Bronchiolitis (The Snotty Lung): Prevention Is Likely to Be More Helpful Than a ‘Cure’

In 1963, Reynolds and Cook observed that oxygen is vitally important (in the treatment of acute bronchiolitis) and there is little evidence that any other therapy is consistently or even occasionally useful [1] and this still holds true more than 60 years later. In the study by Loveys et al. published in this issue [2] the authors address the suggestion that the macrolide antibiotic, azithromycin, may reduce the severity of the acute illness and the prevalence of subsequent respiratory symptoms. They concluded ‘There is insufficient evidence to support the use of azithromycin as part of hospital care for infants with bronchiolitis’. While none of the included studies individually found evidence to support the use of macrolides, the initial meta-analysis suggested that it may have a small effect on the length of stay. However, in their sensitivity analysis, which involved removing the studies that reported longer durations of stay than the authors felt were typical for Australasia [2], this apparent effect disappeared. Azithromycin joins an extensive list of potential therapies which fell by the wayside when subject to more rigorous testing. These include ‘asthma therapies’ such as β-agonists, corticosteroids, theophylline, anti-cholinergics and a leukotriene antagonist; antibiotics and antivirals and approaches to improve airways clearance including inhaled hypertonic saline and physiotherapy. Despite the evidence, adherence to guidelines is frequently poor as illustrated by the two Australasian studies in which non-macrolide antibiotics were used in 60%–70% of patients. The rationale for using a macrolide antibiotic in these studies was based on having anti-inflammatory, immunomodulatory and anti-viral effects [2]. Macrolides appear to have a role in downregulating neutrophilic inflammation and, as noted by Loveys et al., the airways inflammation in bronchiolitis is dominated by neutrophils. The use of azithromycin has become ubiquitous, particularly in adult respiratory medicine, largely because of its perceived anti-inflammatory effects (even though, as in these studies, it is used at doses that have antibacterial activity). The downside of using this convenient ‘magic bullet’ so widely is, of course, the fact that macrolides are extremely effective in driving antimicrobial resistance [3]. Every paediatrician knows what ‘acute bronchiolitis’ looks like when they see it, but there is no universally agreed definition. There is no definitive test for the condition, and the diagnosis is based on a cluster of signs [4]. The studies included in the review allow subjects to have crackles and/or wheeze as a sign of airways obstruction. Crackles are generally observed in young infants (< 6 months) and represent the snapping opening of alveolar units. Secretions in the airways and mucosal oedema are almost certainly responsible for the closure of distal airways. In older infants and toddlers with larger airways, complete closure is far less common. However, the secretions and mucosal oedema can still cause flow limitation which results in the generation of a wheeze (all that wheezes is not asthma). Thus, the same pattern of inflammation can result in two different clinical pictures: one with crackles and one with wheeze. The third common sound, a ruttle resulting from airways secretions, is generally misrecorded as a wheeze despite its harsh quality in both inspiration and exhalation [4]. Conversely, a viral infection with associated wheeze can be caused by two different pathophysiological processes since flow limitation can also be caused by constriction of airways smooth muscle, the defining feature of asthma. Asthma appears to be an acquired loss of homeostasis of airways smooth muscle with its prevalence increasing with age through the early years of life [5]. In contrast, the incidence of significant airflow obstruction attributable to viral-induced neutrophilic inflammation without bronchoconstriction (bronchiolitis) falls progressively through the pre-school years. Thus, in the pre-school years, a cohort of wheezing children with an apparent viral infection will contain both types of patients, the proportion with asthma increasing with age. The inclusion of a mix of clinically indistinguishable patients with and without asthma would account for the contradictory results observed in studies of the treatment of ‘pre-school wheeze’. Any signal that drugs such as corticosteroids are helpful will depend on the proportion of subjects who have asthma vs. bronchiolitis. Loveys et al. state that their aim was ‘to synthesize evidence on the efficacy and safety of azithromycin in infants (aged < 12 months), presenting or admitted to hospital with bronchiolitis’ presumably to ensure the vast majority had bronchiolitis. Interestingly, only two of the studies they included limited recruitment to those under 12 months of age with the other 5 having a cut-off of 18 months or 24 months. The third common airways disease in the pre-school years is persistent bacterial bronchitis, though it is relatively uncommon for these patients to present to hospital even during an acute exacerbation. They do not wheeze but in those with a ruttle, parents commonly report this as a wheeze. Given that acute bronchiolitis is, in the vast majority, a relatively brief, self-limiting illness, one might question whether it will be possible to find a treatment that has a dramatic impact on the clinical course. As Lovey et al. note, the essence of high-quality care involves good supportive care. Supplemental oxygen helps prevent significant agitation that can lead to exhaustion and eventually death. This agitation typically becomes evident when the infant's saturation falls into the high 80s. Unfortunately, mortality rates remain significant in those countries with less developed medical infrastructure with estimates of deaths worldwide running into the hundreds of thousands [6]. Hence, an intervention that would prevent progression to severe illness would be invaluable in these settings and even in developed countries, such an intervention would be of value given the very large numbers of patients admitted each winter. The answer to whether such an intervention is possible may lie in our understanding of the pathophysiology of the condition. Subjects included in trials are almost always hospitalised representing the most severely affected subgroup of patients. Even for these patients, the median length of stay in hospital is widely reported to be two to three days giving little opportunity to impact on the course of the illness. In addition, there is evidence, at least for RSV, that the viral titres and neutrophil numbers are reaching a peak around the time of admission again making it difficult to significantly impact on the subsequent course [4]. If an agent were to be found that could safely mitigate the severity of the disease, it is likely that it would need to be administered before the onset of lower airways obstruction, a challenging prospect. Of the studies included in the systematic review, three required the identification of RSV as the cause of the acute illness. One of two was driven by a belief that early severe RSV infections have a unique role in the causation of asthma. Once almost ubiquitous, this idea first put forward nearly 70 years ago [7] has largely been abandoned. That RSV is the most common cause for admission with bronchiolitis is probably attributable to its ability to impair the development of effective long-term immunity. Hence, passively acquired immunity in the youngest infants is relatively poor [4] and it is the youngest infants (1–6 months of age) that are most likely to experience the most severe LRTIs, in large part, due to the relatively small diameter of conducting airways. Curiously, a number of clinicians now champion the suggestion that it is the human rhino virus that is unique in its ability to cause asthma! The remaining four studies included patients with a clinical diagnosis of ‘bronchiolitis’ irrespective of viral status. The proportion of patients in whom no virus was identified varied between 26% and 60%. These investigators presumably accept that the underlying pathophysiology is similar irrespective of the virus. The evidence is that all of the respiratory viruses induce a neutrophilic influx into the airways and that this is true for both the upper and lower airways. As such acute bronchiolitis can be considered to be a ‘snotty lung’ analogous to the snotty nose in those with an URTI. The airway obstruction is not primarily due to smooth muscle constriction as in asthma. Studies have shown that it is not unusual to identify more than one virus in samples from infants with bronchiolitis and that the presence of two or more viruses does not appear to be associated with more severe disease. In contrast, a study of pre-school children attending a nursery found that the quantity and purulence of the nasal discharge with a cold were much greater in those colonised with potentially pathogenic bacteria [8]. Similar results have been found in infants with acute bronchiolitis, suggesting that the impact of acquiring a new virus is strongly influenced by the host microbiome [5]. Our understanding of the role of the resident microbiome in influencing the manifestations of acute and chronic airways disease is still at a very rudimentary stage not least because it can be very difficult to study in the lower airway. Moreover, the differences in the airway's microbial profiles between those with and without disease appear to be part of a continuum without a clear division between health and disease [9]. Recent RCTs have indicated that maternal vaccination with an RSV vaccine provides significant protection against hospitalisation as does a monoclonal preparation [10]. It will be interesting to see the impact of these interventions on admissions over the coming years with the potential for other viruses to fill a partially vacated niche and, perhaps more importantly, the potential for mutations to start appearing in the face of increased pressure to mutate if all infants are being protected (though they do represent only a very small proportion of the population). The challenge of diagnosing and managing bronchiolitis will not disappear even with these preventative interventions. The systematic review published in this issue helps highlight the many controversies and challenges that surround the all-too-common condition of bronchiolitis and the challenge of distinguishing the snotty lung from those with a virus and asthma in young children. Mark L. Everard: conceptualization, writing – original draft, writing – review and editing. Kate Loveys et al. Efficacy and Safety of Azithromycin in Infants With Bronchiolitis: A Systematic Review and Meta-Analysis. DOI: https://doi.org/10.1111/apa.70339. The author has nothing to report.