Abstract
Acute viral bronchiolitis is a common viral lower respiratory tract infection in young children. Most typically caused by respiratory syncytial virus in 70% of cases, the condition lasts for 4 to 7 days, with a prolonged cough in many. Children with comorbidity, particularly those born prematurely or with significant congenital heart disease, are at risk of more severe disease. Nasal obstruction progresses over 3 to 4 days to difficulty with feeding and increased work of breathing with hypoxemia. Crackles and/or wheeze may be auscultated. Apnoea may be a presenting sign in those less than 3 months of age. Viral load is highest at peak of symptoms and in those with more severe disease. Approximately 2% to 3% of all children are admitted to hospital with bronchiolitis. The differential diagnosis may include bacterial pneumonia, congenital lesions of the lung or heart, or an interstitial lung disease. There are no effective treatments, and admission is for feeding support (by nasogastric or intravenous fluids) or treatment of hypoxemia. Critical care support is required for some infants experiencing respiratory failure, though mortality rates remain unchanged. Practice within and between countries varies significantly and alignment of practice is a common goal of guidelines. Vaccines for RSV are in advanced development, as are several antiviral therapies for RSV. In most children, acute symptoms improve within 5 to 7 days and cough by 2 weeks. Recurrent wheeze is common following acute bronchiolitis and a good association with a diagnosis of asthma in childhood.
Keywords
bronchiolitis, viral lower respiratory tract infection, wheeze, respiratory syncytial virus
Epidemiology
Bronchiolitis is the most common lower respiratory tract infection in children. The condition forms part of the spectrum of viral lower respiratory tract infection that includes bronchiolitis, viral pneumonia, and viral-induced wheeze. In polar hemispheres (north and south), bronchiolitis is a seasonal disease, dominating winter months, with a peak over 6 to 8 weeks around the winter solstice. In tropical climates, the disease is associated with rainy months and is seasonally more dispersed. Climate and environment appear to influence both season and severity.
Bronchiolitis is diagnosed clinically by integrating characteristic but variable signs and symptoms across a broad age range, though the majority of cases occur in children under 1 year of age. The condition can be caused by any respiratory virus and has a wide spectrum of disease severity.
A “classic” case would be an infant aged 3 to 5 months of age who develops coryza and over the subsequent 3 to 4 days has increased difficulty with breathing, and consequent inability to maintain adequate oral feeding. Wheeze or crackles can be heard on auscultation. Improvement occurs by days 5 to 7, though a characteristic harsh cough may persist for 21 days or more.
While the diagnosis often appears straightforward, the wide range of disease severity across a skewed but broad age range and the need for clinical diagnosis (with associated inconsistency) creates difficulty in establishing precise data. In addition, while bronchiolitis is a clinical diagnosis applied to any infecting agent, the majority of data available relate to bronchiolitis caused by respiratory syncytial virus (RSV) infection; and within RSV bronchiolitis is a focus on those at high risk, in particular, those born prematurely. Reference to these groups synonymously with bronchiolitis can make interpretation of epidemiological data difficult and may reduce the understanding of bronchiolitis caused by non-RSV and in lower risk patients (particularly children born at term).
Population Risk for Bronchiolitis Associated With All Respiratory Viruses
There are only limited estimates of population risk for bronchiolitis associated with all respiratory virus infections, but approximately 40% of infants are affected by bronchiolitis in the first year of life. In the United Kingdom, using primary care databases, the 1 year incidence of children given a specific diagnosis of bronchiolitis is 58 to 65 per 1000 children, rising to 204 per 1000 when a broader definition of bronchiolitis was used to capture potential cases. This study highlights that in children with typical lower respiratory tract signs and symptoms, clinicians may not ascribe the discrete diagnosis of bronchiolitis; a finding also found in other countries such as Spain and across health care systems, with evidence that a diagnosis of bronchiolitis is more likely to be made in secondary than primary care. The hospital admission rate for bronchiolitis in children without high-risk conditions is 1.9% in the United States using coded hospital data, showing a decline from 2.7% in the period 2000–2009. In contrast, UK data suggest that admission rates are continuing to increase over time (to 4.0% in 2011). Of those admitted to hospital, 85% are born at term and 15% are born preterm. Additional factors also place children at higher risk of admission including, age (<3 months), male sex, being bottle-fed, multiple birth, and family smoking. Rates of admission for infants with a diagnosis of bronchiolitis can vary up to threefold across hospitals in the same country. Duration of admission is also highly variable within countries and internationally.
Mortality for bronchiolitis is low ; United States 0.03% overall, with an adjusted odds ratio (OR) of 0.25 for mortality in children less than 1 year of age without previous health condition and primary diagnosis of bronchiolitis. Admissions to intensive care have remained constant over time although related costs are increasing.
Population Risk for Respiratory Syncytial Virus Bronchiolitis
RSV infects 69% to 98% of infants in the first year of life. The rapid development of vaccines and treatment therapies for RSV has added impetus to the need to better define the burden of RSV disease. Globally there are an estimated 33.8 million cases of RSV lower respiratory tract infection each year in children under 5 years of age, resulting in 3.4 million admissions to the hospital and 66 to 199 thousand deaths (with the majority in low- and middle-income countries).
In the United States an estimated 20% of children will attend primary care each year with RSV bronchiolitis, and up to 7% attend an Emergency Department (ED). Admission to hospital with RSV bronchiolitis is typically around 2.4% of all infants, though in previously healthy term infants, the admission rate to hospital with RSV bronchiolitis can be as low as 0.7%.
High-Risk Population for Bronchiolitis Associated With All Respiratory Viruses
In infants who are born preterm at 32 to 35 weeks’ gestation, 48% will develop bronchiolitis and 6% require admission to the hospital. The risk of bronchiolitis is increased in a range of conditions compared with term infants, including preterm birth (respiratory rate [RR] 1.89), cystic fibrosis (RR 2.45), congenital heart disease (RR 3.35), chronic lung disease (RR 1.61), immunodeficiency (RR 1.73), Down syndrome (RR 2.53), and cerebral palsy (RR 2.43).
High-Risk Population for Respiratory Syncytial Virus Bronchiolitis
For infants born ≤ 32 weeks gestation, 75% of infants will have a lower respiratory tract infection in the first year of life, with 35% RSV positive and 40% RSV negative; of these infants, 41% of RSV positive will be admitted to the hospital versus 18% of RSV negative. Recent studies suggest that hospitalization rates for high-risk infants due to RSV are reducing over time and are now similar to those for RSV negative, possibly as a result of improvements in neonatal care or immunoprophylaxis in high-risk groups ( Fig. 24.1 ). Risk of death is much higher amongst high-risk groups who are RSV positive, including preterm (1.2%), congenital heart disease (5.2%), and bronchopulmonary dysplasia (7.0%).
Etiology
Bronchiolitis has a viral etiology, with RSV the most common cause, reported in 43% to 75% of cases. Other viruses associated with bronchiolitis are human rhinovirus (18%), influenza, coronavirus, human metapneumovirus, adenovirus, parainfluenza virus and human Boca virus ; that is, “any respiratory virus.”
RSV has two strains, A and B, with RSV A associated with more severe disease. Reinfection in the same season with the same or different strain is possible. As a sole infecting agent, RSV is associated with more severe bronchiolitis than other single respiratory virus infections. Coinfection of RSV with rhinovirus can produce even more severe disease. RSV is the most common infectious agent in children admitted to the hospital with radiological features consistent with pneumonia (occurring in 28% of children—most commonly those under 5 years of age). In young children who are well immunized, RSV represents the most common cause of lower respiratory tract infection.
Pathology/Pathogenesis
What commences as an upper respiratory tract infection becomes a lower respiratory tract infection over the course of 2 to 5 days. Infants are particularly susceptible as they have small bronchi that are more likely to become blocked by secretions and edema, and a less well-developed ability to respond to and clear viral infection.
Histopathology is naturally limited to the most severe cases who have died, where the bronchioles are edematous and blocked by necrotic epithelium and neutrophils, with some mucus binding this debris together. Airway obstruction is intensified by poor airway clearance associated with loss of cilia function occurring within 24 hours and persisting for up to 3 months after the illness. Destruction of cilia is considered to be caused by virus replication and not mediated by inflammation. RSV is associated with more severe airway pathology than that found in children dying from other respiratory viruses, even in those not mechanically ventilated.
Viral shedding is higher and more prolonged in younger infants and those with more severe disease. Increased disease severity, longer hospital stay and use of intensive care is associated with higher viral load for RSV in nasopharyngeal secretions. Severity of disease is associated with both infant risk factors (including lack of adaptive T cell response), but also RSV virus specific factors (viral antigen load and direct cytotoxic effects). Determining the relative contribution of both of these to disease severity will be important; if the latter is dominant, antiviral agents provided early in the course of the disease may reduce severity, whereas dominance of the former might need additional immunomodulators.
Biomarkers are now sought to better characterize those at risk of greater disease severity and to indicate recovery. Infants hospitalized with RSV bronchiolitis have increased interleukin (IL)-33 and IL-13 in secretions. Polymorphisms of surfactant protein A are associated with increased risk of intensive care admission. Cysteinyl leukotrienes are increased in infants with RSV bronchiolitis and are still increased 1 month following infection. More severe disease is also associated with increased serum cathelicidin, lactate dehydrogenase, caspase and IL-15. There is some evidence that more severe disease may be associated with an insufficient inflammatory response. The interrelationship of the microbiome in bronchiolitis is also being actively explored.
Clinical Features
Bronchiolitis is diagnosed clinically. Variance in the clinical interpretation of symptoms and physical findings lead to inconsistency in diagnosis, particularly in milder cases and children over 1 year of age.
Symptoms
Typical symptoms are rhinorrhea, proceeding over 2 to 4 days to a characteristic harsh moist cough with pyrexia that is typically below 39°C, although fever above 38.5°C is seen in 50% of infants. Ability to achieve adequate oral feeding declines as nasal obstruction with secretions develops and work of breathing increases. The time to peak symptoms of 4 days is associated with the peak in viral load, varying from infant to infant.
In younger children (particularly <6 weeks of age), apnea may be a presenting sign, sometimes in the absence of other features of bronchiolitis. Apnea may be temporarily improved by nasal suctioning, but it is most likely a direct viral effect in young infants. Apnea is a “red flag” sign in bronchiolitis that warrants a period of review in a supervised clinical setting to ensure that it has resolved.
Patients more likely to require intensive care include preterm infants and those with apnea, low birth weight, or a respiratory rate greater than 70/min. Children tend not to relapse during the improving phase of the illness, which should give confidence to clinicians when considering discharge from ED or hospital.
Physical Findings
Physical findings include an increased respiratory rate, chest recession, use of accessory muscles, hyperinflation, wheezing, crackles, and reduced arterial oxygen saturations. Physical findings vary depending on sleep state (and associated changes in tidal volume). Respiratory rate is a key marker of disease severity, with ≥60/min considered severe and ≥70/min critical. Oxygen saturation may be improved (at least temporarily) by removal of nasal secretions.
Clinical Scores
Bronchiolitis is a highly variable disease that requires assessment of disease severity by clinicians for decision making, some of which is subjective. Clinical scoring systems have been developed in an attempt to standardize care and minimize variance. Many early scores derived from asthma scores. The most commonly applied scores for bronchiolitis are outlined in Table 24.1 . Within this table, the most widely quoted is the Respiratory Distress Assessment Instrument (RDAI) (and the resulting Respiratory Assessment Change Score, RACS). More recent scores were developed to have more detailed validation (Liverpool Infant Bronchiolitis Severity Score–Proxy Reported Outcome Measure [LIBSS PRO] and Genetics, Vaccines and Infectious Diseases Paediatrics Research Group [GENVIP] ) and to improve the ability to identify those at risk of deterioration. The ability of clinical scores to retain precision and reliability, when scoring is performed by larger numbers of health care professionals in the context of multicenter Phase III trials, is of current interest.
| Score | Tal a | Lowell b | Wang c | Wilson d | Jacobs e | Liu f | Walsh g | Marlais h | Van Miert i | Cebey-Lopez j |
|---|---|---|---|---|---|---|---|---|---|---|
| Name | Tal and later Modified Tal (SpO 2 not cyanosis) | Respiratory Distress Assessment Instrument (RDAI) | No names | Comprehensive Severity Index (pediatric component) | Canadian Acute Respiratory Infection and Flu Scale (CARIFS) | No name | Bronchiolitis Assessment Severity Tool | Bronchiolitis Risk of Admission Scoring System | LIBSS-PRO | GENVIP |
| General respiratory or bronchiolitis specific | General | General | General | General | General | General | Bronchiolitis | Bronchiolitis | Bronchiolitis | General |
| Date published | 1983 | 1987 | 1992 | 2000 | 2000 | 2004 | 2006 | 2011 | 2015 | 2016 |
| Number of items | 4 | 7 (in 3 domains) | 4 | 27 (in 7 domains) | 18 (in 3 domains) | 4 (age specific ranges) | 4 | 5 | 10 | 7 |
| Subjective/objective | 2/2 | 2/1 | 3/1 | 11/14 | 18/0 | 3/1 | 2/2 | 0/5 | 3/7 | 3/4 |
| Scoring | 0–3 per item | 0 to max 4 per item. Total max = 17 | 0–3 per item | 1–4 | 0–3 per item | 0–3 per item | 0 to max 3 + age | 0–1 | 0 to max 8 per item | 0–3 (max 20) |
| Score | Mean score | Sum | Sum | Sum | Sum | Sum | Sum of weighted scores | Sum | Sum | Sum |
| Interpretation | Relative change | Change in score >4 = improvement, <4 no improvement | Relative change | Relative change | Relative change | Relative change | ≤0.654 mild disease, >1.866 severe | ≥3 predicted admission | Cut of scores for mild, moderate, and severe | Relative change |
| For completion by | Health care | Health care | Health care | Health care | Parents | Health care | Health care | Health care | Health care | Health care |
| Interrater reliability | ||||||||||
| Correlation | Length of stay r 2 = 0.23 | PPV 67% NPV 83% | ||||||||
| Kappa | 0.7 k | Not provided for total score | 0.48 | 0.36–0.52 | 0.52–0.65 | 0.68 | 0.83 | 0.74 |
a Tal A, Bavilski C, Yohai D, Bearman JE, Gorodischer R, Moses SW. Dexamethasone and salbutamol in the treatment of acute wheezing in infants. Pediatrics. 1983;71(1):13-18.
b Lowell DI, Lister G, Von Koss H, McCarthy P. Wheezing in infants: the response to epinephrine. Pediatrics. 1987;79(6):939-945.
c Wang EE, Milner RA, Navas L, Maj H. Observer agreement for respiratory signs and oximetry in infants hospitalized with lower respiratory infections. Am Rev Respir Dis. 1992;145(1):106-109.
d Wilson DF, Horn SD, Smouth R, Gassaway J, Torres A. Severity assessment in children hospitalized with bronchiolitis using the pediatric component of the comprehensive severity index. Pediatr Crit Care Med. 2000;1(2):127-132.
e Jacobs B, Young NL, Dick PT, et al. Canadian Acute Respiratory Illness and Flu Scale (CARIFS): development of a valid measure for childhood respiratory infections. J Clin Epidemiol. 2000;53(8):793-799.
f Liu LL, Gallaher MM, Davis RL, Rutter CM, Lewis TC, Marcuse EK. Use of a respiratory clinical score among different providers. Pediatr Pulmonol. 2004;37(3):243-248.
g Walsh P, Gonzales A, Satar A, Rothenberg SJ. The interrater reliability of a validated bronchiolitis severity assessment tool. Pediatr Emerg Care. 2006;22(5):316-320.
h Marlais M, Evans J, Abrahamson E. Clinical predictors of admission in infants with acute bronchiolitis. Arch Dis Child. 2011;96(7):648-652.
i van Miert C, Abbott J, Verheoff F, Lane S, Carter B, McNamara P. Development and validation of the Liverpool infant bronchiolitis severity score: a research protocol. J Adv Nurs. 2014;70(10):2353-2362.
j Cebey-Lopez M, Pardo-Seco J, Gomez-Carballa A, et al. Bacteremia in children hospitalized with respiratory syncytial virus infection. PLoS One . 2016;11(2):e0146599.
k McCallum GB, Morris PS, Wilson CC, et al. Severity scoring systems: are they internally valid, reliable and predictive of oxygen use in children with acute bronchiolitis? Pediatr Pulmonol. 2013;48(8):797-803.
Disease Severity
Symptoms in bronchiolitis vary across a wide but skewed continuum from mildly increased work of breathing with cough to respiratory failure and death. Often divided into mild, moderate, and severe disease, the perspective on these gradations varies across health care systems. A World Health Organization (WHO) workshop has provided candidate definitions differentiating a diagnosis of RSV lower respiratory tract infection (SpO 2 <95%) from severe (<93%) and very severe RSV disease (SpO 2 <90%, inability to feed orally, or reduced level of consciousness). Infants can display variance in SpO 2 within this range (90% to 95%) over short periods of observation without significant change in clinical status, which may limit the discriminatory reliability of these definitions. From a secondary care perspective, moderate severity is often considered a need for admission to hospital and severe by need for critical care (positive pressure support). Clinical scores are often designed to identify transition points in the level of care required. The currently available evidence concerning transition points in level of care is poor. Treatment guidance, particularly benefit from use of interventions at the ED/Ward (i.e., SpO 2 ) and ward/critical care floor interface (i.e., high-flow nasal cannula [HFNC] oxygen and continuous positive airway pressure [CPAP]) is much needed. Guidelines have provided signs and symptoms that should alert clinicians to a child at risk of deterioration and suggested criteria for admission to the hospital. In hospitals, those most likely to deteriorate to the extent of being provided with critical care support are of lower birth weight (<5 lbs, 2.25 kg) and/or have a respiratory rate ≥70/min on day 1 of admission.
Imaging, Laboratory Findings
Chest radiography is not required to confirm a diagnosis of bronchiolitis. A chest radiograph often leads to increased diagnostic uncertainty as the features may be similar to those of pneumonia (atelectasis, mucous plugging, and loss of volume) and consequently lead to greater inappropriate use of antibiotics. Chest radiography should be reserved for a child who is atypical, for example, showing persistently focal crackles, a temperature remaining above 39°C despite antipyretics, or respiratory failure requiring critical care support.
Laboratory tests do not aid in the clinical diagnosis of bronchiolitis. Serious bacterial infection is unusual and complete blood counts and blood cultures are unhelpful (though recent evidence suggests that although still uncommon, it may be more frequent than previously considered). Dehydration is usually mild and best assessed clinically without electrolyte measurement. Approximately 6% of infants with bronchiolitis can have concurrent urinary tract infection, so urine culture may be of value in persistently febrile infants, particularly those under 3 months of age.
Measurement of arterial/capillary carbon dioxide is commonly performed, but can be restricted to those children with increased respiratory rate and work of breathing despite oxygen supplementation.
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