The post-viral infection disorder spectrum speculation.
A striking pathophysiological commonality between post-RSV pulmonary dysfunction and NEHI is the upregulation of neurotransmitters. As described above, during and after RSV lower respiratory tract infection airway hyperresponsiveness, increased vascular permeability and neurogenic inflammation are largely attributed to substance P and its upregulated NK1 receptor (figure 2A). In NEHI, bombesin is thought to be involved in the pathogenesis of small airway obstruction but may also play a protective role against noxious agents, such as respiratory viruses (figure 2B and table 1). The hypothesis that viral infections might underlie NEHI is supported by Gomes et al., reporting viral infection preceding the onset of clinical symptoms in all infants in a large NEHI case series 44. While both bombesin and substance P are neurotransmitters, and intuitively could have similar functional roles, bombesin is viewed as the marker of NEHI while Sub P has not been studied in NEHI. The reverse has been the case for post-RSV wheezing models, where substance P has been the extensively studied neurokinin and bombesin has not. In these and other disorders characterized by airflow limitation it would therefore be interesting to evaluate a pathogenetic role of both these neurokinins, as well as other “bronchoconstrictor” neuropeptides, such as the calcitonin gene-related peptide that is known to be released by both NENC fibers and NEC47,48. Combined effects of substance P and bombesin were found in pathologies such as rheumatoid arthritis and histamine-independent itch and both neurokinins are secreted by neurons in other organ systems49-51. Both these respiratory entities have airway obstruction as their main clinical presentation. This is more severe and long term in NEHI patients, and often associated with persistent hypoxemia, but with symptoms improving over time, although non-atopic asthma may develop in the follow-up42. While the presentation is milder in post-RSV wheezing, the affected children have increased risk of bronchial hyperreactivity and asthma persisting into older ages52,53. Physiologically, pulmonary function tests in post- RSV wheezing and NEHI showed similar obstructive pattern (Table 1), except for consistent absent response to 2-agonists in NEHI 20,42,52,54. Radiologic studies in NEHI, in addition to the ground-glass opacification predominantly involving the right middle lobe and lingula, indicate a mix of hyperinflation with collapsed areas, pointing towards small airway obstruction in line with the clinical and PFT changes 38,45. These observations for NEHI suggest functional air-trapping, i.e., increased tone of airway smooth muscle, much like that described in airway hyperreactivity post-RSV, but with the distinction of being persistent, not intermittent and irreversible by bronchodilators. Fluctuation of symptom severity over time in NEHI and patchy radiological distribution further point to functional vs . structural pathogenesis of NEHI. These data suggest that increased neurokinin activity is involved in the pathophysiology of both conditions, with persistence thereof in NEHI, and oscillations in post-RSV wheezing. Whether these differences veritably reflect a biological difference where the contribution of different cells and the relative abundance of the two neurokinins, and possibly involvement of other neurotransmitters, might play different roles in determining the characteristics of one entity or the other,vs. having been serendipitously differentially researched in the two entities, is a matter of speculation. Genetic mutations may be involved in the pathogenesis of both disorders. While in the cases of post-RSV wheezing, a “familial” presentation may go unnoticed, or interpreted as being a marker of familial asthma, in NEHI, due to the rarity of the disease, its severity and long-term morbidity, the condition may be clearly identified when it affects multiple family members. NEHI familial cases are described and a heterozygousNKX2.1 mutation has been identified in an infant with classic presentation of NEHI and in four other adult family members with histories of childhood lung disease 55,56. This mutation strongly segregated with lung disease in this family but not in eight others unrelated NEHI subjects, suggesting that altered expression of NKX2.1 target gene may be involved in pathophysiology of NEHI, but is not the predominant cause of the disease56. Therefore, one may speculate that subjects with genetically determined or acquired autonomic pathway defects may have a more profound response to a second hit (e.g., viral infection), as has been shown for the predictable tendency to wheeze following rhinovirus infections based on genetics57. The recent observation that a significant proportion of NEHI children may have evidence of immune system abnormalities support the notion that defects in the immune response to infection might be involved 41.
These observations may point to a continuum of airway disease determined by an innate or acquired tendency to respond to some hits (likely viruses) with a disproportionate response. In this context, that in post-viral obstructive disease the severity of the response might be determined by an underlying genetic abnormality. Alternatively, if one accepts the notion that the presence of bombesin is a marker of dysmaturity 18,19,43 the fact that the presentation of NEHI is delayed beyond the neonatal period, points to the need for a second hit for a clinical presentation to emerge. It is tempting to expand the hypothesis to include post-infectious bronchiolitis obliterans (PIBO), a disorder where viral infection leads to severe structural airway damage58. While discussion on PIBO has focused on adenovirus, recent literature expands the spectrum of underlying organisms to include RSV as a possible trigger58. Neurokinins have not been studied in PIBO during the acute or chronic phases, but along the lines of the discussion on “familial” cases of NEHI, some individuals respond to adenoviral infections and develop PIBO, while most do not. An Argentinean study identified children with PIBO as having mannose-binding lectin insufficiency, supporting the notion that a genetic abnormality may determine severity of the response59. This innate tendency could be the unifying factor that determines at which level on the spectrum - from wheezing to NEHI to PIBO - will individuals end post viral infection.