Bronchiolitis is an acute, infectious, inflammatory disease of the upper and lower respiratory tract resulting in obstruction of the small airways. Although it may occur in all age groups, the larger airways of older children and adults better accommodate mucosal edema and severe symptoms are usually only evident in young infants.
Respiratory syncytial virus (RSV) is the most commonly isolated agent in 75% of children less than 2 years of age hospitalized for bronchiolitis.1 Other agents that cause bronchiolitis include parainfluenza virus types 1 and 3, influenza B, parainfluenza type 2, adenovirus types 1, 2 and 5 and Mycoplasma (primarily in school aged children).2,3 There is abundant evidence that complex immunologic mechanisms play a role in the pathogenesis of RSV bronchiolitis.3 Type I allergic reactions mediated by IgE antibody may account for clinically significant bronchiolitis.4 Breast fed babies with colostrum rich in IgA appear relatively protected from bronchiolitis.5
Twenty-five percent of children under one and 13% of children from one to two years of age will have respiratory infections.1 Of these, half will have a "wheezing associated respiratory disease".6 RSV can be cultured from one third of these outpatients7 and from 80% of those less than 6 months of age whom are hospitalized.8 Among healthy, full term infants, 80% of hospitalizations occur in the first year of life6 and 50% of hospitalizations occur in children 1-3 months of age. Less than 5% of hospitalizations occur in the first 30 days of life presumably due to transplacental transfer of maternal antibody.9 Risk factors for early onset disease and subsequent hospitalization include low birth weight, prematurity, lower socioeconomic group, crowded living conditions, parental smoking, absence of breast-feeding, and day care.
In temperate climates, RSV epidemics generally develop yearly in winter and late-spring, while parainfluenza outbreaks usually occur in the fall.4 There is evidence that in the sub-tropical areas of the southeastern United States, RSV is endemic throughout the year with peaks from October to February and subsidence only from March through July.10 Two RSV subtypes have been identified: A and B, with type A causing the majority of severe infections.11 One subtype usually predominates during a given season thus there are "good" years and "bad" years for RSV disease to occur.12
The disease is highly contagious. Viral shedding in nasal secretions continues for 6 to as long as 21 days after the development of symptoms.13 Incubation period is from 2-5 days.2 Secondary infections occur in 46% of family members,14 98% of other children in day care,15 42% of hospital staff, and 45% of previously uninfected hospitalized infants.16 Infection is spread by fomites via environmental surfaces. Hand washing and the use of disposable gloves and gowns may reduce nosocomial spread.17-19
Profuse coryza, congestion and a low-grade fever initially characterize the clinical syndrome in children. Sixty percent of primary RSV infections are confined to the upper airway.20 During a period of 2-5 days this may progress to lower respiratory tract involvement with the development of cough, dyspnea, wheezing and feeding difficulties. By the time the patient is brought to medical attention, the fever has usually resolved. Infants less than 1 month of age may present hypothermic.21 Severe cases progress to respiratory distress with tachypnea, nasal flaring, retractions and irritability and possibly cyanosis. Physical examination often reveals otitis media, retractions, fine rales and diffuse, fine wheezing. The severity of the disease is directly related to post-conceptual age. Infants less than six months of age are the most severely affected due to smaller, more easily obstructed airways and decreased ability to clear secretions.
Diagnosis is based on the infants' age, seasonal occurrence, and physical findings. Chest radiographs usually reveal hyperinflation and 20-30% will show lobar infiltrates and/or atelectasis.2 White blood cell counts are usually between 8000 and 15,000/cc and may be left shifted due to stress. Hypoxia is the best predictor of severe illness and correlates best with the degree of tachypnea. The degree of wheezing or retractions correlates poorly with hypoxia.22 First infections are usually most severe, with subsequent attacks generally milder. Non-respiratory manifestations of RSV infections include otitis media, myocarditis, supra-ventricular and ventricular dysrrhythmias23 and secretion of antidiuretic hormone.24
Eighteen to twenty percent of hospitalized infants with RSV bronchiolitis develop apnea.25 Frequency of apnea increases among premature infants whose gestation was less than 32 weeks, infants who have not yet reached the age of 44 weeks from conception and especially among those who have neonatal apnea. It occurs early in the course of the disease and may be the presenting symptom. The apnea is non-obstructive central apnea occurring during quiet sleep.26 Apnea rarely lasts more than a few days but about 10% of these patients require intubation and mechanical ventilation.
Although viral culture for RSV is available and must be considered the "gold standard" in making a definitive diagnosis, several immunologic tests are more convenient, rapid and less costly. Commercially available tests detect RSV antigen in epithelial cells from nasopharyngeal secretions, bronchoal-veolar lavage or lung tissue. These tests are performed by either direct immunofluorescent antibody (IFA) staining or an enzyme-linked immunosorbent assay (ELISA). Although ELISA is somewhat quicker and easier to interpret due to a more objective endpoint, the IFA technique may be preferable because the number of epithelial cells recovered can be determined thus verifying the adequacy of the sample. With adequate sampling, IFA requires 2-6 hours for processing and is 90% sensitive and specific. ELISA requires 30 minutes for processing and is 85-90% sensitive when compared to viral culture. 27
Most patients have mild clinical illness and recover uneventfully in 5-7 days but coughing may persist for up to 2 weeks.28 Median hospital stay for normal children is 3-5 days and less than 10% require ventilation.9,29 Most will have normal respiratory parameters 2 weeks after the height of the illness and radiologic abnormalities will clear within 9 days of admission.30 However, 20% of normal children will have a protracted course with wheezing and abnormal pulmonary function studies for many months.31 Prospective studies of children with bronchopulmonary dysplasia (BPD) found that 53% of 30 children on home oxygen acquired RSV in one 4-month respiratory season. Hospitalization was required for 69% of these infants. Sixty-four percent were hospitalized for more than 7 days, 32-36% were admitted to intensive care and 13-19% required mechanical ventilation.10,32,33
Children with congenital heart disease (CHD) and pulmonary
hypertension are also a high-risk population when they acquire
RSV. In 1982, MacDonald and others34 found that
RSV-infected infants with CHD required a 13.5-day
hospitalization. Sixty-three percent required intensive care and
22% required mechanical ventilation. Mortality rate was 37% for
the CHD with RSV children, 6.5% for CHD without RSV and 1.5% for
RSV children without CHD. A 1991 Canadian multi-institutional
study of 260 hospitalized children with CHD and RSV found that
33% required intensive care and 18% required mechanical
ventilation.33 Mortality rates in this study were 3.4%
of CHD patients overall: 9.4% if the children had CHD with
pulmonary hypertension and 1.5% if the CHD was not accompanied by
pulmonary hypertension. The difference in mortality rate between
the 1982 study and the 1991 study was attributed to advances in
intensive care and the use of antiviral therapy.33 Recently,
Moler et al 35 reviewed 740 RSV admissions to the
University of Michigan. Seventy-nine of these children had
clinically significant CHD. They found no difference in mortality
between patients with CHD (with or without
pulmonary hypertension) when compared to children with no CHD.
Additionally, they found no effect of antiviral therapy on
mortality, mean length of stay, ICU days, or days on mechanical
ventilation. They concluded that the decrease in mortality from
CHD with RSV was due to improvements in intensive care management
and advances in the surgical correction.
The relationship between acute bronchiolitis in infancy and the subsequent development of asthma remains confusing. Some studies have shown that asymptomatic children examined 10 years after an acute episode of bronchiolitis may have abnormal small airway resistance and decreased transcutaneous oxygen saturation (SpO2)36 and up to 50% will have recurrent wheezing later in life.37 However, these are retrospective studies with no controls and the majority of these children had either a family history of allergy, prematurity, small for gestational age, or born into families where there is exposure to passive cigarette smoke. A recent study found no difference in pulmonary function studies between 29 full term, age, race and sex matched control infants without prior wheezing, asthma or lower respiratory illness when compared to a similar group of 29 previously healthy infants admitted with a first episode of acute RSV bronchiolitis.38 These infants were evaluated at a median interval of 36 weeks after admission.
The infant with acute bronchiolitis and respiratory distress should be hospitalized if sustained SpO2 is below 92% in room air, is less than six months old, cannot maintain oral hydration, has a markedly elevated respiratory rate, or has a history of chronic cardiorespiratory disease. Desaturation in 40% O2 (3-4 l/min O2), cyanosis, extra pulmonary symptoms, apnea or acidosis are indicators for pediatric intensive care referral. Hypoxemia is the most common laboratory abnormality detected and supplemental oxygen administration is common. The mainstays of therapy for patients with bronchiolitis are fluid replacement and oxygen supplementation. These infants are mildly dehydrated because of decreased fluid intake and increased fluid losses from fever and tachypnea. The goal of fluid therapy is to replace deficits and provide maintenance requirements. Excessive fluid requirements should be avoided as this may promote interstitial edema formation.19 Supportive care for hospitalized infants also includes careful monitoring to detect apnea and attention to temperature regulation in the very small infant.
The use of bronchodilators in the treatment of bronchiolitis in infants and young children has been controversial.39 In 1993, a Lancet editorial still did not recommend the use of bronchodilators in the treatment of bronchiolitis, as they were considered ineffective.40 Kellner and colleagues41 in a meta-analysis, reviewed fifteen randomized, placebo-controlled trials of bronchodilator treatment in bronchiolitis. They concluded that bronchodilators produce modest short-term improvement in clinical features of mild or moderately severe bronchiolitis. A more recent meta-analysis of eight clinical trials by Flores and Horwitz42 concluded that conclusive analysis for the efficacy of ß2-agonist therapy for bronchiolitis remains unavailable and that there is no support for the use of ß2-agonist therapy for bronchiolitis. Although there is conflicting evidence in regards to the efficacy of bronchodilators in bronchiolitis, it is reasonable to administer a ß-agonist such as albuterol (0.15mg/kg/dose) on a trial basis to patients with bronchiolitis and assess the clinical response. Initially, drug response should be evaluated every 5-10 minutes. If improvement in retractions, respiratory rate and wheezing is noted, scheduled aerosol treatments may be continued with additional treatments given as needed.
Despite the prominent rule inflammation plays in the pathogenesis of airway obstruction, corticosteroids have not proven beneficial in improving clinical status in a large controlled multi-institutional study.43 Several other studies evaluating the effect of corticosteroids in children with bronchiolitis have been performed, but results of these studies were inconsistent.44-47 Based on the available current evidence, the use of dexamethasone or other glucocorticosteroids for children with bronchiolitis cannot be supported.
Nebulized epinephrine (0.1 ml/kg) has been found to be more efficacious than the ß-agonist salbutamol for infants with acute bronchiolitis.48,49 However, in a study by Henderson et al50 no significant improvements in respiratory function measured from baseline were observed for up to 30 minutes following inhaled adrenaline. The authors concluded that inhaled adrenaline did not relieve airways obstruction. The sample size of this study was very small (11) and there was no mention of cultures being sent for viral studies. Randomized controlled trials comparing subcutaneous epinephrine51 and nebulized racemic epinephrine52 to placebo found a greater improvement in the epinephrine-treated group in terms of oxygenation and clinical signs.
Ipratropium bromide, an aerosolized anticholinergic agent, has not been demonstrated to be of help in the management of the wheezy infant.53 It appears to offer no further clinical benefit compared with albuterol alone in moderately severe acute bronchiolitis.54
Viruses are the primary etiologic agents in bronchiolitis and
therefore the routine administration of antibiotics has not been
shown to influence the course of this disease.41,55 If
an infant rapidly deteriorates, has elevated or shifted
peripheral white blood cell counts or has clinical features
suggesting sepsis, then bacterial cultures of blood, urine and
cerebral spinal fluid should be obtained and followed immediately
by the administration of broad-spectrum antibiotics. A
prospective cohort study by Kuppermann and colleagues56
of 156 previously healthy febrile children age 24 months or
younger with bron
chiolitis, revealed that these children were unlikely to have
bacteremia or urinary tract infections. The authors concluded
that routine cultures of blood and urine in these patients were
unnecessary. The routine administration of antibiotics has not
been shown to influence the course of bronchiolitis.
Heliox (a helium/oxygen mixture) has been used in patients with acute asthma.57 There has been one case report describing the use of heliox therapy in a 4-month old boy with RSV-positive bronchiolitis.58 Heliox may be a beneficial addition to the conventional therapeutic armamentarium in critically ill children with RSV bronchiolitis. However, clinical studies of this agent will be required to assess the efficacy of this therapy. It is possible that heliox-driven nebulized therapies may be useful in infants with very severe bronchiolitis and/or patients who are intubated and are not responding to conventional therapy.
Infants with bronchiolitis occasionally require mechanical ventilation in cases of recurrent apnea or increased work of breathing with respiratory failure.59,60 The treatment of these patients is supportive, with provision of adequate oxygen, ventilation and hydration. Both continuous positive airway pressure (CPAP)61 and intermittent mandatory ventilation (IMV) with positive end-distending pressure (PEEP) have been used successfully in the treatment of these infants. Aggressive weaning over the first two or three days is not warranted and is usually unsuccessful. Once the illness subsides, weaning can proceed quickly.3 Infants with progressive hypoxemia unresponsive to conventional ventilation may respond to high-frequency jet ventilation62 or extracorporeal membrane oxygenation.63,64 Current experimental therapies for infants with pulmonary insufficiency from bronchiolitis, include surfactant and nitric oxide.65,66
Ribavirin (1-beta-D-ribafuranosyl-1,2,4-triazole-3-carbox-amide) is a synthetic nucleoside analog that resembles guanosine and inosine. It appears to interfere with the expression of messenger RNA and inhibit viral protein synthesis.67 Ribavirin has a broad spectrum of antiviral activity in vitro, where it inhibits replication of RSV, influenza, parainfluenza, adenovirus, measles, Lassa fever, and Hantaan viruses.68 Ribavirin treatment for RSV infections have been controversial because of the aerosol route of administration, the variable course of RSV infection, cost of the drug, toxicity, and side effects.
Presently, the recommendations of the AAP are that Ribavirin aerosol therapy may be considered in the following list of selected infants and young children at high-risk for serious RSV disease:
They added "more definitive answers to the questions of Ribavirin efficacy and effectiveness would require multi-institutional prospective randomized clinical trials. Recommendations may be modified as new information becomes available."85
Subsequent studies have shown that Ribavirin does not significantly reduce mortality rate or lower the probability of respiratory deterioration.69 Ribavirin treatment did not reduce the diagnosis of reactive airway disease and there were no differences in pulmonary function tests when assessed five to six years after their initial RSV infection.82
In summary, Ribavirin appears to be safe but expensive. Efficiency and effectiveness have not been clearly demonstrated in large randomized placebo controlled trials. Routine use of Ribavirin at this time cannot be recommended.
Transmission of RSV probably occurs by contact with secretions of infected patients. Meticulous attention to hand washing between patient contacts should reduce the likelihood of hospital staff acquiring RSV infection from patients or of spreading infection by carrying RSV on their hands.19 Recently, the use of respiratory syncytial virus immunoglobulin intravenous (RSV-IGIV) at high doses (500-750 mg/kg) has been shown to prevent RSV in high-risk patients.70,71 In addition, aerosolized RSV-IGIV was thought to be beneficial in the treatment of children with RSV bronchiolitis.72 However, a recent study by Rimensberger, et al73 concluded that a single dose of 0.1 g of RSV-IGIV per kg of body weight in a 5% solution had no substantial beneficial effect on acute RSV bronchiolitis.
Presently, there are a number of disadvantages to the parenteral administration of human polyclonal RSV-specific immunoglobulin antibodies to infants. These include intravenous administration monthly over 2-4 hours, the need to administer it in a clinic or hospital and the potential for excessive fluid load. A more convenient RSV-specific monoclonal antibody preparation that can be given as a single injection, is presently being investigated.87 RSV-IGIV is a fairly expensive product and has potential for adverse reactions, including fluid overload, decreased oxygen saturation and respiratory failure requiring mechanical ventilation.74,75 However, after reviewing the clinical data detailing the use of RSV-IGIV in infants and children, Wandstrat76 concluded it was an effective prophylactic agent against serious RSV disease in select groups of infants and children.
The peak incidence of hospitalized cases of RSV bronchiolitis occurs in infants' 2-5 months of age. Because of this, vaccination was thought to be capable of stimulating effective resistance by the second month of life.90 The first trials of active immunization in children involved the use of a formalin-inactivated vaccine.77 Results of these trials indicate a failure to protect against RSV infection as the vaccine did not induce adequate levels of neutralizing antibody.
Bronchiolitis is the most frequent lower respiratory tract infection during infancy requiring hospitalization. There is no effective treatment for bronchiolitis and approaches to therapy varies widely and is controversial.
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