Elsevier

The Lancet

Volume 368, Issue 9532, 22–28 July 2006, Pages 312-322
The Lancet

Seminar
Bronchiolitis

https://doi.org/10.1016/S0140-6736(06)69077-6Get rights and content

Summary

Bronchiolitis is a distressing, potentially life-threatening respiratory condition that affects young babies. Around 2–3% of all infants younger than 1 year are admitted to hospital with bronchiolitis, usually during the seasonal epidemic. The majority of these infants are infected with respiratory syncytial virus and all have an intense inflammatory response in their airways. Although most infants recover, they have an increased risk of recurrent wheezing. Although bronchiolitis is common, little is known about what causes infants to be susceptible. Diagnostic interventions have little effect on clinical outcome, and apart from supportive measures, there is no specific treatment. Bronchiolitis therefore presents an intriguing clinical conundrum and a major challenge to researchers. High quality clinical studies are needed to clarify assessment of disease severity and criteria for hospital admission, particularly the use of pulse oximetry and chest radiography. Careful mapping of the inflammatory pathways in the pathogenesis of bronchiolitis should lead to development of new therapies to alleviate symptoms.

Section snippets

Epidemiology

Hospital admission rates in the USA and Europe for bronchiolitis are reported to be around 30 per 1000 for children younger than 1 year.3, 4 High-risk groups for severe infections are infants younger than 6 weeks; premature infants; and those with chronic lung disease of prematurity, congenital heart disease, neurological disease,5 or immunodeficiency.6 The mechanisms that contribute to increased disease severity in infants in each of these risk groups are not fully understood, but are probably

Clinical diagnosis

Although most clinicians would find bronchiolitis a straightforward diagnosis during the epidemic months, the lack of a standard definition of bronchiolitis presents challenges to clinicians and clinical researchers. Bordley and colleagues undertook a systematic review of diagnostic testing in acute bronchiolitis.19 Most of the 65 studies reviewed included tachypnoea and wheezing in the case definition, but many stated only that “infants with signs and symptoms consistent with bronchiolitis”

Clinical assessment

The decision to admit a baby to hospital is usually made in the emergency department. A routine part of this assessment is measurement of oxygen saturation by pulse oximetry. Detection of hypoxia in infants is thought to be responsible for an increase in admission rates since its increased use over the past two decades might have resulted in the hospitalisation of infants whose other symptoms were too mild to result in admission.23

Mallory and colleagues undertook a randomised controlled survey

Viral diagnosis

The initiating event in RSV disease is infection of the epithelial cells in the respiratory tract (figure 4). In the USA, most children admitted to hospital with bronchiolitis have specific diagnostic tests to identify RSV infection and this has been associated with a decreased likelihood of antibiotic treatment.25, 27 In one study, compared with nasopharyngeal swabs, nasal swabs were negative in about a third of RSV-positive cases,30 which is perhaps because RSV grows better at 37°C than 33°C.

Acute complications

Bronchiolitis is associated with acute inflammation of the respiratory tract, including the Eustachian tubes and middle ear. The reported prevalence of otitis media among children with bronchiolitis varies from 16% to more than 50%.1, 17, 41 We suspect that this complication is frequently undiagnosed, in view of the difficulties in examining the middle ear of a small baby with acute respiratory distress.

In the USA there is controversy over whether infants with clinical bronchiolitis should

Special features of bronchiolitis and the immunobiology of RSV

As has already been described, RSV seems to have several features that distinguish it from other respiratory viruses (panel). Viral infections typically induce T-helper-1 (Th-1) cell responses, characterised by high levels of interferon-gamma production; by contrast, asthma and atopy are typically characterised by T-helper-2 (Th-2) cells producing interleukin 4 and interleukin 5. These responses are easily demonstrated in animal models, but have not been thoroughly examined in human infants. It

Biological effects of RSV proteins on host cells

Like many viruses, RSV is not just a passive target for the host's immune response, but is well adapted to control and manipulate the host. The RSV glycoprotein G has been shown to have structural homology with the CX3C chemokine, CX3CL1 (fractalkine). RSV glycoprotein G binds the human CX3CR1 receptor and mediates chemotaxis of cells that respond to CX3CL1.66 This interaction could facilitate RSV binding to CX3CR1-bearing cells, including mast cells and neuronal cells.67 The RSV fusion protein

Delayed respiratory sequelae

Bronchiolitis obliterans is increasingly recognised as a serious sequel to severe respiratory infection in early childhood frequently resulting from adenovirus infection.73 It has been suggested that RSV might cause bronchiolitis obliterans, but, the only reports have been of infants in whom adenovirus has also been detected.73, 74, 75

The relation between RSV bronchiolitis and subsequent wheezing illnesses in childhood has been consistently shown in clinical studies76 but it seems that not all

Pathogenesis of delayed effects of RSV bronchiolitis

There is no clear explanation for the association between RSV bronchiolitis and recurrent wheeze in later life. The association could be causal (ie, RSV bronchiolitis could lead to long-term changes in the lungs), or bronchiolitis could act as a marker for genetic predisposition or impaired respiratory reserve, which will later manifest as allergy or recurrent wheeze. Lower than normal lung function prior to RSV infection is a risk factor for the development of bronchiolitis.83

Genetic

Prevention of RSV infection with passive antibody in high-risk groups

The introduction of palivizumab to prevent RSV bronchiolitis has been hailed as a major advance in RSV disease control. Palivizumab is the first humanised monoclonal to be used to prevent infection in humans, and it seems to be highly effective. However, the cost is about US$5000–6000 per patient per season and use of prophylactic therapy varies greatly from one country to another.

The authors of a systematic review of all published economic analyses of RSV immunoprophylaxis in high-risk infants

Management

Surveys of clinical practice in the acute management of bronchiolitis from many centres across the world have shown wide variations, even within the same country.10, 25, 27, 103, 104 There is much controversy, confusion, and lack of evidence over the best treatments for this common, life-threatening condition.3, 105 Clinical trials of interventions in bronchiolitis have been criticised for being too small and focusing on short-term outcomes, rather than reporting outcomes of interest to

Potential for novel antiviral treatments and vaccines

The value of antiviral agents in acute, transient infections seems limited. To be effective, they have to be given early, ideally within 1 or 2 days of disease onset. This stage could be before many infected children reach medical attention and moreover, precedes the peak of disease severity, which is caused by the inflammatory immune response and occurs when viral load is already declining.115

Despite these problems, there are several novel antiviral drugs under development. An exciting area

Search strategy and selection criteria

We searched Embase, MEDLINE, and the Cochrane Library for articles published between 2003 and 2005, using the terms “respiratory syncytial virus” and “bronchiolitis” in combination with the terms “viral”, “infections”, “humans”, “bovine”, “pneumovirus”, and “vaccines”. We selected publications from this list that seemed to be of the greatest originality and relevance to this Seminar. Additionally, we searched publications cited in these items and our own bibliographic databases on this

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