Bronchiolitis Josephine FOCUS
R. Welliver,
MD* and Robert
1. What are the clinical manifestations of bronchiolitis? 2. How is bronchiolitis associated with recurrent wheezing and asthma? 3. Which conditions predispose infants with bronchiolitis to develop progressive or lifethreatening illness? 4. When should a child with bronchiolitis be admitted to the hospital? 5. What is the connection between bronchiolitis and respiratory syncytlal virus and what are the indications for the use of antiviral agents?
Bronchiolitis is an acute respiratory illness precipitated by a viral infection and resulting in obstruction of the small airways. While mortality due to bronchiolitis is low in developed countries, it remains an important illness because of the frequency with which infants require hospitalization and because of the potential association with asthma during later life.
Epidemiology
Definition An enduring definition of bronchiolitis has been the first episode during infancy of an illness beginning as an upper respiratory infection that progresses to the development of wheezing. This definition is inadequate for a number of reasons. First, infants who have obstructive airway disease do not always wheeze audibly. Second, many infants have two or more episodes of viral bronchiolitis within an interval of only a few months. The recurrent wheezing episodes are clinically quite similar to the first episode. Finally, some children may have their first episode of virus-induced wheezing during the second year of life, with the age of onset being the only feature that is differ-
*14jjpJ
Professor Medicine, Hospital
Professor
infectious Children’s
134
of Pediatrics, SUNYaI of Buffalo,
Division Buffalo NY.
of Pediatrics, Division of Diseases, SUNYa Buffalo Hospital of Buffalo, NY
of and
and
MDt
ent from a typical episode of bronchiolitis. It has been suggested that clinicians use the response of the wheezing infant to a single subcutaneous dose of epinephrine to distinguish bronchiolitis from asthma. This is inappropriate because a small number of infants who have true bronchiolitis respond to the first course of betaadrenergic agents while many patients with status asthmaticus do not. It probably is best to refer to any wheezing-associated illness in early life preceeded by signs and symptoms of an upper respiratory infection as bronchiolitis. This definition is compatible with there being no epidemiologic, clinical, or laboratory features that distinguish infants who have a single episode of bronchiolitis from those who have multiple episodes in the first few years of life.
QUESTiONS
Emergency Children’s
C. Welliver,
The epidemiology of bronchiolitis has been determined in longitudinal studies at several locations around the world. Bronchiolitis is seen frequently in all geographic areas. It is a highly seasonal disease-comparatively few cases occur during the summer months, and activity peaks during the winter months. In the northern hemisphere, bronchiolitis occurs most frequently in mid-December and mid-March; in the southern hemisphere, most cases are seen during the winter months of July and August. In tropical climates, where cold weather does not occur, bronchiolitis is seen most commonly during the rainy seasons, when crowding occurs as a result of populations being driven indoors. Serious cases of bronchiolitis occur most commonly in infants younger than 1 year, particularly in the 1- to 3-month age span. In the general population of the United States, the incidence of bronchiolitis is 11.4 cases per 100 children-years during the first year of life. Bronchiolitis is observed more commonly in infants from families of low socioeconomic status, in infants raised in crowded living conditions, in infants passively Pediatrics
exposed to cigarette smoke within the home, and in infants who have not been breastfed. These variables are not entirely independent, and the variable most closely associated with the development of bronchiolitis appears to be “crowding.” The epidemiology of bronchiolitis is intimately linked to that of respiratory syncytial virus (RSV) infection. All epidemiologic studies of bronchiolitis indicate that RSV is the most common cause of this illness. Peaks of RSV activity in the community occur simultaneously with increases in numbers of cases of bronchiolitis seen in medical offices, in hospitalizations for bronchiolitis, and in deaths from bronchiolitis and other respiratory illnesses among infants and children. The risk of hospitalization for RSV infection also appears to be increased by low socioeconomic status. In a study of seven medical centers in the United Kingdom, the rate of hospitalization for RSV infection among infants reached a peak between 1 and 3 months of age. The highest rate (2.5% per 100 children-years) occurred in infants living in densely populated areas. RSV is probably transmitted by direct contact with nasal secretions of infected individuals much more frequently than by aerosol spread. In one study, RSV infection was not transmitted to nursing students who sat 6 feet away from the crib of a child with RSV bronchiolitis who had a noticeable cough. In contrast, RSV infection was readily transmitted after an infected patient had left the hospital room to volunteers who touched items that had been contaminated by secretions and then rubbed their eye(s). Shedding of virus from an infected patient can be documented 1 to 2 days before symptoms occur and for 1 to 2 weeks thereafter. A given patient probably is not contagious during this entire period of time, but should be considered contagious during the 24 to 48 hours before the onset of symptoms and for several days thereafter. Although the incubation period of RSV has never been determined conclusively, symptoms occur an average of 5 days folin Review
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Bronchiolitis lowing experimental infection of volunteers. A number of other viral agents also can cause bronchiolitis, although the severity of illness generally is somewhat less than when RSV is the etiologic agent. The parainfluenza viruses are the second most common cause of bronchiolitis and are responsible for autumn and spring epidemics usually preceding and following the RSV outbreak. Influenza type A virus also can precipitate bronchiolitis, along with adenovirus, rhinovirus, and Mycoplasma pneumoniae. These last two agents are responsible for an increasing number of cases of wheezing-associated respiratory illness with increasing age, but RSV and the parainfluenza viruses have been shown to provoke wheezing at all ages.
inactivated RSV vaccine has led to more severe disease in vaccine recipients than in infants injected with placebo. This suggests that immunologic hypersensitivity may play some role in severe forms of bronchiolitis. Subsequent studies have demonstrated the synthesis of RSV-specific IgE antibody more frequently in infants who have RSV bronchiolitis than in infants who have upper respiratory illness alone due to RSV. These RSV-IgE responders also release chemical mediators, such as histamine and leukotriene C4, into the airway at the time of RSV infection. Each of these compounds can constrict smooth muscle, and leukotriene C4 also can induce mucus secretion in the airway. Eosinophil cationic protein has been present in secretions of infants with bronchiolitis.
Finally, it should be noted that bronchiolitis virtually never is precipitated by bacterial infection. In developed countries, bacterial superinfection is very uncommon in cases of bronchiolitis due to RSV or other viral agents.
Clinical
Manifestations
Infants and children presenting with bronchiolitis usually have a history of rhinorrhea and cough for 3 to 5 days. The cough becomes deeper and more frequent, and respiratory distress becomes evident. There is usually a history of reduced feeding. Frequently, an older sibling in the home has symptoms of a viral respiratory illness. Fever usually is low grade or absent, except in the presence of otitis media, when temperatures as high as 104#{176}F (40#{176}C) may be present. The
Pathogenesis Although cases of bronchiolitis rarely are fatal in otherwise healthy infants, autopsy cases have demonstrated unequivocal evidence of the virus being replicated in the lower airway, particularly the small bronchioles. The necrosis of the respiratory epithelium is the earliest lesion, followed by regeneration of non-ciliated epithelial cells. This regenerative epithelium is not well-equipped to transport secretions from the lower airways upward to the larger airways, and obstruction of the airway by intraluminal secretions is observed frequently. Leukocytes, predominantly lymphocytes, infiltrate the peribronchial tissues and intraepithelial areas. In addition, the submucosa and adventitia are considerably edematous. An accompanying interstitial pneumonia characterized by lymphocytic infiltration and edema of the interalveolar walls frequently is seen, as is a variable degree of atelectasis and hyperinflation. It is conceivable that all of the clinical features of bronchiolitis could occur as a result of the virus being replicated in the terminal airway together with the subsequent inflammatory response. However, several aspects of RSV bronchiolitis suggest that other host factors are involved in the pathogenesis of this disease. Most strikingly, immunization of infants and children with a formalinPediatrics
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Patients who have bronchiolitis are contagious during 48 hours before the onset of symptoms and for several thereafter.
Some children have a single episode of bronchiolitis, others have recurling episodes, and still others develop classic asthma during later life. These observations also suggest that certain host factors determine the pathogenesis of RSV bronchiolitis during infancy. Several potential factors have been identified. First, the airways of infants have been shown to be more hyperreactive to provocative challenges with substances such as methacholine and cold air than have the airways of older infants. Also, prospective studies have demonstrated that certain infants are born with smaller or more dysfunctional airways than are other infants. These infants subsequently were shown to develop wheezing during infancy and childhood more frequently than did similar infants who have airways that are not dysfunctional. Therefore, a population of infants who have smaller or more hyperreactive airways or who have a tendency to overproduce virus-specific IgE may be at risk both for more severe forms of RSV bronchiolitis and for recurrent wheezing following bronchiolitis during infancy.
the 24 to days
respiratory rate is variable, depending on the severity of illness, and tachycardia generally is present. Cyanosis of the oral mucosa and nailbeds may be present in severe cases, and the infant may appear restless if respiratory failure is imminent. The tympanic membranes may be inflamed, and marked nasal congestion due to copious thick secretions is very cornmon. The most striking physical findings are those found on examination of the chest. Depending on the severity of illness, the chest may be hyperinflated, with marked retractions of the chest wall. The chest also may be hyperresonant to percussion. On auscultation, most infants who have bronchiolitis also have wheezing that is readily detectable (often without a stethoscope), particularly over the anterior aspect of the chest. The wheezing of bronchiolitis may be harsher and lower in pitch than that of older individuals who have asthma. Fine “crackles� often are heard on inspiration and, occasionally, on expiration. Infrequently, an infant who has obvious small airway obstruction (clinical and radiographic evidence of 135
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Bronchlolltls a hyperinflated chest) may not have detectable wheezing at the time of a given examination. These infants may wheeze audibly on subsequent examination and are similar in all respects to other infants who have bronchiolitis. While RSV is the principal cause of bronchiolitis, it is also a frequent cause of pneumonia, both in healthy and immunocompromised children. The liver and spleen also may be several centimeters below the costal margin as a result of a hyperinflated chest.
Diagnosis The diagnosis of bronchiolitis usually is made clinically. A wheezing infant with a history of symptoms of upper respiratory illness for the past few days, particularly when it is the peak season for RSV activity in the com-
who have values below 66 mm Hg. Pulse oximetry has become a useful, noninvasive method of assessing illness severity in infants who have bronchiolitis. Reliable readings are not always easy to obtain for technical reasons. Nevertheless, oxygen saturation values, obtained when the heart rate on the monitor accurately reflects the heart rate of the infant, are a useful way of assessing the need for hospitalization and of following changes in the clinical course. Other laboratory investigations are not particularly useful in bronchiolitis. The white blood cell count may be increased mildly or may be within the normal range. Differential white cell counts may show neutrophilia or relative neutropenia. Rapid advances in the ability to diagnose RSV infection have been made over the past decade. The stan-
either immunofluorescence or enzymelinked immunosorbent assays, are replacements for culture for diagnosing RSV infections. Rapid
diagnostic
methods,
munity, can be assumed to have bronchiolitis. When respiratory distress is present but wheezing is not audible, chest radiographs may be helpful. The usual findings include hyperinflation of the chest, with flattening of the diaphram and patchy areas of atelectasis, infiltrates, or both. It may be very difficult to determine whether dense areas in the lung fields are infiltrate or atelectasis. The areas of atelectasis occasionally are quite large, reflecting collapse of segments or even lobes of the lung. Diffuse interstitial infiltrates commonly are observed, but the associated hyperinfiltration distinguishes bronchiolitis from viral pneumonia without small airway obstruction. Arterial blood gas sampling is useful in establishing the severity of illness. Partial pressures of carbon dioxide usually are in the range of 30 to 35 mm Hg, but are an ominous finding when in the range of 45 to 55 mm Hg, because this may suggest that respiratory failure is imminent. Arterial oxygen tensions are a good index of disease severity; particular attention should be paid to infants 136
dard method has been isolation of virus in tissue culture, but this procedure takes at least several days. In addition, RSV is somewhat labile, and infectivity may be lost during transportation of cultures. Many laboratories have now found that rapid diagnostic methods (either immunofluorescence or enzyme-linked immunosorbent assays) performed on respiratory secretions are satisfactory replacements for tissue culture as far as the diagnosis of RSV infection is concerned. These procedures can be carried out by the use of commercially available kits and are highly sensitive and specific compared with tissue culture isolation. Serologic tests for the diagnosis of RSV infection generally are available, but are not of much interest to clinicians because of the time required for diagnosis by seroconversion. In addition, the antibody response in young infants (those who have the highest risk of severe bronchiolitis) often is blunted by the presence of transplacentally acquired maternal antibody in the serum. Rapid diagnosis of RSV infection may be important because infants who have RSV as the
cause of bronchiolitis can be expected to have more severe forms of illness than other infants and may respond to specific antiviral therapy (see below). Documentation of RSV infection also is of assistance in excluding allergies and other processes as the cause of the wheezing episode and is helpful in infection control within the hospital.
Management Given the frequency with which bronchiolitis occurs, there is a surprising degree of confusion regarding the optimal approach to management. Most cases of bronchiolitis are mild and can be managed without hospitalization. These infants will recover without beta-adrenergic agents or other medications used for relief of wheezing. The decision to hospitalize an infant who has bronchiolitis should be based on a number of dinical criteria in addition to the usual considerations-reliability of parents, duration of present illness, and likelihood of obtaining acceptable followup. Infants who are born prematurely, have underlying heart or lung disease, are in the first 3 months of life, or have low initial oxygen saturation are more likely to develop progressive or life-threatening illness. In addition, infants who are not feeding well or who are already dehydrated should be considered carefully for hospitalization. In a recent study (Table 1), a multiple-factor analysis was used to identify groups of infants who were found retrospectively either to have required hospitalization or to have been managed successfully on an outpatient basis. Infants who had a generally ill or “toxic� appearance, who had a gestational age of less than 34 weeks or a current age of less than 3 months, who had a respiratory rate of more than 70 breaths per minute, who had oxygen saturations of less than 95% by pulse oximetry, and who had chest radiographs showing atelectasis were much more likely to require hospitalization than infants who were missing one or more of these criteria. The best individual predictor of the need for hospitalization was an oxygen saturation of less than 95% followed by a generally ill or toxic appearance. It is difficult to define the term
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Bronchiolltla Tablo 1. Features for Hospitalizatlon*
of Infants
Who Have Bronchiolltis
That
Predict
tho Nood PREDICTIVE
SENSITIVITY
Ill or toxic Pulse
appearance
oximetry age
Respiratory
rate
Chest
>70
or without
76
60
87
32
98
87
73
wk
27
95
74
71
breaths/mm
29
95
75
71
21
98
82
70
38
83
55
72
76
91
81
88
atelectasis
<3 mo
All features
present
(ie,
all of the above) Based on a retrospective review All figures indicate percentages. Data reproduced with permission
of 213 patients. from
Shaw
and
toxic specifically, but it can be useful in describing children who appear seriously ill. Unfortunately, a pulse oximeter or other method of assessing oxygenation will not be available to most practitioners. The overall appearance of the infant-a subjective measuretherefore becomes the best indicator of need for hospitalization. Respiratory rates are so variable during the first year of life that rates in the range of 40 to 70 breaths per minute are not good indicators of the need for hospitalization (although higher rates are probably good indicators). It may be very helpful for the clinician to attempt to feed the infant. If respiratory distress is not severe and the infant feeds reasonably well, hospitalization usually is not needed. In contrast, the child in sufficient distress to limit feeding significantly will require hospitalization. Infants for whom hospitalization is being considered should receive at least one course of an aerosolized beta-adrenergic agent, if this is possible in the setting where the patient is being seen. A small percentage of individuals who have bronchiolitis seem to respond to such therapy, although the response is less consistent and less striking than that observed in older individuals who have classic asthma. If a good response occurs and the patient is to be sent home, a course of oral beta-adrenergic agents Pediatrics
NEGATIVE
radiograph
with Age
<34
POSITiVE
76
<95%
Gestational
SPECIFICITY
VALUE
in Review
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colleagues,
Am
J Dis Child.
1991;145:1S1-1S5.
should be prescribed. Oral therapy probably will not benefit those patients who are unresponsive to aerosolized beta-adrenergic agents. Once hospitalized, most patients will respond well to replacement of fluid deficits and administration of increased ambient oxygen that will maintain an oxygen saturation of more than 92% to 93% by pulse oximetry. If the patient has responded well to aerosolized bronchodilators, they clearly should be continued. The continued use of such agents in the absence of an initial beneficial clinical response is controversial. No study has clearly shown a marked improvement in respiratory rate or in oxygenation as a result of the use of aerosolized bronchodilators. On the other hand, some studies have demonstrated improvements in clinical illness scores in infants who have bronchiolitis. The matter is complicated further by the results of some studies that demonstrate deterioration in oxygenation or pulmonary function tests in patients receiving aerosolized beta-adrenergic agents. This may be due to the hypoosmolar or acidic nature of the aerosol, because transient bronchoconstriction sometimes may occur when airways are exposed to hypoosmolar or acidic substances. It is not possible to predict clinically which individuals who have bronchiolitis will respond well to betaadrenergic agents. The hazards of ad1993
ministering these agents seem relatively minor. It is probably reasonable to administer beta-adrenergic agents by aerosol, at least during the first 24 hours of hospitalization, and to continue to do so if the response is beneficial. On the other hand, protracted use in the absence of a beneficial effect seems inadvisable, partly because of the potential for a negative response to the administration of these agents, as well as the considerable amount of time required for respiratory therapy technicians to administer them. The use of intravenous theophylline is becoming less popular for patients hospitalized with asthma, and it has never been shown clearly that infants who have bronchiolitis respond to theophylline therapy. If theophylline is to be used at all in the treatment of bronchiolitis, it probably should be restricted to those infants who experience respiratory failure due to bronchiolitis. The use of corticosteroids in the treatment of bronchiolitis has never been evaluated adequately. Although many studies have been published on this topic, the doses of corticosteroids used generally have been less than those currently recommended for the management of asthma, and studies have not excluded from analysis those patients hospitalized for mild forms of bronchiolitis, who would be expected to improve in the 137
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Bronchiolftls absence of any form of therapy other than oxygen. However, although a beneficial role for corticosteroids cannot be excluded, most infants who have bronchiolitis will respond satisfactorily without this form of therapy. In the absence of any clearly effective therapy for airway obstruction in bronchiolitis, the antiviral agent ribavim has received considerable attention. Ribavirin is a synthetic nucleoside with activity against a broad variety of viral agents. Several studies of the effect of ribavirin in RSV bronchiolitis have appeared; the majority report modest improvements in clinical illness scores and in oxygenation in ribavirin recipients. However, the general use of ribavirin has been challenged both on the basis of criticisms of the design of those studies and on the comparatively modest beneficial clinical effects that have been observed. A recent study of ribavirin use in patients on mechanically assisted ventilation indicated that the time on ventilatory assistance, on supplemental oxygen, and in the hospital all were reduced by ribavirin therapy. Therefore, it may be that the beneficial effects of ribavirin are more evident in patients who have more severe forms of illness. Concern has arisen about the potential toxicity of ribavirin to healthcare workers. The drug, when ad-
ministered orally, is highly teratogenic to rodents. It is not known if the drug is teratogenic in humans. Concentrations of the drug in respiratory secretions of infants receiving aerosolized ribavirin are approximately 1000 times the concentration of drug measurable in their plasma. Therefore, it can be assumed that ribavirin is not absorbed well by infants or by health-care workers exposed while caring for infants receiving ribavirin. Two studies have demonstrated that ribavirin concentrations are, in fact, undetectable in the urine and plasma of health-care workers exposed for at least 4 hours to ribavirin aerosols at the bedside. In one case, ribavirin was detectable in red blood cells, although it is known that the drug is concentrated 60-fold in red blood cells. In summary, there seems to be relatively little reason to be concerned about absorption of ribavirin by health-care workers or by parents in rooms where ribavirin is being administered. Medical personnel may choose to shut off inflow to hoods and tents when possible when examining patients. Another problem is the high cost of ribavirin. Drug cost and the cost of time required by pharmacists, respiratory therapists, and nurses for administration of the drug totals in excess of $350 at our institution for
Infants at increased risk for severe or complicated virus infection because of other conditions: Congenital heart disease Bronchopulmonary dysplasia Cystic fibrosis Other chronic lung conditions Certain prematurely born infants
respiratory
Infants who have severe respiratory as indicated by: Arterial Po2 <65 mm Hg Rising arterial Pco2
syncytial
virus
lower
Other infants who have respiratory factors: Age <6 weeks Multiple congenital anomalies Neurologic or metabolic diseases
syncytial
virus
infection
Modified Village,
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with permission 1L 1991:581-587.
from
the
Report
of the Committee
each day of ribavirin therapy. Taking all factors into consideration, including the drugâ&#x20AC;&#x2122;s efficacy, its potential toxicity, and the cost of its administration, the use of ribavirin can best be justified in certain patient groups, including patients who have bronchiolitis or pneumonia due to RSV in whom respiratory failure is present or imminent. Patients with underlying cyanotic congenital heart disease, heart failure, or bronchopulmonary dysplasia are particularly likely to develop respiratory failure when infected with RSV. Ribavirin should be used in conjunction with inotropic agents, diuretics, and corticosteroids in these patients. Ribavirin use also may prove beneficial to other groups of patients, as outlined in the American Academy of Pediatricsâ&#x20AC;&#x2122; guidelines for ribavirin therapy (Table 2). These other groups represent infants unlikely to tolerate a serious respiratory infection and who, therefore, also may benefit from ribavirin therapy. Convincing data supporting the use of ribavirin in these groups of patients are lacking, however. The use of antibiotics generally will not affect the clinical course of bronchiolitis because bacterial infection is almost never simultaneously present, at least in developed countries. The presence of unexplainable high fever in the course of illness may be an indicator for temporary
syncytial Immunodeficiency due to chemotherapy for malignancies, recent renal transplantation, or severe combined immunodeficiency
on Infectious
respiratory
disease,
and certain
Diseases,
1991,
risk
ed 22. American
Pediatrics
Academy
in Review
of Pediatrics:
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LTTIIIIIIIIIIII antibiotic
coverage.
Prevention Currently, there is no acceptable means of preventing RSV infection or bronchiolitis. Several vaccine candidates are being investigated. These consist of surface proteins of the virus that are important in viral attachment to respiratory epithelial cells and to fusion of the viral and cellular membranes, allowing penetration of viral RNA. Meaningful use of these vaccines is at least several years away. Also under investigation is the use of an intravenous immunoglobulin preparation with high titers of RSV neutralizing antibody. Frequent infusions of this compound may prevent RSV infection in infants at high risk for serious disease due to RSV. Other commercial intravenous immunoglobulin products have insufficient antibody against RSV to be protective. As noted previously, transmission of RSV probably occurs by contact with secretions of infected patients. Meticulous attention to handwashing 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.
Prognosis There should be almost no mortality from bronchiolitis occurring in infants and children who otherwise are in good health. Although bronchiolitis, particularly RSV bronchiolitis, can be fatal in such individuals, deaths should be preventable by early recognition that respiratory failure is imminent and by referring such patients to institutions where adequate
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Bronchiolitis ventilatory support is available. In contrast, there is appreciable mortality from bronchiolitis in infants who have moderate-to-severe bronchopulmonary dysplasia or who have cyanotic congenital heart disease. Infants who have these underlying conditions as well as even mild bronchiolitis should be referred to tertiary care institutions because the course of illness may be long and complicated. An equally important question is the long-term prognosis of bronchiolitis. It is known that 40% to 50% of infants hospitalized with bronchiolitis will have recurrent episodes of wheezing. Some infants will have frequent wheezing episodes until age 2 or 3 years, but not thereafter. Some will have classic asthma, induced by exposure to allergens, other infections, and exercise. Finally, some of these infants will have abnormal pulmonary function tests when followed into later childhood. It is not yet clear whether these abnormalities persist into adult life; more importantly, it is not clear whether these long-term changes are a result of airway dysfunction induced by bronchiolitis or whether the airways of infants with bronchiolitis were abnormal from birth, with bronchiolitis being the first indication of underlying airway dysfunction. Several lines of evidence suggest that host factors, rather than damage due to the initial RSV infection, are primarily responsible for post-bronchiolitic wheezing. Recurrent wheezing seems to be more common in infants whose pulmonary function during infancy (before bronchiolitis occurs) is abnormal, in infants passively exposed to cigarette smoke, and in infants who produce virus-specific IgE responses at the time of initial RSV infection. There do not seem to be
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any other clinical features that identify those infants at risk for repeated wheezing episodes following bronchiolitis. Pulmonary function deteriorates more rapidly in subjects who have underlying airway hyperreactivity if they are exposed to cigarette smoke or to air pollution in the work environment. Therefore, infants who have bronchiolitis, whether their airway dysfunction is primary or seeondary, represent a group of individuals at special risk for early loss of airway function if the environmental circumstances during later life are less than optimal. SUGGESTED
READING
Glezen WP, Taber LH, Frank AL, Ct al. Risk of primaiy infection and reinfection with respiratory syncytial virus. Am I DLc Child. 1986;140:543-546 Holberg Ci, Wright AL, Martinez FD, Ct al. Risk factors for respiratory syncytial virusassociated lower respiratory illnesses in the first year of life. Am J Ep#{252}kmiol. 1991; 133:1135-1151 Kiassen TP, Rowe PC, Sutcliffe T, Ct al. Randomized trial of salbutamol in acute bronchiolitis. I Pediatr. 1991;1 18:807-811 Martinez FD, Morgan wi, Wright AL, et al. Initial airway function is a risk factor for recurrent wheezing respiratory illnesses during the first three years of life. Am Rev Respir Dis. 1991;143:312-316 McConnochie KM. Hall CB, Walsh EE, et al. Variation in severity of respiratory syncytial virus infectious with subtype. I Pediatr. 1990;117:52-62 McConnochie KM, Roghmann KJ. Bronchiolitis as a possible cause of wheezing in childhood: New evidence. Pediatrics. 1984;74:1-10 Muiholland EK, Olinsky A, Shann FA. ainicul findings and severity of acute bronchiolitis. Lancet. 1990;335:1259-1261 Shaw KN, Bell LM, Sherman NH. Outpatient assessment of infants with bronchiolitis. Am IDis Child. 1991;145:151-155 Smith DW, Frankel LR, Mathers LH, et al. A controlled trial of aerosolized ribavirin in infants receiving mechanical ventilation for severe respiratory syncytial virus infection. N Engi I Med. 1991;325:24-29
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