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Respiratory Physiology & Neurobiology
journal homepage: www.elsevier.com/locate/resphysiol
Editorial
Cough and airway defence – Special issue of respiratory physiology and
neurobiology
Airway defensive reflexes serve an important role for the respiratory
system to fulfil physiological gas exchange at a rate which matches metabolic
demands of tissues. These reflexes are specific, spatio-tem-porally
orchestrated motor acts, main purpose of which is to prevent aspiration of
liquids or corpuscular material into the airways, or eventually expel mucus
and other potentially harmful substances out of the respiratory tract.
These motor acts are precisely regulated to provide sufficient airway
protection and defence. Decreased performance of these complex neu-
romuscular behaviours can lead to the aspiration with further con-sequences,
e.g. aspiration pneumonia, which considerably increase re-spiratory morbidity
and mortality in specific populations of patients. Strategies serving to increase
effectiveness of these motor acts or to substitute them are of high clinical
importance.
On the other hand, exaggerated airway defensive reflexes – mainly cough
– to otherwise innocuous stimuli lead to intractable coughing, which
manifests as hypersensitive cough syndrome. It considerably decreases
patient’s quality of life, and may lead to secondary damage of the airway wall.
Therapeutic strategies developed in this filed so far are of debatable efficacy.
Further research is necessary to understand pa-thogenesis of this syndrome to
find reliable treatment.
Both up-regulation and down-regulation of airway defensive re-flexes
should be studied to develop optimal clinical approaches. In this special issue,
Spinou introduces the clinical entity of cough as the continuum with two
extremes at its sides. From extremely exaggerated cough, which reduces
quality of life to attenuated cough, which re-presents a risk of aspiration
pneumonia. Together with the extensive research of pharmacological
strategies, non-pharmacological ap-proaches were developed and validated to
help patients with either cough control or cough augmentation. The main
direction of these techniques is the support of cough motor output and
exercising the cognitive control on coughing. Their article discusses the
techniques which can empower patients to increase their supramedullary
control of cough or augment the cough motor drive e.g. manual or mechanical
hyperinflation, manually assisted cough or respiratory muscles training
(Spinou, 2018).
Chronic hypersensitivity cough syndrome, which was recently de-fined as
a new clinical entity to embrace all coughers with “unknown” cause of cough
but hypersensitivity of airway sensory afferents (Morice, 2013) affects mainly
postmenopausal women. Why hypersensitivity develops in this demographic
group is not entirely understood, but Kavalcikova-Bogdanova and co-workers
threw some light to this field. They showed that sensitivity of airway afferents
to the tussive agent
https://doi.org/10.1016/j.resp.2018.04.004
1569-9048/ © 2018 Published by Elsevier B.V.
capsaicin varies during menstrual cycle and this functional change is not
present in women taking contraceptive pills. According their find-ings the
cough sensitivity to capsaicin correlates with ratio of proges-terone/oestrogen
and relative lack of oestrogen in luteal phase is as-sociated with higher
sensitivity to inhaled capsaicin. The ratio of progesterone/oestrogen seems to
be the target for further studies to elucidate relationships between hormonal
withdrawals in menopause and cough hypersensitivity (Kavalcikova-
Bogdanova et al., 2018).
Next contribution points to the not entirely understood pathogen-esis of
cough in sarcoidosis. Cough is a common and significant symptom in
sarcoidosis, which is a multisystem disease of unknown aetiology
characterized by presence of non-caseating granulomatous inflammation.
Objective cough monitoring proved that sarcoidosis pa-tients have
significantly higher cough frequency compared to control subjects. Their
cough exhibits diurnal variation, it is gender specific and shows racial
differences. While it correlates with the presence of the airway inflammation,
it shows relationship neither with the X-ray sta-ging, nor the degree of airway
obstruction. The most relevant cough triggers interacting with the airway
sensory nerves are not only the airway inflammation with its consequences,
but also the presence of considerable biomechanical forces in pathologically
changed airways (Kovacova et al., 2018). Better understanding of the
pathogenesis of cough in sarcoidosis patients may lead to the improvement of
their quality of life by application of targeted treatment.
Chronic cough is frequently associated with the gastroesophageal reflux
(GER). Subjects with reflux have heightened cough sensitivity, and this
phenomenon is attributed to the neuroplastic changes of vagal C-fibres
innervating the airways and oesophagus, as well. Sensations perceived in
reflux patients such as heartburn is however perceived via fibres derived from
dorsal root ganglia. Relationship between cough sensitivity measured by
inhalation of capsaicin and oesophageal sen-sitivity measured by intensity of
heartburn induced by oesophageal acid infusion was studied by Duricek and
his team in patients with symp-tomatic GER. The measurement was repeated
after 3 months on treat-ment by proton pump inhibitors. This medication
substantially reduced oesophageal sensitivity to acid but it did not influence
sensitivity of airway afferents to inhaled capsaicin. The results of this group
indicate that spinal and vagal afferents are influenced separately in patients
with GER (Duricek et al., 2018).
Cough and airflow limitation are predominant symptoms and signs in
chronic obstructive pulmonary disease (COPD). The natural history of the
disease includes progressive development of mentioned problems punctuated
by acute exacerbations COPD during which they rapidly
Editorial
deteriorate. The increased risk of resulting disability places significant burden
on health and social care system. Cough is the second most common
symptom reported by COPD patients and it is a source of significant distress
associated with adverse outcomes. It is linked with exacerbation frequency
and predicts clinical deterioration. A paper by Crooks and co-workers
discusses that whilst the precise mechanism of cough in COPD is not
understood, but airway inflammation and neu-rogenic factors are clearly
important. Even though the suppression of cough is not the goal of COPD
treatment, normalising the cough reflex intensity and frequency will alleviate
patient’s suffering. On the other hand, detection of an increased cough
frequency may prove to be a useful predictor of exacerbation allowing timely
intervention (Crooks et al., 2018).
Clinical evaluation of cough is difficult, because physicians do not have
objective information about the cough frequency during the day or night-time,
so they can barely recognize its true significance for the patient’s quality of
life or observe the success or a failure of applied treatment regimes. The
objective assessment of cough frequency is es-sential for evaluation,
nonetheless, available algorithms for automatic detection of cough sound
have limited sensitivity and the analysis of cough sound often requires a
human observer. Klco and co-workers developed a novel algorithm of
automated cough sound recognition based on eight dimensional numbers
called “octonions” and compared it with the algorithm based on classic
neuronal network. The authors showed that use of octonions for classification
of cough sounds im-proves sensitivity and specificity of cough sound
detection. Hopefully, their further research can provide accurate devices
useful for objective measurements of cough frequency in everyday clinical
setting (Klco et al., 2018).
Along with the cough frequency, another parameter of cough is clinically
relevant – it is cough intensity, which defines how strong the expiratory
expulsion removing the mucus and other potential hazards out of the airways
is. One can easily assume that robust cough sound indicates also high speed
of expiratory expulsions. McGuiness with his team studied the effects of
cough effort and the volume inspired prior to coughing on surrogate measures
of cough intensity measured by re-spiratory muscle electromyogram,
intrathoracic and intraabdominal pressure and finally the cough sound. They
found that effort and op-erating volume have important influences on cough
mechanics in healthy volunteers, but they modulate muscle activation,
pressure and sound differently. Importantly, this study showed that cough
sound poorly represents the cough mechanics and has limited potential as a
surrogate intensity measure (McGuinness et al., 2018).
Cough challenges in specialized cough clinics are usually performed by
inhalation of a tussive agent in doubling concentrations, until the cough
threshold is reached. The current guidelines recommend in-halation of either
capsaicin or citric acid. Citric acid has been used for over six decades to
induce cough; however, the mechanism of its pro-tussive effect is still not
fully understood. Rai and co-workers evaluated the response to inhalation of
citric acid at varying levels of acidity to determine if the pH of the solution
plays a role in the induction of cough. Study was conducted in both healthy
volunteers and patients with chronic cough. The subjects were inhaling
aerosol of 300 mM citric acid solution, while the concentration of the citrate
anion remained constant, the pH of the solution was altered by the addition of
sodium bicarbonate to 3, 5 and 6, representing the pKa values of the
individual acid moieties. The total number of coughs elicited was recorded for
each inhalation. The study showed that chronic cough patients coughed more
than healthy volunteers and did not exhibit a clear pH response. There was
also a greater variability in their response to individual challenges (Rai et al.,
2018).
An interesting study was performed by Wasilewksy and co-workers. The
study assessed the effect of deep inspirations (DIs) on airway be-haviour in
individuals with classic asthma, cough-variant asthma, and methacholine
(MCh)-induced cough but normal airway sensitivity during
bronchoprovocation to understand whether this manoeuver can
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help to distinguish these three clinical entities to establish the proper
treatment for either classic asthma, cough variant asthma and cough
respectively. Twenty-five adults assigned to groups according to the inclusion
criteria completed two single-dose MCh challenges, with and without DIs.
Bronchoprotection was assessed by comparing changes in
bronchoconstriction (according FEV1, FVC, FEV1/FVC, FEF50, FEF25-75),
gas trapping (RV, RV/TLC) and impulse oscillometry (IOS) measure-ments.
This study found that deep inspirations triggered bronchocon-striction in the
group with classic asthma, provided bronchoprotection in subjects with
cough-variant asthma and prevented gas trapping in group with methacholine
induced cough (Wasilewski et al., 2017). The results of this study indicate that
DI manoeuvers can be a helpful tool in differential diagnostic protocols.
Clinical approach to a patient suffering from cough requires special
attention when it comes to the children and the elderly. Obviously, there are
specific features of children that must be taken into con-sideration in clinical
settings, e.g. aetiology, diagnostic tools, age re-strictions for cough sensitivity
tests, treatment options etc. However, there are specific features of cough in
elderly patients, as well. Chronic cough is more prevalent in elderly than in
young subjects, and more challenging to manage due to frequent
comorbidities and possible side effects from medication. Cough reflex does
not decrease with natural ageing but it is often impaired by ongoing
pathological circumstances, such as stroke. The impairment of cough reflex
may lead to fatal complication such as aspiration pneumonia. Therefore, it is
important to note that there are well developed methods and approaches
which can augment the cough reflex to prevent aspiration pneumonia. These
are e.g. treatment by ACE inhibitors, which improve both cough and
swallowing very likely due to the accumulation of substance P and
bradykinin. Also, intensive oral care together with oral administration of
capsaicin troches or use of black pepper oil prior to food have clinical
significance (Won et al., 2018).
There are two contributions discussing cough in paediatric popu-lation.
Since the cough associated with exercise is common symptom in children
with bronchial asthma, cough reflex sensitivity to capsaicin was studied in
children with asthma after the exercise. The authors examined 42 children
with asthma by standardized capsaicin inhalation test and they found out that
exercise in asthmatic children does not influence their cough reflex sensitivity
(Ferenc et al., 2018) like in healthy children and adults, where exercise
significantly reduces this parameter (Demoulin-Alexikova et al., 2017). Since
the cough reflex is not down-regulated in asthmatic subjects, authors
hypothesize that this dysregulation may contribute to the increased frequency
of coughing during and after exercise in this demographics (Ferenc et al.,
2018). Cough sensitivity was also tested in children with adenoid
hypertrophy, which is together with cough a frequent manifestation of the
atopy in childhood. Children in which the adenoid hypertrophy was verified
by fibre-optic endoscopy underwent the capsaicin cough sensitivity tests prior
to the adenoidectomy and after the recovery. The study does not show
significant changes of cough reflex sensitivity after the recovery period in
children after adenoidectomy (Ferenc et al., 2018) This phe-nomenon is worth
of detailed follow-up studies to elucidate the effect of adenoidecotomy on
neurophysiology of the cough reflex in children.
Cough is modulated by many processes, either physiological (e.g. sleep,
exercise) or pathological (e.g. inflammation, oxidative stress). This
modulation may manifest by attenuation or exaggeration of cough response to
the defined stimulus in experimental conditions. Brozmanova and Hanacek
(2018) summarize the results of their pre-vious studies in the guinea pig
model exposed to hyperoxia. The authors documented that hyperoxia-induced
damage of the airway epithelium together with the oxidative stress attenuate
cough response in this an-imal model. These studies also demonstrated that
supplementation of suitable antioxidants has had beneficial effect in restoring
the cough responsiveness to physiological range. Series of these studies have
di-rect clinical application as majority of airway diseases are associated with
oxidative stress, which could be successfully managed by
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supplementation of antioxidants.
Identification of factors which exaggerate cough in pathological
conditions usually lead to the identification of promising targets for cough
treatment and have very important outcomes mainly if these targets are
identified and further tested. Svajdova et al. (2018) tested the ability of pro-
inflammatory signalling molecule sphingosine-1-phosphate (S1P)
concentration of which is increased in inflamed tissue to influence cough
neural pathways. The authors tested hypothesis that S1P either induces cough
or sensitizes cough evoked by TRPA1 or TRPV1 agonists in naïve guinea
pigs. Although this hypothesis was not confirmed in their recent study, further
experiments will be carried out on animals with modelled airway pathologies
to elucidate the effects of S1P signalling cascade on cough.
Hyperinflation of lungs is characteristic feature of COPD. It is known that
lung hyperinflation may alter the pattern of respiratory reflexes in subjects
with chronic respiratory diseases, but the real im-pact on airway defensive
reflexes was never studied so far. The aim of the study by Ioan and her co-
workers was to test the effect of con-tinuous positive airway pressure (CPAP)
on responses to mechanical stimulation of the trachea in rabbits. CPAP was
associated with marked alteration in the response to the tracheal stimulation.
Cough reflex was significantly decreased during CPAP. The sequence of
expiration re-flexes followed by cough (ER-cough) was upregulated during
CPAP (Ioan et al., 2018). Findings related to the cough reflex are consistent
with clinical studies performed in the field of obstructive sleep apnoea and its
treatment. The clinical relevance of up-regulation of ER-cough requires
further elucidation.
Our special issue also includes two interesting contributions related to the
central neural mechanisms regulating cough. Microinjection techniques were
employed in both studies, one performed on anaes-thetized rabbits, the other
on anaesthetized cats. A cholinergic system has been described in the nucleus
of the solitary tract (NTS); however, no information was available on the role
of acetylcholine in the mod-ulation of cough reflex in the caudal NTS.
Microinjections of acet-ylcholine, physostigmine, mecamylamine and
scopolamine into the caudal NTS were performed in anaesthetized
spontaneously breathing rabbits. Acetylcholine and physostigmine caused
depressant effect on cough induced by mechanical and chemical stimulation
of the airways; they also elicited transient increase in respiratory rate and
decreases in activity of abdominal muscles. These effects were prevented by
sco-polamine but not by non-selective antagonist of nicotinic acetylcholine
receptors mecamylamine. These results show that acetylcholine exerts an
inhibitory modulation of cough reflex through muscarinic receptors within the
caudal NTS. This is interesting information for the devel-opment of new
antitussive strategies (Cinelli et al., 2018).
The gamma-aminobutyric acid (GABA) relevant substances are used as
the cough suppressants in specific indications. To understand the mechanisms
of this suppression, GABA A and GABA B relevant sub-stances were injected
into the NTS and the parameters of cough induced by mechanical stimulation
of the trachea were measured in anaes-thetized cats. The GABA-ergic
inhibition of cough relies on afferent, central integrative and efferent levels of
structures responsible for neurogenesis of cough. Based on the study of
Kotmanova and co-workers, GABA-ergic inhibition influences number and
magnitude of expiratory expulsions of mechanically provoked cough and also
in-spiratory timing of this specific motor behaviour (Kotmanova et al., 2018).
Phosphodiesterases (PDEs) are a group of enzymes responsible for
hydrolysis of intracellular second messenger molecules cAMP and cGMP in
various cells of the human body. Non-selective inhibitors of PDEs cause
bronchodilation, share anti-inflammatory and immune modulating effects
however these drugs have quite narrow therapeutic window. Selective PDE
inhibitors have been developed to inhibit PDE isoforms with different
pharmacological effects based on their tissue expression. Mokry et al. discuss
the effects of selective PDEs inhibitors on cough based on animal studies
performed in their laboratory
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together with putative mechanisms of their cough-modulating action. PDE4
and PDE5 inhibitors demonstrated the most significant effect on cough
suppression, confirming their benefits in subjects with chronic inflammatory
airway diseases (Mokry et al., 2018). This is quite in-teresting insight into this
drug category, especially when we consider their potential clinical application
in the future management of cough in clinical settings.
Special issue on “Cough and airways defensive reflexes” contains
information from clinical and experimental studies, and as well as re-cent
review articles. We received contributions from all around the globe –
Canada, South Korea, Italy, UK, USA, France and Slovak Republic.
The last mentioned, small central European country, and particu-larly
Martin – the city in its very centre is considered to be the cradle of
experimental respirology in this region, thanks to prof. Juraj Korpas (∗1926,
†2009) a passionate scientist and the author of the monography “Cough and
other respiratory reflexes” published by Karger in 1979. Prof. Korpas was a
close co-worker of prof. John Widdicombe (∗1925,
†2011), the godfather of cough research, known, loved and memorized by
many. He was the friend and the most significant supporter of sci-entists
studying respiratory reflexes in former Czechoslovakia, and especially in
Slovakia.
We are proud to publish contributions by the scientists from “Slovak
group of experimental respirology” along with the articles of their colleagues
from abroad. Thanks to the contributors, we were fortunate to receive
numerous high-quality submissions that represent the breadth of currently
ongoing research which takes into account dif-ferent aspects of cough.
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Corresponding author.