Bronchiolitis in infants and toddlers

Author : Dr Howard Panitch the Division of Pulmonary Medicine The Children's Hospital of Philadelphia, PA

2008-07-28

Bronchiolitis refers to inflammation of the bronchioles.  Bronchioles are small airways (less than two mm in diameter in adults) in the lower respiratory tract that do not contain cartilage in their walls (figure).  The majority of children who develop viral bronchiolitis are less than two years of age.

The most common cause of bronchiolitis in infants and toddlers is infection, usually by a virus, and the most common virus to cause acute infectious bronchiolitis in infants and toddlers is respiratory syncytial virus (RSV).  Other viruses that cause bronchiolitis include influenza and parainfluenza viruses, rhinovirus, and adenovirus (1).  A recently described agent (though evidence of its role in bronchiolitis has been present for more than 20 years) is Human Metapneumovirus (hMPV), which is genetically related to RSV (2).  In children up to five years of age, a non-viral, non-bacterial organism called Mycoplasma pneumoniae can also cause bronchiolitis. 

Older children and adults experience infections with the same viruses, but usually they do not develop acute bronchiolitis.  One reason for this concerns a change in the distribution of airway resistances that occurs with age.  The bronchioles, or small airways of the lung, are considered a “silent zone” in adults, because collectively they offer little (about 10% of the total) resistance to airflow within the lung.  As a result, diseases that cause small airway obstruction usually do not cause prominent symptoms in older children and adults, until the obstruction becomes widespread and severe. The bronchioles of infants and children, however, contribute about 50% to total airway resistance in the lung.  Because of this, even small increases in bronchiolar resistance will cause symptoms in infants.

In the majority of infants, the course of bronchiolitis is short-lived and there is no permanent scarring of the lung tissue or airways. Many children, however, will develop post-bronchiolitis wheezing during subsequent respiratory illnesses, and asthma is seen more frequently in populations of children who acquired bronchiolitis in infancy. It is not known whether infection at an early age changes the behavior of airways resulting in subsequent recurrent episodes of wheezing, or if bronchiolitis is merely a marker that identifies those infants who would otherwise go on to have recurrent episodes of wheezing.

The Impact of Bronchiolitis on Infants and Toddlers

In the majority of studies that focus on the viruses causing bronchiolitis, RSV is found most frequently.  As a result, it is the best studied of all of the viruses that cause bronchiolitis.  Approximately 65% of all children will be infected with RSV within the first year of life.  By age 2 years, almost everyone has experienced an RSV illness (3).  Most children develop only upper respiratory symptoms, including nasal discharge and cough.  Approximately 25 - 40% of all infants who become infected with RSV will develop bronchiolitis, but only 1 – 2% requires hospitalization.  While this number seems small, it has been estimated that in the US more than 120,000 infants and toddlers are hospitalized because of an RSV lower respiratory tract infection (LRTI, either bronchiolitis or pneumonia) annually (4).  In fact, in the United States, RSV LRTI is the leading cause of hospitalization of infants under one year of age, accounting for 11% of all hospitalizations in that age group (5). 

While bronchiolitis is a very common cause of illness in children, in developed countries it does not usually cause death:  among all children hospitalized with an RSV LRTI, the mortality rate is approximately 0.2 – 0.5% (6).  The mortality rate is higher (approximately 3 - 4%) in those children with certain underlying conditions like chronic lung disease, congenital heart disease, prematurity, or age less than 6 weeks at time of infection.  Globally, however, RSV infection directly or indirectly accounts for 600,000 to 1,000,000 deaths in children less than 5 years of age annually, making it the second most important human childhood respiratory pathogen. 

A report from the Centers of Disease Control and Prevention (CDC), using estimates based on discharge data from the National Hospital Discharge Survey, showed that over a 17-year period from 1980 to 1996, bronchiolitis-related hospitalizations accounted for approximately seven million inpatient hospital days (4).  The number of hospitalizations among infants less than six months of age increased 239% from the beginning to the end of the observation period.  Over the same epoch, hospitalizations from other respiratory pathogens remained constant.  

The factors causing this tremendous increase in bronchiolitis-related hospitalizations are not clear.  Some people wonder if the use of pulse oximetry (a non-invasive method to measure the amount of oxygen in the blood) in emergency rooms and doctors’ offices to detect low oxygen levels is a cause.  This technology was not readily available in the early part of the observation period (the early 1980s).  As a result, at the start of the study some infants who were mildly ill, but who also had a modest reduction in oxygen levels, might not have been admitted into the hospital, whereas those infants would have been detected at the end of the observation period.  Such infants, however, probably represent a small contribution to the overall number of infants hospitalized with bronchiolitis.  Others wonder if the growing number of premature babies and multiple-gestation infants created through in vitro fertilization explain the increase.  The majority of infants hospitalized for bronchiolitis, however, are babies born full term who do not have underlying conditions.  The most likely explanation for the increase probably relates to the growing trend for families to place their infants in day care to allow both parents to work.  Day care attendance has been recognized as one of the strongest risk factors for infants to acquire an RSV infection. 

The Epidemiology of RSV: Who it Affects, Where and When it Occurs

In temperate climates, RSV infections are detected primarily during annual outbreaks that occur between October and April, and which peak during the winter months.  An “epidemic” is present when more than10% of all specimens tested are positive, or when at least half of the laboratories that report results to the CDC note any RSV detected for 2 consecutive weeks.  The start and end of RSV epidemics vary regionally, with Southern states reporting the earliest onset of the epidemic (beginning in late August and concluding in mid-May), with later onset in the northeast (late November lasting to early May), and the latest onset in the Midwest (early December through late May).  Some states (Florida, Hawaii) report RSV at epidemic levels year-round.  The surveillance data are posted on the CDC website so that trends in epidemiology can be tracked (http://www.cdc.gov/surveillance/nrevss/rsv-data.htm).  The immune response to RSV is limited, so everyone experiences repeated RSV infections throughout life.  Usually, people have enough of an immune memory so that subsequent RSV infections are confined to the upper respiratory tract.  Some infants, however, can experience repeated episodes of bronchiolitis with RSV, even in the same season.

While previously healthy infants born full-term constitute the largest number of babies hospitalized with bronchiolitis, there are certain groups of infants who are considered at especially high risk to develop an infection severe enough to require hospitalization (7).  These include infants born prematurely (less than or equal to 28 weeks and under one year of age at the onset of the RSV season, or less than 36 weeks gestation and under six months at the onset of the RSV season), infants with chronic lung disease, and infants with congenital heart disease.  Full term infants who acquire an RSV infection within the first six weeks of life are also considered to be at increased risk for more serious disease.  Infants born with neuromuscular disease and a weak cough are likely to experience a severe course of bronchiolitis.  Children with immunodeficiencies often have prolonged courses of bronchiolitis.

How RSV Infection Causes Bronchiolitis

RSV infects cells lining the respiratory tract.  The portal of entry is through cells that line the nose or the eyes.  From there, infected secretions can be breathed into the lower respiratory tract, and enter the lining cells of the small airways. After entering a cell, the virus replicates and is released when the cell bursts open and dies.  This process causes release of inflammatory substances that in turn cause swelling and inflammation of the small airways, and a resultant narrowing of the airway opening.  The inflammatory mediators also stimulate mucus glands to produce and secrete mucus into the airways.  The openings of the airways become filled with mucus and debris from dead lining cells.  In some infants and young children, airway smooth muscle contracts and contributes to airway obstruction.

The Clinical Presentation of Bronchiolitis

Viral infection of the lower respiratory tract in infants results in a well-described clinical entity, marked by coughing, rapid breathing, and wheezing.  A hallmark of RSV infection in infants is profuse nasal discharge, with thin, clear secretions.  In young infants (less than three months of age), breathing normally occurs primarily through the nose, and having a swollen, stuffy nose may be enough to cause the infant to have respiratory distress, or to have difficulty drinking a bottle.  Infants with bronchiolitis often also have fever, and the combination of decreased fluid intake because of respiratory distress, and increased fluid requirements from fever and more rapid breathing can lead to dehydration. 

Between one and three days after the onset of a runny nose, coughing begins.  Infants with severe bronchiolitis will demonstrate rapid breathing, and the breathing pattern will also appear more labored.  Indrawing of the skin between the ribs or above the collar bones (retractions) reflects the increased effort necessary to overcome the elevated resistance to airflow resulting from small airway obstruction.  Retractions that occur below the rib cage are another manifestation of airway obstruction, and represent overinflation or air trapping in the lung.  As a result of obstruction, the level of oxygen in the blood can decrease.  As the degree of obstruction becomes more severe, the infant’s breathing efforts can become so labored that the infant becomes fatigued and respiratory failure ensues.  Parents should contact the infant’s physician if any of the following is present in their baby:

·       Very rapid breathing

·      Increased breathing effort (the skin in between the ribs, under the ribcage, or at the neck draws in with each breath, the nostrils flare, or there is a “see-saw” motion between the chest wall and abdomen) (Photos at right of retractions with permission of Daniel Schidlow, M.D.)

·      Inadequate fluid intake with dehydration (fewer wet diapers, when the baby cries there are no tears, or the inside of the mouth is dry or tacky)

·     Respiratory fatigue (the baby seems to be getting weary after breathing so hard; there may be pauses in breathing or gasping.  This is an emergency and requires immediate attention)

·      If there is any concern about the welfare of your baby, it is always better to check with your physician and review your baby’s symptoms

The symptoms of bronchiolitis typically resolve in about seven to ten days, usually without the need for directed treatment.  Infants with risk factors for severe disease are more likely to develop respiratory failure requiring mechanical ventilation early in the course of the illness, and the duration of illness will also be protracted.

While the clinical presentation of bronchiolitis is stereotypical, there are instances in which a confirmation of the infecting agent is desirable (for epidemiological data, grouping hospitalized patients, infants less than two months old with fever, immunocompromised hosts).  There are several types of rapid tests that can be performed on washings taken from the infant’s nose.  Depending on the type of tests being used, virology laboratories can detect the most common viruses to cause bronchiolitis in minutes to hours.  “Rapid respiratory panels” are available to detect RSV, influenza A and B, parainfluenza, human metapneumovirus, rhinovirus, and adenovirus.

Therapy for Bronchiolitis

            Fluid replacement and supplemental oxygen use

The mainstays of therapy for this self-limited illness (meaning that it typically resolves without a need for intervention) are careful fluid replacement and administration of supplemental oxygen to infants with low oxygen levels.  The first goal of fluid therapy is to replace the infant’s deficit that has occurred from decreased intake and increased losses resulting from fever and rapid breathing.  In addition, ongoing fluid needs must be met.  Infants are hospitalized when they require supplemental oxygen, usually determined by pulse oximetry.  Alternately, if an infant breathes so quickly that he is unable to drink, or dehydration has already developed, the infant should be hospitalized to receive intravenous fluids.  Sometimes, infants who develop swallowing difficulties because of their rapid breathing will be given formula through a tube passed from the nose into the stomach.  If an infant appears distressed, is very young, or at increased risk because of underlying conditions, or the parents are distressed because of the degree of the infant’s illness, hospitalization for close monitoring and supportive care should be considered.

A number of therapies have been used to try to overcome the various causes of airway obstruction in infants with bronchiolitis.  Since the disease is self-limited, many of the therapies used impact minimally on the duration of symptoms or length of hospitalization.  An expert panel recently reviewed many of the therapies commonly used in infants with bronchiolitis, and published recommendations in a statement from the American Academy of Pediatrics (8).

            Chest physiotherapy

When the events that lead to airway obstruction are considered, it is easy to understand why many of the therapies used in infants with bronchiolitis have been attempted.  Since swollen airways become filled with cellular debris and mucus that further obstruct the airways, maneuvers that help to clear the airways of secretions might reduce the obstruction and help infants to recover more quickly.  For infants hospitalized on a general ward with moderate bronchiolitis, however, there are no data to support the routine use of chest physiotherapy to hasten resolution of symptoms.  This may not be true for infants with severe disease who develop impending respiratory failure, or who develop large areas of lung collapse (atelectasis).  The effect of chest physiotherapy on outcomes of such complications of bronchiolitis has not been studied.

            Bronchodilators

Many infants who have bronchiolitis demonstrate wheezing on examination, so practitioners often associate the illness with asthma, another common wheezing illness in children.  As a result, bronchodilators and steroids, both of which are mainstays of therapy for acute asthma exacerbations, are frequently used in infants with bronchiolitis.  Bronchodilators like albuterol act by relaxing the smooth muscle in the walls of the airways.  Not all infants with bronchiolitis will have increased tone of airway smooth muscle (bronchospasm), but approximately one third of infants will demonstrate some response to bronchodilators.  Another third will have no response, and in another third wheezing might actually increase.  There are no demographic factors that predict how a particular infant will respond to bronchodilator therapy.  If the infant is symptomatic enough for bronchodilator use to be considered, the medications should only be used after a critical evaluation of their response in the infant.  This is easily done by examination of the infant before and again 10 – 15 minutes after administration of the drug by either small volume nebulizer (a device that administers medication as a liquid mist) or metered-dose inhaler (The photo at right is a metered dose inhaler attached to a valved holding chamber and mask for use in infants and toddlers).  Reduction in respiratory rate, degree of chest retractions, and wheezing are all signs of bronchodilator responsiveness.  Bronchodilators in liquid form that have to be swallowed have not been shown to be effective in the small number of infants in whom they have been critically evaluated.  Furthermore, they take longer to work and expose the infant to a much higher dose of the medication compared with the inhaled route, so that side effects are more common.

            Corticosteroids

Corticosteroids, like prednisone or dexamethasone, are medications that reduce inflammation.  They are particularly useful in reducing the “allergic” type of inflammation typically found in the airways during asthma exacerbations.  The inflammatory cells most commonly found in the airways of infants with bronchiolitis, however, are different from the inflammatory cells in the airways of asthmatics.  This is one reason why corticosteroid use does not impact significantly on the course of infants hospitalized with bronchiolitis.  Another reason that steroids are not overly effective in truncating the course of bronchiolitis involves the time course of release of inflammatory mediators.  By the time an infant becomes symptomatic with bronchiolitis, the release of inflammatory mediators has already been well established. 

There is some suggestion, however,  that the sickest infants hospitalized with bronchiolitis, including those who require mechanical ventilation for respiratory failure, are more likely to experience a beneficial response to steroid administration with a reduction in the duration of hospitalization.  It is important to note that there is little “down side” to the use of steroids.  Steroid administration is associated with prolonged shedding of virus from the respiratory tract, but this is not associated with prolongation of illness.  Specifically, there are no reports of infants who received systemic (intravenous, intramuscular or enteral) steroids experiencing a more severe or protracted course of bronchiolitis.  Furthermore, when steroids are used to treat bronchiolitis, the course is typically short (less than two weeks).  In this brief period of time, it is unlikely that serious side effects related to steroid use will occur.

On the other hand, some investigators have attempted to use inhaled steroids during the acute course of bronchiolitis or in the weeks following the acute illness, with the aim of decreasing post-bronchiolitis cough and wheezing.  Based on the findings of several such studies, there is no role for the use of inhaled steroids in these situations, where the treatment is aimed at infants with acute viral bronchiolitis who have no previous history of wheezing.

            Antiviral therapy

Ribavirin is an anti-viral drug with activity against RSV and some other viruses.  It works by interfering with the virus’s ability to replicate.  It was used commonly in the mid-1980s through the early 1990s in infants hospitalized with RSV bronchiolitis.  Subsequent studies, however, showed that ribavirin does not appreciably shorten the course of hospitalization for infants with RSV bronchiolitis.  By the time an infant with RSV infection is brought to medical attention, viral replication has nearly peaked.  Thus, administration of the anti-viral therapy does little to hasten the reduction of viral load.  Ribavirin is expensive and somewhat cumbersome to use.  The one area in which it may confer some benefit is in a case of RSV bronchiolitis so severe that the infant requires mechanical ventilation. There is a handful of studies that suggest that those infants who developed respiratory failure and required mechanical ventilation from RSV bronchiolitis got better faster and experienced shorter courses of mechanical ventilation with ribavirin use versus those who received a placebo.  The information is not straightforward, however, because the infants in the placebo groups received inhaled fluids that may have worsened their courses. Furthermore, the therapy, especially in this setting, has potential complications; ribavirin is delivered via a small particle aerosol generator over several hours.  The particles can clog small endotracheal tubes or interfere with the proper working of mechanical ventilators.  If used for intubated infants in respiratory failure, meticulous attention must be paid to maintaining patency of the breathing tube and making sure the ventilator components work properly.

            Other therapies

Other interventions have either been studied in small series or published in case reports (9).  Because of the small numbers of patients in which they have been investigated, they cannot be considered as standard therapy for bronchiolitis at present. 

One such therapy is the inhalation of hypertonic saline.  Hypertonic saline increases the water content of secretions by drawing fluid from inside airway lining cells into the airway lumen.  Those infants who were given nebulized 3% saline along with epinephrine (another type of bronchodilator) had faster resolution of symptoms than infants given epinephrine alone (10).  Several trials have now been published that support the effectiveness of hypertonic saline in infants with bronchiolitis.

In another instance, a small number of infants at risk for respiratory failure from bronchiolitis were treated with a mixture of helium and oxygen (heliox), which has a lower density than air (composed of about 79% nitrogen and 21% oxygen).  That property results in a decreased resistance in airways where the flow of air is turbulent.  The infants treated with heliox demonstrated lower respiratory rates and heart rates, and were able to leave the intensive care unit sooner than those infants receiving oxygen-enriched air.  The heliox did not alter the course of bronchiolitis, but it made breathing easier for the infants while the disease ran its course.

Prevention of Bronchiolitis

There are simple yet effective and inexpensive interventions that can decrease the risk of acquiring an RSV illness. Transmission of RSV is from hand (touching infected secretions or surfaces) to nose, so hand washing is a highly effective way to prevent spread of infection.  Some viruses like influenza can be spread in small droplets that remain suspended in the air when an infected person coughs.  Avoidance of crowded locations during the winter virus season, and avoidance of people with obvious upper respiratory illness are two other ways to reduce the risk of an infant acquiring an acute viral respiratory infection.  Factors recognized to increase an infant’s risk of acquiring a severe RSV infection include day care attendance, having young siblings who attend day care or school, exposure to second hand tobacco smoke both pre- and post-natally, absence of breast feeding, crowded living conditions, and multiple births.  Some of these factors are avoidable, like environmental tobacco smoke exposure. It would be desirable for infants at high risk for serious RSV disease to avoid day care attendance until they are older, but this may not be feasible for certain families.

Presently, there are no effective vaccines that confer active immunity against most of the common viruses that cause bronchiolitis, other than the influenza vaccine.  For infants at high risk for severe RSV disease, however, passive immunoprophylaxis (disease prevention by the development of immunity through administration of an antibody against the virus) with an engineered monoclonal antibody is available.  Injections of the drug, called palivizumab, must be given monthly throughout the RSV epidemic season.  In infants born prematurely, infants with chronic lung disease following neonatal respiratory distress (often called bronchopulmonary dysplasia, or BPD), and in infants with congenital heart disease, palivizumab has been shown in large randomized studies to reduce the incidence of hospitalization for severe RSV bronchiolitis (11, 12).  Because palivizumab is a monoclonal antibody, it is only effective against RSV, and so does not confer protection against the other viruses that commonly cause bronchiolitis.  Additionally, palivizumab does not prevent infection with RSV:  rather, it reduces the chance that the upper respiratory infection will progress to a severe lower respiratory tract infection.  Palivizumab is expensive, and so guidelines have been proposed to maximize the effectiveness of the therapy by targeting those groups at greatest risk for severe RSV disease (13).  These include:

• Infants born at less than or equal to 28 weeks gestation, without chronic lung disease, who are 12 months of age or younger at the start of the RSV season
• Infants born between 29 and 32 weeks gestation, without chronic lung disease, who are six months or younger at the start of the RSV season
• Infants between 32 and 35 weeks gestation, without chronic lung disease, who are six months or younger at the start of the RSV season, and who have at least two risk factors for acquiring an RSV infection
• Infants with chronic lung disease who are 24 months of age or younger at the start of the RSV season, and who have received treatment (i.e., supplemental oxygen, diuretics, bronchodilators) within six months of the RSV season
• Infants with hemodynamically significant congenital heart disease (commonly defined as those infants who require medications to treat their heart disease) who are 24 months of age or younger at the start of the RSV season

These are guidelines. Occasionally infants with special conditions who are felt by their physicians to be at increased risk for severe RSV disease – or those who have one of the above conditions but fall slightly outside of the guidelines – are also treated with palivizumab.

Respiratory symptoms after bronchiolitis

Of those infants who have an episode of bronchiolitis, as many as 60% will experience recurrent episodes of wheezing over the first few years of life.  This is especially true of infants who developed bronchiolitis from RSV infection.  RSV, however, is not the only agent that has been associated with persistent or recurrent lower respiratory tract symptoms in children who experience infection in early life.  Other early viral infections most notably with rhinovirus, human metapneumovirus, parainfluenza, and influenza A have all been associated with increased risk for subsequent chronic lower respiratory tract symptoms.  Because RSV is the most common infection associated with bronchiolitis and subsequent recurrent wheezing, however, most studies have concentrated on host responses to that virus. For example, careful prospective epidemiological studies have shown that the frequency of wheezing illnesses is significantly greater among those infants who experienced even a mild RSV LRTI within the first three years of life compared with those who never had RSV bronchiolitis (14).  This effect lasts through the first decade, but by 13 years of age, differences in frequency of wheezing illnesses can no longer be demonstrated between the groups of children who did and those who did not experience an RSV LRTI in infancy.

While an association between bronchiolitis in infancy and recurrent episodes of wheezing has been recognized for almost 40 years, a cause and effect relationship has yet to be established.  The question is: does RSV infection somehow alter the host so that on subsequent presentation of viral or other antigens, the host develops a wheezing response and airway inflammation?  On the other hand, is wheezing in an infant infected with RSV just a marker for someone predisposed to do this with other illnesses throughout life?  The topic is one of intense investigation and of tremendous importance, since a causal relationship would suggest that preventing bronchiolitis in infancy could reduce the incidence of asthma later in life (15).

If viral lower respiratory tract infections cause recurrent wheezing or asthma, then the initial infection must alter either airway biology or the host’s immune response.  Several animal and human studies suggest that both alterations may exist, and that these mechanisms need not be mutually exclusive.  Experimental viral infection of the respiratory tract will cause bronchospasm (an abnormal contraction of the smooth muscle of the bronchi, which usually results in wheezing or cough) in otherwise healthy adults when exposed to irritants, an effect that can last for weeks after the infection.  Similar findings have been demonstrated in animal models.  In addition, RSV has been shown to increase production in the lung of the receptor for Substance P, a chemical mediator of the non-adrenergic, non-cholinergic excitatory system that causes bronchospasm, edema (swelling), release of inflammatory mediators, and recruitment of inflammatory cells into the airway upon its release.

The timing of the initial RSV infection may be a critical factor for how the body responds to subsequent infections.  The immune system matures after birth, and it has been postulated that certain infections can drive the immune system towards either an allergic or non-allergic response when it is presented with other infections or antigens subsequently.  In several animal studies, respiratory infection with RSV soon after birth, but not later in life, causes the animal to respond to subsequent RSV infections with a prominent allergic-type response.  Missing from this line of reasoning is evidence that RSV (or other viruses) also increases the likelihood for those infected early in life to develop allergies.  Most studies do not show an increased incidence of skin test positivity to common allergens in older children who experienced an RSV LRTI in infancy.  Nevertheless, it is compelling to think that by delaying an RSV illness until later in childhood, when the immune system has passed a critical period in its maturation process, recurrent wheezing illnesses or asthma could be avoided.

That very point has recently been addressed.  Investigators retrospectively reviewed the outcomes of infants in several centers across Europe who were eligible to receive palivizumab, at a time when the drug was not universally available (16).  In this way, they could compare populations of infants born prematurely who were otherwise healthy, and distinguished from each other by whether or not they had received palivizumab.  The infants who received prophylaxis were found to be about half as likely to have experienced three or more recurrent wheezing illnesses over the ensuing 24 months as those infants who did not receive prophylaxis, whether the latter group required hospitalization for bronchiolitis or not.  This is only one study in a narrowly defined group, and the findings will have to be confirmed in larger samples of children.  If, however, prevention of bronchiolitis in infancy does indeed lead to a reduction in asthma and recurrent wheezing illnesses in later childhood, the improvement in long term respiratory health and reduction in health care costs could be enormous.

References

1.         Mansbach JM, McAdam AJ, Clark S, Hain PD, Flood RG, Acholonu U, et al. Prospective multicenter study of the viral etiology of bronchiolitis in the emergency department. Acad Emerg Med 2008;15:111-8.

2.         van den Hoogen BG, de Jong JC, Groen J, Kuiken T, de Groot R, Fouchier RA, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med 2001;7:719-24.

3.         Glezen WP, Taber LH, Frank AL, Kasel JA. Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child 1986;140:543-546.

4.         Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA 1999;282:1440-6.

5.         Leader S, Kohlhase K. Respiratory syncytial virus-coded pediatric hospitalizations, 1997 to 1999. Pediatr Infect Dis J 2002;21:629-32.

6.         Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289:179-86.

7.         Weisman LE. Populations at risk for developing respiratory syncytial virus and risk factors for respiratory syncytial virus severity: infants with predisposing conditions. Pediatr Infect Dis J 2003;22:S33-7; discussion S37-9.

8.         Diagnosis and management of bronchiolitis. Pediatrics 2006;118:1774-93.

9.         Panitch HB. Respiratory syncytial virus bronchiolitis: supportive care and therapies designed to overcome airway obstruction. Pediatr Infect Dis J 2003;22:S83-7; discussion S87-8.

10.       Mandelberg A, Tal G, Witzling M, Someck E, Houri S, Balin A, et al. Nebulized 3% hypertonic saline solution treatment in hospitalized infants with viral bronchiolitis. Chest 2003;123:481-7.

11.       Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants.  The Impact-RSV Study Group. Pediatrics 1998;102:531-537.

12.       Feltes TF, Cabalka AK, Meissner HC, Piazza FM, Carlin DA, Top FH, Jr., et al. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease. J Pediatr 2003;143:532-40.

13.       American Academy of Pediatrics. Respiratory syncytial virus. In: Pickering L, editor. Red Book. 27th ed ed. Elk Grove Village, Il: American Academy of Pediatrics; 2006. p. 560-566.

14.       Stein RT, Sherrill D, Morgan WJ, Holberg CJ, Halonen M, Taussig LM, et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 1999;354:541-5.

15.       Panitch HB. The relationship between early respiratory viral infections and subsequent wheezing and asthma. Clin Pediatr (Phila) 2007;46:392-400.

16.       Simoes EA, Groothuis JR, Carbonell-Estrany X, Rieger CH, Mitchell I, Fredrick LM, et al. Palivizumab prophylaxis, respiratory syncytial virus, and subsequent recurrent wheezing. J Pediatr 2007;151:34-42, 42 e1.