovirus, measles, and mycoplasma. Bronchiolitis is observed in all geographic areas, and the peak period for bronchiolitis ranges from October or November through April. It is encountered more often in children of lower socioeconomic status with their more crowded living conditions. Exposure to secondhand smoke predisposes to bronchiolitis, whereas breastfeeding appears to confer a protective advantage.
RSV is generally transmitted by contact with infected nasal secretions and much less frequently by aerosol spread. There are two major strains of RSV, A and B. Within each strain are numerous genotypes and subtypes, although one or two usually predominate during an outbreak.2 However, shifts in die predominant strain make it possible for individuals to remain susceptible to reinfection from year to year or even within the same season. RSV infection is common, with estimates that more than half of infants are infected during the first year of life and more than 80% by the age of 2 years.3 Approximately 1% to 2% of those infected with RSV require hospitalization, with younger children generally being more seriously affected. Between 1980 and 1996, bronchiolitis accounted for 1.65 million hospital admissions in the United States. Children younger than 1 year accounted for more than 80% of these hospitalizations, with hospitalization rates increasing from 12.9 per 1,000 in 1980 to 31.2 per 1,000 in 1996.4
PATHOPHYSIOLOGY AND CLINICAL FEATURES
Aside from bronchiolitis, RSV may also cause an uncomplicated upper respiratory tract infection or pneumonia or be a trigger of asthma in older children with this preexisting condition. In the lower respiratory tract, the virus induces necrosis of the airway epithelium and its ciliated lining. The ensuing mucosal inflammation impacts most severely on the smaller-caliber peripheral airways, without significant involvement of alveoli. There is a predominantly lymphocytic infiltrate into the peribronchial and peribronchiolar epithelium that promotes edema of the submucosa and adventitia. Intraluminal plugs of mucous and cellular debris accumulate secondary to impaired mucociliary clearance, leading to ball-valve obstruction and hyperinflation.1,5
For most individuals, bronchiolitis is a self-limited infection. The incubation period for RSV varies from 2 to 8 days.6 After a prodrome of several days, the acute illness often lasts 3 to 7 days, followed by a gradual recovery during 1 to 2 weeks/ Rhinorrhea, cough, and low-grade fever are common. Changes in behavior may occur and vary from restlessness to lethargy, often with decreased oral intake. Findings on physical examination may include tachypnea and the use of accessory muscles of breathing; a prolonged exhalatory phase; and wheezes, crackles, or both. Hypoxemia results from ventilation-perfusion mismatch of gas-exchange units. Chest radiographs typically reveal hyperinflation with patchy atelectasis. The severe complications of respiratory failure and apnea occur most often in very young children or those with underlying conditions such as prematurity, bronchopulmonary dysplasia and other chronic lung diseases, congenital heart disease, and immunodeficient states.
Although many infants are infected with RSV, only approximately 40% have lower respiratory tract complications.8 Characteristics of the host apparently predispose to bronchiolitis and its sequelae. Compared with children with other manifestations of RSV infection, children with bronchiolitis have a higher overall histamine content and more RSV-specific IgE recovered from their airways.9 Elevated levels of either correlate inversely with the patient's oxygen saturation. In a follow-up study through 4 years of age, 70% of children with elevated RSV-specific IgE at the time of bronchiolitis subsequently had recurrent wheezing, compared with 20% without detectable RSV-specific IgE.10 It has been suggested that infants who have bronchiolitis caused by RSV may have abnormal pulmonary function prior to acquiring the acute illness.11·12 Thus, it appears that infants who have bronchiolitis with RSV are predisposed by their immune responses and airway physiology.
Despite the frequency of bronchiolitis, its treatment is far from straightforward. With the lack of an unquestionably effective remedy, the therapy remains controversial.
Supplemental Oxygen and Positive Airway Piessuie Support
Supplemental oxygen should naturally be given to children with inadequate oxygénation. In general, an oxygen saturation greater than 90% is sufficient, because that value keeps the child within the flat portion of the oxyhemoglobin dissociation curve and affords adequate oxygénation to the tissues. However, because the airways of infants are at greater risk of atelectasis from mucous secretions, maintaining an oxygen level of more than 93% may be advantageous. Uncertain pulse oximetry readings, prolonged high supplemental oxygen requirements, and impending respiratory fatigue are all indications for an arterial blood gas sample. Noninvasive ventilatory assistance should be considered for patients demonstrating persistent hypoxemia, acidosis, or recurrent apneic spells. Early institution of continuous positive airway pressure, applied via nasal prongs, may avert the need for mechanical ventilation.13 Chest physiotherapy is often employed as a supportive measure, but evidence has not supported its use.14
Adequate fluid intake remains an important factor for infants with bronchiolitis. For some, parenteral fluids may be necessary. Furthermore, there is an increased frequency of aspiration in infants with acute RSV bronchiolitis. Of 12 previously healthy infants, 3 had evidence of aspiration during acute RSV infection.15 All returned to normal after the acute infection. During the acute respiratory illness, infants are less efficient feeders and have poorer coordination of their breathing with swallowing.16 Thus, if tachypnea and increased work of breathing interfere with oral intake, intravenous fluids may be prudent until the respiratory status improves. Yet care must be taken to avoid overly aggressive hydration, Thinning of secretions through the use of systemic fluids is not possible without exposing the patient to water toxicity. Additionally, the physician must remain attentive to the occurrence of inappropriate antidiuretic hormone secretion that may result in pulmonary congestion.8
Beta-adrenergic Agonists. Beta2-adrenergic agonist inhalation therapy with albuterol has been studied at length. However, convincing evidence that supports or disproves a beneficial effect is lacking, as concluded by a meta-analysis of several randomized, controlled trials.17 The data were pooled from five studies of patients with bronchiolitis seen on an outpatient basis only. The authors precluded analysis of inpatient studies, citing méthodologie differences in terms of variability in disease severity, treatment, and outcome. Some studies have shown a modest short-term beneficial effect on clinical scores, but there was no improvement in oxygénation nor in the rate and duration of hospitalization.18'19 Although large cohorts do not display uniform improvement, testing of infant lung function reveals that some infants exhibit a positive response.20 At the more severe end of the spectrum, children in whom mechanical ventilation is required are more likely to show a response to bronchodilators.21 Pointing out that there may be a subgroup of individuals who improve after bronchodilator therapy in an emergency department setting and are subsequently discharged, McBride argues that most nonresponders require hospitalization. This would explain the concept that inpatients are less likely to respond to betaagonist bronchodilation.22
As a guideline, if no clinical effect or improvement in oxygénation is seen after two trial nebulizations of albuterol administered within 1 hour, it is not recommended that such therapy be continued.23 However, a recent retrospective study demonstrated that physicians often continue beta-agonist therapy despite this lack of improvement.24 Potential drawbacks to continued betaagonist therapy include the occasional paradoxic effect of increased airway resistance and worsening hypoxemia.25,26
Epinephrine and Alpha-adrenergic Agonists, In contrast to the largely disparate data on betaagonist therapy, investigation of alpha-adrenergic agents has yielded more consistent findings. Foremost among these agents is epinephrine, which was initially proposed by Wohl and Chernick as a superior therapy because of its combination of alpha-adrenergic and beta-adrenergic agonist activity.27 Epinephrine administered subcutaneously acutely ameliorated respiratory distress in wheezing infants.28 Furthermore, compared with beta-agonists such as salbutamol, inhaled epinephrine improved clinical scores and decreased airway resistance.29 In children presenting to an emergency department, epinephrine resulted in higher oxygen saturation levels at 1 hour and significantly lower hospitalization rates than did salbutamol.30 Moreover, repeated administration of inhaled epinephrine led to a faster improvement in clinical scores and earlier hospital discharge than did salbutamol and was not associated with adverse cardiovascular effects.31
Anticholinergics and Methylxanthines. The limited data on anticholinergic agents such as ipratropium do not support their use as a principal therapy or in combination with a beta-agonist.32'33 Theophylline has long been used to treat asthma and was previously used for bronchiolitis, yet the literature has not attributed any benefit to its use in either the outpatient or the inpatient setting for the first-time wheezer.34 It may be argued that there could be a role for its use as an adjunct in cases of bronchioliris-associated apnea. Theophylline may be of some benefit for more severely ill infants requiring admission to a pediatrie intensive care unit.
Clinical studies dating back more than 40 years have essentially concluded that corticosteroide lack therapeutic efficacy in bronchiolitis.35 Nonetheless, their use and investigation persist in the face of contrary data, probably because of the recognized inflammatory process in bronchiolitis. More recent studies continue to show a lack of efficacy of systemic corticosteroide, whether delivered orally or parenterally.36"39 As for inhaled steroids, a 6-week course of nebulized budesonide did not alter the severity and course of symptoms, nor did it affect the prevalence of recurrent wheezing in a post-recovery period of 6 months.40 Another study of 3 months of inhaled fluticasone during convalescence demonstrated no significant difference between fluticasone and placebo regarding respiratory symptoms and the use of rescue medication in children observed for 1 year.41 However, as with beta-agonist therapy, there may be some benefit for infants who are more severely affected, van Woensel et al. found a decreased hospital stay with prednisolone (1 mg/kg/d) in patients with bronchiolitis who were being treated with a mechanical ventilator, but no difference in time of intubation.42 This benefit was restricted to acute bronchiolitis, with long-term follow-up demonstrating no beneficial effect on the prevalence of recurrent wheezing through the age of 5 years.43
Antibiotic therapy is occasionally employed in the management of viral bronchiolitis, but there is no support for this practice.44 The fever that may accompany bronchiolitis generally does not signal a bacterial infection. Differentiation from a serious bacterial infection should be possible based on clinical and laboratory evaluation. Acute otitis media is a frequent complication in children with bronchiolitis and should be treated appropriately.45
Antiviral Therapy; Rlbavlrin
Although most healthy children who have bronchiolitis require only supportive care for their self-limited illness, there are select groups of children who are recognized to be at high risk for increased morbidity from lower respiratory tract infection caused by RSV. These include children with (1) chronic lung diseases, including bronchopulmonary dysplasia and cystic fibrosis; (2) complex congenital heart disease, particularly with a predisposition toward pulmonary hypertension; and (3) underlying immunosuppressive disease or therapy. Also considered at high risk are previously healthy premature infants (< 37 weeks of gestation); those who are younger than 6 weeks; and patients with an underlying condition such as multiple congenital anomalies, neurologic disease, or metabolic disease.46
For those in the high-risk groups who have an RSV infection, the antiviral agent ribavirin has been available since the mid-1980s. Ribavirin is a synthetic guanosine derivative that suppresses viral RNA polymerase activity. It is therefore a virustatic agent that should be more effective when used early in the course of infection, before viral replication peaks.8 American Academy of Pediatrics (AAP) guidelines that previously recommended standard use in high-risk groups have been revised, because of concerns over ribavirin' s clinical efficacy, high cost, protracted aerosol delivery, and potential toxicity to health care personnel. Updated guidelines allow for the consideration of ribavirin therapy in high-risk groups at the physician's discretion.6,46
Since those guidelines have been issued, further study into ribavirin has continued to yield equivocal results. Duration of hospitalization is not reduced; indeed, ribavirin has been associated with increased length of stay and hypoxemia in patients who do not require therapy with a ventilator.47 Conflicting results also characterize investigations into the possible long-term benefits of ribavirin for severe RSV infection. There was a reduction in the use of asthma medication in a group treated with ribavirin at 2 years following hospitalization.48 Furthermore, in a 7-year follow-up study, a group treated with placebo presented with more moderate to severe impairment in their pulmonary function and greater airway reactivity to a methacholine challenge than did a group treated with ribavirin.49 This contrasts with other studies with 5 to 10 years of follow-up that demonstrated no differences in reactive airway sequelae or pulmonary function measurements between ribavirin and placebo groups. This suggested no long-term adverse or beneficial effects of ribavirin.50,51
With direct antiviral therapy lacking definitive efficacy, the most recent advances in the strategy against RSV lower respiratory tract disease have emphasized prevention. Two formulations of passive prophylaxis have been approved: an intravenous immune globulin and an intramuscular monoclonal antibody.
RSV Immune Globulin Prophylaxis. RSV immune globulin (RSV-IGIV) was developed in the early 1990s, with the intent of augmenting the amount of specific RSV-neutralizing antibody and thus protecting against severe infection. Compared with conventional intravenous immune globulin, RSV-IGIV is enriched approximately sixfold for RSV-spedfic antibodies. Two major studies corroborated the prevention of severe RSV in children with prematurity or bronchopulmonary dysplasia.52·53 A monthly intravenous dose of 750 mg/kg of RSV-IGIV was safe and well tolerated in both studies and was associated with a reduced incidence of lower respiratory tract infection and a reduced rate and duration of hospitalization from RSV. An additional observation from one study53 was an overall decrease in hospitalizations for respiratory illness of any cause.
In contrast to these two studies, investigation into RSV-IGIV for children with congenital heart disease did not reveal a statistically significant decrease in hospitalization rates for all age groups. Along with reports of increased cyanotic episodes and poor surgical outcomes among children with cyanotic heart disease, current AAP guidelines do not support RSV-IGIV for individuals with any congenital heart disease.54·55 As an exception, those infants with asymptomatic, acyanotic congenital heart disease who are affected by chronic lung disease or prematurity may be considered for prophylaxis.
Monoclonal Antibody Prophylaxis. The effectiveness of passive immunity conferred by RSVIGIV stimulated research into alternatives to intravenous infusion. A significant disadvantage of RSV-IGIV is the inconvenience of administration, including difficulty in securing intravenous access, the duration of delivery (4 to 6 hours), and the personnel and environment required for these infusions. These concerns prompted the development of palivizumab, a humanized monoclonal RSV antibody that is delivered intramuscularly. Because palivizumab specifically targets an epitope on the F protein (a fusion protein that is well conserved between strains of RSV) and is approximately 50 to 100 times more potent than the polyclonal RSV-IGIV, the volume of the preparation is reduced, enabling intramuscular administration.56 Cost comparisons also may favor the use of palivizumab. The minimum expense for dispensing 5 monthly doses of RSV-IGIV for a 3kg infant is estimated at $4,300, whereas an equivalent course of palivizumab is approximately $2,300 if the vials are shared.57 Of course, these comparisons do not hold for older children, who require more palivizumab. Palivizumab also does not interfere with the immunogenicity of other vaccinations, such as measles-mumps-rubella or varicella vaccines. It is recommended that these immunizations be deferred for 9 months after a dose of RSV-IGIV.54
Even with palivizumab's ease of administration, its efficacy determines whether it is the preferred method of passive protection. At a monthly dose of 15 mg/kg, palivizumab was studied in premature children with or without bronchopulmonary dysplasia. In the group treated with palivizumab, there was a 55% reduction in hospitalizations resulting from RSV, with a more pronounced effect in premature children without bronchopulmonary dysplasia (hospitalizations reduced by 78%). A more limited benefit was noted in those affected by prematurity with bronchopulmonary dysplasia (39% reduction). Other favorable outcomes for the group treated with palivizumab were decreased duration of hospitalization, lower incidence of admission to the intensive care unit, fewer days requiring supplemental oxygen, and fewer days characterized by moderate to severe illness.58
In 1998, the AAP issued recommendations for the prevention of RSV infections, with palivizumab favored over RSV-IGIV, suggesting prophylaxis in the following circumstances: children younger than 2 years with chronic lung disease who required medical therapy for their condition within 6 months prior to the RSV season; infants up to 12 months of age, without evidence of chronic lung disease, born before 29 weeks of gestation; and infants up to 6 months of age, without evidence of chronic lung disease, born between 29 and 32 weeks of gestation.54 Existing AAP guidelines do not recommend palivizumab for infants born after 32 weeks of gestation unless additional risk factors are present.6/54 The term chronic lung disease includes bronchopulmonary dysplasia and "chronic lung disease of infancy," but not asthma or recurrent wheezing. The Cystic Fibrosis Foundation has sponsored a multicenter trial of palivizumab in infants with cystic fibrosis, but no recommendations can be made for infants with cystic fibrosis because there are no resulte available.
The desire to develop an RSV vaccine produced difficult lessons in the 1960s, when a formalin-inactivated RSV vaccine resulted in enhanced disease in infants who were subsequently exposed to the wild-type virus. Since then, cautious development of active RSV prophylaxis continues with research into live-attenuated vaccines, recombinant genetically engineered virus vaccines, and glycoprotein subunit vaccines. Several issues have surfaced in the attempt to find a broad-based, cost-effective means of prophylaxis. Developers of a vaccine are compelled to address the appropriateness of the delivery systems, inclusion of A and B strains of RSV, and the satisfactory attenuation of the vaccine while maintaining adequate immunogenicity, especially with immunization of the very young.59 A complementary approach might also incorporate maternal vaccination, because increased cord antibody titers of naturally acquired RSV-neutralizing antibody are associated with an infant's older age at presentation with RSV infection and a milder form of the illness.60 Maternal vaccination would likely take place during the third trimester, when active transfer of maternal IgG antibody to the developing fetus occurs.61 Unfortunately, infants born prematurely would not benefit from such an intervention.
The extensive impact of bronchiolitis on our children and health care system necessitates the continued examination of policies related to the treatment and prevention of this disorder. In most self-limited cases, care to ensure the adequacy of the child's hydration and oxygénation status suffices. The efficacy of beta2-adrenergic bronchodilators is inconsistent, but more favorable evidence for inhaled epinephrine exists. Attempts to prove a beneficial effect of corticosteroids for bronchiolitis continue, but are not promising. Antibiotics are unnecessarily used and direct antiviral therapy with ribavirin is hampered by limited effectiveness, high cost, and the complexity of administration. With recognition of RSV as the leading cause of bronchiolitis, active immunization against RSV has appeal, but it is still in the developmental stages. In the interim, morbidity and hospitalization rates can be reduced in select high-risk groups through the use of passive immunization with either RSV-IGFV or preferably palivizumab.
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61. Englund JA. Prevention strategies for respiratory syncytial virus: passive and active immunization. / Pediatr. 1999;135:38-44.