Anne Marie Gadomski

 Bronchiolitis dilemma:
  A happy wheezer and his unhappy parent 

 A baby who is wheezing but in no apparent respiratory distress,   a worried parent, and a nasal antigen test positive for respiratory syncytial   virus. What to do? Or, perhaps more important, what 

It is December, and you walk into your examining room to see an infant with   difficulty breathing, according to the mother. He is 7 months old, has a respiratory   rate of 60 per minute, a pulse of 170 per minute, and a temperature of 38.1º   C. He has a cough that started with a cold that "went into his chest," his mother   reports. The physical exam is remarkable for a smiling, interactive infant,   who is audibly wheezing. He has intercostal retractions as well as mild chest   indrawing. You note the absence of nasal flaring or grunting. While wrestling   with the child for your stethoscope, you auscultate wheezes, crackles, and occasional   rhonchi. There is a knock on the door and your nurse hands you a report of a   nasal antigen test for this child that is positive for respiratory syncytial   virus (RSV). A collective groan rolls through the office. The yearly RSV epidemic   is here.

 Bronchiolitis usually is seen as the first episode of expiratory wheezing   for an infant who also has cough, runny nose, fever, and rapid respiration.   Characteristically, the infant first develops mild rhinorrhea and cough, and   sometimes a low-grade fever. These symptoms are followed by a more severe cough   and the onset of rapid respiration, chest retractions, and wheezing, usually   by day 3 or 4. On auscultation, wheezing predominates, but rhonchi and crackles   may be widespread. Pulse oximetry may detect hypoxia caused by abnormal gas   exchange. Chest radiographic findings include hyperinflation, perihilar infiltrates,   and atelectasis. Because radiographic findings may not differentiate bacterial,   viral, chlamydial, and mycoplasmal causes, they may not be helpful in making   therapeutic decisions.

 The clinical presentation of bronchiolitis reflects underlying bronchiolar   obstruction leading to distal collapse or air trapping and resulting in ventilation-perfusion   mismatch. The obstruction is caused by viral destruction of the respiratory   epithelium and plugging of small airways by associated cellular debris. Chemical   mediation of airway obstructionthat is, bronchoconstriction caused by   the release of IgE antibody, histamine, and other elements of the inflammatory   responsealso may contribute to the pathogenesis of bronchiolitis. This   is more likely to occur among older infants or those with a personal or family   history of asthma, however. 

 During the respiratory infection season, it is important to differentiate   pneumonia and bronchiolitis. Symptom analysis has demonstrated a greater frequency   of wheezing and increased work of breathing in bronchiolitis.

 Even   though many signs and symptoms overlap (tachypnea, chest indrawing, fever),   bronchiolitis can be recognized easily by its distinctive clinical presentation,   predictable seasonality, and findings on viral antigen testing. 

 The primary cause of bronchiolitis is RSV, although parainfluenza, adenovirus,   influenza viruses, and rhinoviruses also can produce the condition. The peak   incidence of RSV bronchiolitis occurs between 2 and 6 months of age, and over   80% of cases occur in the first year of life. 

 In the United States, the hospitalization rate for bronchiolitis nearly doubled   between 1988 and 1996 with no significant change in mortality.

 Bronchiolitis   accounts for an increasing percentage of total hospitalizations as well as hospitalizations   for lower respiratory tract disease (Figure 1). Postulated reasons for the rise   include increased detection of hypoxia using pulse oximetry, higher day-care   attendance at younger ages, and survival of greater numbers of premature infants.

 Analysis of procedure codes for hospital discharges of patients with bronchiolitis   indicate significant variation in managing the condition. Codes for discharges   between 1994 and 1996 included nebulization (17%), supplemental oxygen (8.6%),   lumbar puncture (4.8%), and antibiotic injection (1.3%), all of which were probably   underreported.

 Despite variation among Canadian tertiary care centers   in the types of medications used to treat infants with bronchiolitis, these   centers reported duration of hospitalization similar to that in the US.

   A study of 601 infants admitted for bronchiolitis or RSV pneumonia at 10 academic   medical centers in the US, documented similar practice variation. Institutional   or individual physician practice preferences showed a strong direct correlation   with the intensity of care received and cost but correlated inversely with disease   severity.

 Despite widespread practice variation and increased medication use in the   US, the mortality rate for bronchiolitis remained stable, at approximately two   deaths for every 100,000 live births, from 1979 to 1997.

 Higher   risk infantswith a history of prematurity, congenital heart disease, or   underlying pulmonary diseasemade up a small and stable percentage of bronchiolitis   hospitalizations and deaths during this period. 

 Bronchiolitis and asthma: What's the connection? 

 An association between bronchiolitis and asthma has long been observed, although   the etiologic connection is not clear.

 What does an episode of bronchiolitis   tell us about an infant's chances of developing asthma? Does bronchiolitis cause   asthma, trigger it, or have no etiologic relationship? Several studies suggest   that infants hospitalized with acute bronchiolitis have an increased risk of   developing persistent wheezing, allergic sensitization, and asthma later in   childhood.

Evidence of immune activation following bronchiolitis   has been used to postulate that subsequent persistent inflammation heightens   sensitization to airborne allergens and therefore may contribute to the evolution   of asthma.

In this view, viruses may cause airway hyperreactivity. 

 On the other hand, an episode of bronchiolitis may be a viral trigger for   the host's genetically determined bronchial hyperresponsiveness, atopy, asthma,   or other immunologic predispositions. Eosinophilia and the level of eosinophil   cationic protein and serum immunoglobulin E at the time of bronchiolitis appear   to predict wheezing in later childhood for some infants.

   In this view, viruses may trigger airway hyperreactivity only in certain infants. 

 A third scenario proposes that the wheezing associated with bronchiolitis   is a function of pre-existing host factorssuch as reduced lung function   and small airways in the infantand has little to do with airway hyperreactivity   or a differential inflammatory response.

 Finally, bronchiolitis   can be a self-limited infection with no sequelae in some infants. Given the   multifactorial nature of chronic disease (Figure 2), it is likely that individual   host factors (family history of asthma and atopy) and environmental factors   (exposure to tobacco smoke) play a more important role than bronchiolitis in   determining whether or not an infant develops asthma.

The bronchiolitis dilemma begins with the mechanisms of pathogenesis. The question of which is a more important contributor to the pathogenesis of bronchiolitissmall airways and plugging or inflammatory mediators and bronchial hyperreactivityhas been central to the controversy that has plagued the management of this common illness for the past 30 years. As a reflection of that controversy, considerable variation in the treatment of bronchiolitis exists worldwide. This variation may result in part from the difficulty of differentiating between infants who have bronchiolitis and those who have asthma triggered by an upper respiratory infection. Treatment variation also arises from differences in training, anecdotal experiences, atopic mix among patient populations, environmental exposures that predispose to wheezing (smoking, air pollution), and local styles of clinical practice.

Despite the fact that bronchodilators, corticosteroids, antivirals, and antibiotics have not been shown conclusively to reduce disease progression, probability of hospitalization, or length of stay, these medicines are still being used. With the exception of ribavirin (Virazole), the use of all these medications to treat bronchiolitis in infants is off-label and unapproved. It is important to review why they are used and whether it makes any clinical sense to continue to do so. 

have been widely used to treat bronchiolitis in the US, Canada, and Europe, with the exception of Great Britain.

 If the predominant cause of wheezing in bronchiolitis is airway obstruction caused by mucous plugs and cellular debris from epithelial necrosis, then ß

-agonists that produce smooth muscle relaxation might not be expected to offer much relief. The small airway thus becomes the predominant treatment limiting factor because bronchodilators are not likely to change the caliber of the infant airway significantly. This is indeed what meta-analyses of several outpatient studies of bronchodilator treatment of first-time wheezers with bronchiolitis suggest. Three meta-analyses have shown that bronchodilators may improve clinical symptom scores but do not affect disease resolution, need for hospitalization, or length of stay.

-adrenergic agent such   as epinephrine has been suggested to reduce bronchial secretions, mucosal edema,   inflammation, and mast cell activation and to achieve smooth muscle relaxation.

   Studies comparing nebulized epinephrine with ß

-agonists have   shown that epinephrine improves clinical scores more effectively and produces   less tachycardia.

 Epinephrine also has been shown to be   effective in treating croup, which is caused by the same viruses that cause   bronchiolitis. Another advantage to epinephrine is that it can be less expensive   than selective ß

-agonists, although the cost of nebulization   remains. 

 Inadvertent inclusion of asthmatic children in some of the studies of ß

-adrenergic agents introduces   a bias toward showing that bronchodilator treatment is effective for bronchiolitis.   Studies with more ambiguous entry criteria, resulting in inclusion of asthmatic   children, demonstrate more clinical improvement than studies with stricter first-time   wheezer criteria. When evaluating a first-time wheezer, however, it is difficult   to ascertain that this is indeed the first episode of wheezing, that the child   is destined to have asthma, or that he is likely to respond to asthma therapy.   There lies the dilemma. 

Inpatient studies have shown that giving a bronchodilator to a hospitalized infant with bronchiolitis has no impact on the rate of symptom improvement or length of hospitalization.

 In one such study, implementing a clinical practice guideline for hospital management that recommended response-dependent use of inhaled epinephrine and advised against routine use of bronchodilators resulted in a 30% decrease in bronchodilator use and 51% fewer repeated inhalations.

 Length of stay was reduced by 17%, and ancillary service costs decreased 37% with no change in family satisfaction. 

Studies of the worst-case scenario of bronchiolitisrespiratory failure among infants requiring ventilation in an intensive care unithave not clarified the controversy. Lung function studies of ventilated infants have shown a small but significant improvement in lung function after metered-dose inhalation of albuterol in 45% of infants studied.

 Length of hospitalization among responders was no different from that of nonresponders, however. Similarly, nebulization with epinephrine among ventilated infants with bronchiolitis has been shown to reduce resistance but not improve oxygenation or ventilation.

 At the severe end of the disease spectrum, the physician is left to weigh the advantages of time-limited improvements in lung function against the adverse effects of bronchodilators, which include increased oxygen consumption, worsened ventilation-perfusion mismatches, and tachycardia. 

Because bronchodilators may produce modest, short-term symptom improvement for infants with bronchiolitis, an initial trial of these drugs, particularly epinephrine, is an option, with continuation contingent on observed clinical response. Without a clearly demonstrated response, continued use cannot be justified. Bronchodilators cannot be recommended for routine management of infants with a first episode of wheezing, given the lack of conclusive efficacy studies and the expense associated with their use. 

 Steroid treatment of bronchiolitis has been common in Europe

 Two meta-analyses of the treatment of bronchiolitis with corticosteroids came to conflicting conclusions. One, which included six trials, concluded that steroids may be effective in reducing length of hospitalization and improving clinical symptom scores. The authors propose that this may be particularly true if steroids are given early to more severely affected infants. Once again, inclusion of asthmatic infants may bias the results of this analysis toward treatment because such infants are likely to be steroid-responsive. The other meta-analysis included 11 trials and showed no demonstrable beneficial effects of steroid use on length of hospital stay and clinical symptom scores.

Two European trials, each with a much larger sample than any of the trials included in the above meta-analyses, demonstrate no favorable impact of either nebulized budesonide or systemic prednisolone on length of hospitalization and clinical symptoms.

 Until some way exists to discriminate between infants who are likely to be steroid-responsive and those who are not, using corticosteroids cannot be justified.

 Initial studies of ribavirin for treating RSVassociated bronchiolitis showed that ribavirin appeared to improve arterial oxygen tension and decrease severity of illness scores.

 In a study of 28 infants hospitalized for severe RSV infection who required mechanical ventilation and were also treated with aminophylline and antibiotics for the first 48 hours, ribavirin reduced the duration of mechanical ventilation, days of supplemental oxygen use, and length of hospitalization.

 have been less definitive, however, and ribavirin treatment remains controversial, as reflected by the 1996 statement of the American Academy of Pediatrics's Committee on Infectious Diseases.

 A Cochrane review of randomized, controlled trials of ribavirin showed that ribavirin reduces length of mechanical ventilation and total hospital days but does not significantly reduce mortality or slow respiratory deterioration.

Intended primarily for infants with underlying illness who are hospitalized with RSV bronchiolitis or pneumonia, ribavirin is expensive and cumbersome to administer. Because the drug is virustatic and not virucidal, it needs to be given early in the illness to reduce viral replication effectively.

 Until research proves otherwise, ribavirin should only be used for severe RSV infection in infants with underlying cardiac, pulmonary, congenital, or immunologic disease. 

Other immunotherapy, such as RSV immune globulin, has been studied but not found to significantly improve clinical course or length of stay in hospital. One recent study of recombinant human deoxyribonuclease I (rhDNase I) used to treat infants hospitalized with bronchiolitis showed no effect on the duration of hospitalization.

Clarifying the underlying immunopathogenesis associated with bronchiolitis may lead to more specific therapies that prevent the immunologic and inflammatory cascade leading to epithelial necrosis and bronchial constriction. At this point, however, no antiviral therapy is available to treat mild or moderate bronchiolitis.

 Infants with bronchiolitis appear to have a low risk of serious bacterial coinfection.

 A study of 211 bronchiolitic infants younger than 90 days reported no cases of bacteremia, urinary tract infection, or meningitis among those tested for serious bacterial infection.

 Infants with RSV bronchiolitis rarely develop subsequent bacterial infection.

 Indeed, prolonged use of antibiotics tends to be associated with, first, a higher rate of subsequent bacterial infection than that among infants who do not receive antibiotics and, second, with emergence of resistant microorganisms.

Despite the low risk of bacterial infection, a large percentage of infants (more than half in some studies) who are hospitalized with bronchiolitis receive empiric antibiotic therapy.

 Use of viral diagnostic tests (RSV nasal antigen) has been associated with decreased use of antibiotics or earlier termination of antibiotic coverage.

Although empiric antibiotic coverage does not appear to be justified, close clinical surveillance of young infants during hospitalization is warranted. Deviation from the usual clinical resolution of the disease (recrudescence of fever, prolonged respiratory distress, increasing white blood cell count) should prompt reevaluation. 

Acute otitis media often accompanies bronchiolitis and may occur in more than half of infants with RSV-positive bronchiolitis. Not surprisingly, many infants with bronchiolitis are given a diagnosis of otitis media in the days preceding lower respiratory tract involvement and are prescribed an oral antibiotic. Tympanocentesis has demonstrated that the etiology of otitis occurring with bronchiolitis includes the usual middle-ear bacterial pathogens but rarely RSV alone.

 Therefore, continuing an oral antibiotic prescribed for true acute otitis media that occurs in the context of bronchiolitis infection appears justified. 

In this era of increasing antibiotic resistance, empiric use of parenteral antibiotics to treat bronchiolitis is unjustified. Coincident use of oral antibiotics to treat otitis media associated with bronchiolitis, particularly RSV-positive disease, is justifiable given the reasonably high likelihood that the otitis media has a bacterial cause. 

 For most infants with bronchiolitis, treatment options remain limited to supportive   care (Table 1). Correction of hypoxia and monitoring for signs of respiratory   failure are the most important components of hospital management. The

 recommends hydration and supplemental oxygen to treat hypoxia.

   In an intensive care setting, administering a helium-oxygen mixture (heliox)   may avoid intubation and mechanical ventilation, as suggested by one randomized   trial of heliox in infants with severe bronchiolitis.

Apnea may be the first presenting sign of bronchiolitis caused by RSV, particularly   among premature infants. Apnea monitoring may be necessary for these infants. 

 Recent studies have documented feeding difficulties and increased risk of   aspiration among infants in the acute phase of bronchiolitis.

   Thickened feeds have been shown to improve swallowing dysfunction and prevent   aspiration in infants with RSV bronchiolitis.

 Because thickened   feeds are relatively simple and safe, this could be a cost- effective intervention   to recommend to parents for outpatient care (Table 2). Breastfed infants may   require more frequent breastfeeding with shorter times at the breast because   of the increased work of breathing associated with bronchiolitis. Smaller volume,   more frequent feedings benefit formula-fed infants as well. 

What to tell parents about outpatient care

Upper airway obstruction can contribute significantly to the respiratory distress that infants with bronchiolitis experience. It can be alleviated by clearing the upper airway of secretions, thus reducing some of the work of breathing. Parents should be taught how to remove secretions by careful bulb suctioning, particularly on days 4 to 6 of the illness, when the infant is mobilizing more secretions, and before feeding. 

Although infants with bronchiolitis are often placed in mist tents, no data support this practice.

 Pediatric folklore encouraging the use of mist includes the belief that aerosolized water acts as a mucolytic, decreases sputum viscosity, and promotes expectoration.

 Given the relatively large particle size generated by most mist tents, 90% to 95% of the particles are deposited in the nose or nasopharynx,

 acting as an upper airway wash. Although large particles may in this way reduce upper airway resistance, smaller particles produced by nebulization may increase resistance and induce bronchospasm in children with asthma. A cautionary note that should be added to any discussion of home humidifiers is the risk of bacteria- or fungus-contaminated aerosols produced by humidifiers that are not cleaned properly.

Instead of agonizing over agonists, delivering adrenergic whipping, debating over steroids, or launching empiric antibiotic coverage, physicians would do better to provide much less dramatic supportive care. This may be all that an otherwise normal infant needs to recuperate from what, for most, will be a self-limiting infection. Until further studies demonstrate more conclusive results using more objective outcomes, larger sample sizes, and clearer inclusion criteria, treatment options for bronchiolitis remain limited to supportive care.

The nurse concludes her pulse oximetry wrestling match with the infant and tells you that he's "sat'ing" at 96% on room air. As you turn to the mother to explain, you remember to use the words that convey the nature of the illness ("viral"), its usual course ("gets worse before it gets better"), treatment ("none"), what to do at home ("bulb suction"), how to feed the baby ("slowly," "smaller amounts," "more often," "try thickened feeds") and when to return to your office ("if the baby is working harder to breathe"). You realize that you will be repeating these words a lot over the next five months and begin to feel a little weary already. Mother chimes in and says, "My other child had RSV, and I've been through all this  before." Then she asks, "Aren't there any medicines to treat it?" And you say what?

1.	Bettenay FAL, Campo JF, Crossin DB: Differentiating   bacterial from viral pneumonias in children. 

 	2.	Grossman LK, Caplan SE: Clinical, laboratory   and radiological information in the diagnosis of pneumonia in children. 

 	3.	Court SDM: The definition of acute respiratory   illnesses in children. 

 	4.	Shay DK, Holman RC, Roosevelt GE, et al: Bronchiolitis-   associated mortality and estimates of respiratory syncytial virus-associated   deaths among US children, 19791997. 

 	5.	Shay DK, Holman RC, Newman RD, et al: Bronchiolitis-associated   hospitalizations among US children, 19801996. 

 	6.	Wang EE, Law BJ, Boucher FD, et al: Pediatric   Investigators Collaborative Network in Infections in Canada (PICNIC) study of   admissions and management variation in patients hospitalized with respiratory   syncytial virus lower respiratory tract infection. 

 	7.	Wilson DF, Horn SD, Hendley JO, et al: Effect   of practice variation on resource utilization in infants hospitalized for viral   lower respiratory illness. 

 	8.	Welliver RC: Immunologic mechanisms of virus-   induced wheezing and asthma. 

 	9.	Kattan M: Epidemiologic evidence of increased   airway reactivity in children with a history of bronchiolitis. 

 	10.	Sigurs N, Bjarnason R, Sigurbergsson F, et   al: Respiratory syncytial virus bronchiolitis in infancy is an important risk   factor for asthma and allergy at age 7. 

 	11.	Panitch HB: Bronchiolitis in infants. 

 	12.	Smyth RL, Fletcher JN, Thomas HW, et al: Respiratory   syncytial virus and wheeze. 

 	13.	Welliver RC, Sun M, Rinaldo D, et al: Predictive   value of respiratory syncytial virus-specific IgE responses for recurrent wheezing   following bronchiolitis. 

 	14.	Ehlenfield DR, Cameron K, Welliver RC: Eosinophilia   at the time of respiratory syncytial virus bronchiolitis predicts childhood   reactive airway disease. 

 	15.	Pifferi M, Ragazzo V, Caramella D, et al: Eosinophil   cationic protein in infants with respiratory syncytial virus bronchiolitis:   Predictive value for subsequent development of persistent wheezing. 

 	16.	Martinez FD, Morgan WJ, Wright AL, et al: Diminished   lung function as a predisposing factor for wheezing respiratory illness in infants.   

 	17.	Kattan M: Epidemiologic evidence of increased   airway reactivity in children with a history of bronchiolitis 

 	18.	Prober C, Wand EEL: Reducing the morbidity   of lower respiratory tract infections caused by respiratory syncytial virus:   Still no answer. 

 	19.	Goodman BT, Chambers TL: Bronchodilators for   bronchiolitis. 

 	20.	Kellner JD, Ohlsson A, Gadomski AM, et al:   Bronchodilators for bronchiolitis (Cochrane Review), in 

   Issue 3. Oxford, Update Software, 2000, or 

Cochrane Database of Systematic   Reviews 

 	21.	Kellner JD, Ohlsson A, Gadomski AM, et al:   Efficacy of bronchodilator therapy in bronchiolitis: A meta-analysis. 

 	22.	Flores G, Horwitz RI: Efficacy of ß

-agonists   in bronchiolitis: A reappraisal and meta-analysis. 

 	23.	Klassen TP: Recent advances in the treatment   of bronchiolitis and laryngitis. 

 	24.	Reijonen T, Korppi M, Pitkakangas S, et al:   The clinical efficacy of nebulized racemic epinephrine and albuterol in acute   bronchiolitis. 

 	25.	Sanchez I, De Koster J, Powell RE, et al: Effect   of racemic epinephrine and salbutamol on clinical score and pulmonary mechanics   in infants with bronciolitis. 

 	26.	Menon K, Sutcliffe T, Klassen TP: A randomized   trial comparing the efficacy of epinephrine with salbutamol in the treatment   of acute bronchiolitis. 

 	27.	Dobson JV, Stephens-Groff SM, McMahon SR, et   al: The use of albuterol in hospitalized infants with bronchiolitis. 

 	28.	Perlstein PH, Kotagal UR, Bolling C, et al:   Evaluation of an evidence-based guideline for bronchiolitis. 

 	29.	Hammer J, Numa A, Newth CJL: Albuterol responsiveness   in infants with respiratory failure caused by respiratory syncytial virus infection.   

 	30.	Numa AH, Williams GD, Dakin CJ: The effect   of nebulized epinephrine on respiratory mechanics and gas exchange in bronchiolitis.   

 	31.	Kimpen JLL, Schaad UB: Treatment of respiratory   syncytial virus bronchiolitis: 1995 poll of members of the European Society   for Pediatric Infectious Diseases. 

Articles

A baby who is wheezing but in no apparent respiratory distress and a nasal antigen test positive for respiratory syncytial virus. What to do? Or, perhaps more important, what not to do?

Author | Anne Marie Gadomski

Articles

Bronchiolitis dilemma: A happy wheezer and his unhappy parent