Abstract
Purpose
Based on a potential shared pathophysiology tied to mast cell activity and neurogenic inflammation that may link pruritus and chronic cough (CC), this study, leveraging the All of Us database, examines the association between the two conditions.
Materials and methods
A nested case-control comparison was used to examine the association, identifying cases with SNOMED codes 418363000 (pruritus) and 68154008 (CC). Matching was performed on a 1:4 ratio by age, sex, and ethnicity using the MatchIt package in R, followed by maximum likelihood method to estimate odds ratios (ORs) and 95% confidence intervals from 2x2 contingency tables.
Results
CC patients (n = 2,388) were more than twice as likely to be diagnosed with pruritus (OR: 2.65) and pruritus patients (n = 22,496) were more than twice as likely to be diagnosed with CC (OR: 2.57), than respective matched controls.
Conclusions
These results highlight the potential bidirectional relationship between CC and pruritus, suggesting possible shared immune and neural pathways. Treatments like difelikefalin and nalbuphine that modulate these pathways, alongside P2X3 targeting agents, are emerging as potential therapeutic approaches for itch and chronic cough given the possible interconnected pathophysiology. This study’s insights into the associations between pruritus and CC may pave the way for targeted therapeutic strategies that address their shared mechanisms.
Introduction
Pruritus is a common cutaneous symptom that is a feature in a myriad of dermatological and systemic diseases. Although the pathophysiology of pruritus is incompletely understood, increasing evidence suggests that the interaction of mast cells with the nervous system and neurogenic inflammation may play a role (Citation1,Citation2). This interplay may extend beyond dermatological symptoms and impact other body systems. Studies have shown an increase in submucosal mast cells in chronic chough, defined as a cough of unknown cause lasting more than eight weeks and refractory to disease-modifying therapies (Citation3). Based on current understandings of cough pathophysiology, mast cell activation may contribute to a process known as central sensitization, in which the release of inflammatory signals from mast cells sensitizes neurons and alters the nervous system’s response to various sensory signals including pain and pruritus (Citation1,Citation4). Over time, the nervous system becomes hypersensitized to both internal and external stimuli and further exacerbates the dysregulated neuronal reflexes associated with each of these conditions (Citation4). Previous epidemiological studies using self-reported patient questionnaires have identified associations between the two conditions (Citation5,Citation6); however, no studies have identified an association using a diverse, nationwide cohort. Given these observations, the objective of this study was to evaluate a potential association between pruritus and chronic cough utilizing the All of Us database.
Material and methods
We performed a nested case-control study in the All of Us database examining pruritus diagnoses in chronic cough cases and vice versa using Systematized Nomenclature of Medicine Clinical Terms (SNOMED) code 418363000 for pruritus and 68154008 for chronic cough. Each case was proximity-matched in a 1:4 ratio based on age, sex, and race/ethnicity among patients without the diagnosis of interest, via the MatchIt package in R. The conditional maximum likelihood method was used to estimate odds ratios (ORs) and 95% confidence intervals from 2 × 2 contingency tables. We exchanged exposure factors to determine if the association between chronic cough and pruritus persists in both directions.
Results
Among 2,388 chronic cough patients matched with 9,552 healthy controls (), chronic cough cases were more than twice as likely to also be diagnosed with pruritus ([OR: 2.65 CI 2.36–2.99, p < 0.0001]). Similarly, among the 22,496 pruritus cases matched with 89,984 controls (), pruritus cases were more than twice as likely to also be diagnosed with chronic cough (OR: 2.57; CI 2.30-2.87, p < 0.0001]).
Table 1. Cohort demographics and 2x2 contingency table of pruritus in patients with chronic cough and 1:4 matched controls.
Table 2. Cohort demographics and 2x2 contingency table of chronic cough in patients with pruritus and 1:4 matched controls.
Discussion
This analysis of patients in the All of Us database supports a statistically significant bidirectional association between pruritus and chronic cough. Contributing to both conditions is immune dysfunction from mast cells and their mediators, which leads to direct activation of pruriceptive neurons in the peripheral nervous system and subsequent sensitization of central nervous system (Citation4). Given the profound impact of these conditions on quality of life, the search for effective treatment remains essential (Citation3). While current treatments are still being explored, clinical trials have identified difelikefalin, a selective kappa opioid receptor agonist that exerts antipruritic effects on peripheral neurons and immune cells, as a therapeutic for pruritus (Citation7). Nalbuphine, a different kappa-opioid receptor agonist and a partial mu-opioid receptor antagonist, has demonstrated statistically significant reductions in refractory cough symptoms in patients with idiopathic pulmonary fibrosis (IPF) (Citation8). Similar targeting approaches through kappa-opioid receptor agnosim in itch and cough-related conditions suggest potential for therapeutic approaches that may reflect a shared pathophysiology between the two. Additionally, ongoing studies have identified P2X3 receptors, expressed on vagal afferent nerves, as contributing to the hypersensitization of vagal sensory neurons. A clinical trial utilizing a P2X3 antagonist demonstrated a reduction in cough frequency relative to controls (Citation9), and P2X3 receptor antagonists have been identified as an investigational target for chronic itch (Citation10). Limitations of our study include reliance on SNOMED codes for diagnosis, the use of the All of Us database which may contain inaccuracies in data, and lack of disease severity data. Furthermore, the relationship between these co-morbidities is still unclear; this study does not reveal whether there is a temporal correlation between the onset of symptoms in a patient diagnosed with both conditions. Further investigations into the cross-benefits of treatments for chronic cough and pruritus may reveal new therapeutic targets and strategies, emphasizing the importance of a holistic understanding of their interconnected pathophysiology.
IRB approval status
Approved by the Icahn School of Medicine at Mount Sinai Institutional Review Board (STUDY-22-00884).
Disclosure statement
BU is an employee of Mount Sinai and has received research funds (grants paid to the institution) from: Incyte, Rapt Therapeutics, and Pfizer. He is also a consultant for Arcutis Biotherapeutics, Bristol Myers Squib, Castle Biosciences, Fresenius Kabi, Galderma, Janssen, Lilly, Pfizer, Primus Pharmaceuticals, Sanofi, and UCB. BSK is an employee of Mount Sinai. He also has received personal fees from Abbvie, Agenx, Abrax, Japan, Almirall, S.A., Amagma, Amgen, Bristol-Myers Squibb, Cara Therapeutics, Eli Lilly and Company, Evommune, Escient Pharmaceuticals, Galderma S.A., GlaxoSmithKline, Genzyme, Granular Therapeutics, Guidepoint Global, Incyte Corporation, Janssen Pharmaceuticals, Inc., LEO Pharma,Pfizer Inc., Novartis, Recens, Regeneron, Medical,Trevi Therapeutics. JCDR is an employee of Mount Sinai. The rest of the authors declare no relevant conflicts of interest.
Data availability statement
Access to the Researcher Workbench and data is free. All researchers must be authorized and approved via a 3-step process that includes registration, completion of ethics training and attestation to a data use agreement.
Additional information
Funding
References
- Lavinka PC, Dong X. Molecular signaling and targets from itch: lessons for cough. Cough. 2013;9(1):1. doi:10.1186/1745-9974-9-8.
- Pecova T, Kocan I, Vysehradsky R, et al. Itch and Cough - Similar role of sensory nerves in their pathogenesis. Physiol Res. 2020;69(Suppl 1):S43–3. doi:10.33549/physiolres.934403.
- Visca D, Beghè B, Fabbri LM, et al. Management of chronic refractory cough in adults. Eur J Intern Med. 2020;81:15–21. doi:10.1016/j.ejim.2020.09.008.
- Ji RR. Neuroimmune interactions in itch: do chronic itch, chronic pain, and chronic cough share similar mechanisms? Pulm Pharmacol Ther. 2015;35:81–86. doi:10.1016/j.pupt.2015.09.001.
- Misery L, Shourick J, Reychler G, et al. Association between chronic idiopathic cough and sensitive skin syndromes is a new argument in favor of common neuropathic pathways: results from a survey on 4050 subjects. Sci Rep. 2021;11(1):16976. doi:10.1038/s41598-021-96608-w.
- Ficheux A-S, Brenaut E, Taieb C, et al. Chronic cough, itch, skin pain and other unpleasant skin sensations are frequently associated: results from survey on 8077 individuals. JEADV Clinical Practice. 2024;3(1):100–109. doi:10.1002/jvc2.248.
- Wala K, Szepietowski JC. Difelikefalin in the treatment of chronic kidney disease-Associated pruritus: a systematic review. Pharmaceuticals. 2022;15(8):934. doi:10.3390/ph15080934.
- Maher TM, Avram C, Bortey E, et al. Nalbuphine tablets for cough in patients with idiopathic pulmonary fibrosis. NEJM Evid. 2023;2(8):EVIDoa2300083. doi:10.1056/EVIDoa2300083.
- Abdulqawi R, Dockry R, Holt K, et al. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2015;385(9974):1198–1205. doi:10.1016/S0140-6736(14)61255-1.
- Li M, Wang Y, Banerjee R, et al. Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP. Elife. 2019;8:e47060. doi:10.7554/eLife.47060.