Cough is an essential defence mechanism [1]. However, chronic cough is a significant cause of morbidity, seriously impairing quality of life [2]. Previously, chronic cough was considered a consequence of various diseases, such as asthma/eosinophilic bronchitis, rhinitis and gastro-oesophageal acid reflux disease [3,4]. Recent evidence, however, suggests that chronic cough is a clinical syndrome with distinct intrinsic pathophysiology characterised by neuronal hypersensitivity [5][6][7]. Here, we estimated the worldwide epidemiological burden of chronic cough irrespective of putative diagnosis in general adult populations using a comprehensive systematic literature review.We searched the literature for prevalence of chronic cough in community-based adult populations using Pubmed and Embase databases according to the recommendations of the PRISMA statement [8]. The search terms were "cough AND (epidemiology OR epidemiologic OR epidemiological OR prevalence OR

Excessive accumulation of histamine in the body leads to miscellaneous symptoms mediated by its bond to corresponding receptors (H1-H4). Increased concentration of histamine in blood can occur in healthy individuals after ingestion of foods with high contents of histamine, leading to histamine intoxication. In individuals with histamine intolerance (HIT) ingestion of food with normal contents of histamine causes histamine-mediated symptoms. HIT is a pathological process, in which the enzymatic activity of histamine-degrading enzymes is decreased or inhibited and they are insufficient to inactivate histamine from food and to prevent its passage to blood-stream. Diagnosis of HIT is difficult. Multi-faced, non-specific clinical symptoms provoked by certain kinds of foods, beverages and drugs are often attributed to different diseases, such as allergy and food intolerance, mastocytosis, psychosomatic diseases, anorexia nervosa or adverse drug reactions. Correct diagnosis of HIT followed by therapy based on histamine-free diet and supplementation of diamine oxidase can improve patient's quality of life.

PurposeRecent evidence suggests a global burden of chronic cough in general populations. However, the definitions vary greatly among epidemiological studies, and none have been validated for clinical relevance. We aimed to examine previous epidemiological definitions in detail and explore the operational characteristics.MethodsA systematic review was conducted for epidemiological surveys that reported the prevalence of chronic cough in general adult populations during the years 1980 to 2013. A literature search was performed on Pubmed and Embase without language restriction. Epidemiological definitions for chronic cough were classified according to their components, such as cutoff duration. Meta-analyses were performed for the male-to-female ratio of chronic cough prevalence to explore operational characteristics of epidemiological definitions.ResultsA total of 70 studies were included in the systematic review. The most common epidemiological definition was identified as 'cough ≥3 months' duration without specification of phlegm (n=50); however, it conflicted with the cutoff duration in current clinical guidelines (cough ≥8 weeks). Meta-analyses were performed for the male-to-female ratio of chronic cough among 28 studies that reported sex-specific prevalence using the most common definition. The pooled male-to-female odds ratio was 1.26 (95% confidence interval 0.92-1.73) with significant heterogeneity (I2=96%, P<0.001), which was in contrast to clinical observations of female predominance from specialist clinics. Subgroup analyses did not reverse the ratio or reduce the heterogeneity.ConclusionsThis study identified major issues in defining chronic cough in future epidemiological studies. The conflict between epidemiological and clinical diagnostic criteria needs to be resolved. The unexpected difference in the gender predominance between the community and clinics warrants further studies. Clinical validation of the existing definition is required.

The cold-sensitive cation channel TRPM8 is a target for menthol, which is used routinely as a cough suppressant and as an additive to tobacco and food products. Given that cold temperatures and menthol activate neurons through gating of TRPM8, it is unclear how menthol actively suppresses cough. In this study we describe the antitussive effects of (-)-menthol in conscious and anesthetized guinea pigs. In anesthetized guinea pigs, cough evoked by citric acid applied topically to the tracheal mucosa was suppressed by menthol only when it was selectively administered as vapors to the upper airways. Menthol applied topically to the tracheal mucosa prior to and during citric acid application or administered continuously as vapors or as an aerosol to the lower airways was without effect on cough. These actions of upper airway menthol treatment were mimicked by cold air delivered to the upper airways but not by (+)-menthol, the inactive isomer of menthol, or by the TRPM8/TRPA1 agonist icilin administered directly to the trachea. Subsequent molecular analyses confirmed the expression of TRPM8 in a subset of nasal trigeminal afferent neurons that do not coincidently express TRPA1 or TRPV1. We conclude that menthol suppresses cough evoked in the lower airways primarily through a reflex initiated from the nose.

The diseases of the nose and paranasal sinuses (rhinosinusitis) often in combination with asthma and gastroesophageal reflux are common causes of chronic cough in patients with normal chest radiograph. The relationships between rhinosinusitis and cough are incompletely understood. We investigated modulation of the cough reflex by the inputs from the nose. We demonstrate that the cough reflex is sensitized by the intranasal administration of sensory nerve activators in animal models and in humans. Cough reflex is also sensitized in the guinea pig model of allergic nasal inflammation and in patients with allergic rhinitis. In patients with allergic rhinitis the cough sensitization is augmented during the allergen season. We conclude that the cough reflex can be sensitized from the nose. Our data indicate that this sensitization is mediated by nasal sensory nerves. We speculate that by inducing the cough reflex sensitization rhinosinusitis contributes to chronic cough. If combined with environmental or endogenous cough triggers, the cough reflex sensitization is predicted to cause excessive coughing. The potential endogenous cough triggers may be associated with rhinosinusitis (postnasal drip, aspiration of nasal secrets) or secondary to a coexistent disease such as asthma or gastroesophageal reflux.