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.