Mycobacterium tuberculosis Sulfolipid-1 Activates Nociceptive Neurons and Induces Cough.

Pulmonary tuberculosis, a disease caused by Mycobacterium tuberculosis (Mtb), manifests with a persistent cough as both a primary symptom and mechanism of transmission. The cough reflex can be triggered by nociceptive neurons innervating the lungs, and some bacteria produce neuron-targeting molecules. However, how pulmonary Mtb infection causes cough remains undefined, and whether Mtb produces a neuron-activating, cough-inducing molecule is unknown. Here, we show that an Mtb organic extract activates nociceptive neurons in vitro and identify the Mtb glycolipid sulfolipid-1 (SL-1) as the nociceptive molecule. Mtb organic extracts from mutants lacking SL-1 synthesis cannot activate neurons in vitro or induce cough in a guinea pig model. Finally, Mtb-infected guinea pigs cough in a manner dependent on SL-1 synthesis. Thus, we demonstrate a heretofore unknown molecular mechanism for cough induction by a virulent human pathogen via its production of a complex lipid.

An Airway Protection Program Revealed by Sweeping Genetic Control of Vagal Afferents.

Sensory neurons initiate defensive reflexes that ensure airway integrity. Dysfunction of laryngeal neurons is life-threatening, causing pulmonary aspiration, dysphagia, and choking, yet relevant sensory pathways remain poorly understood. Here, we discover rare throat-innervating neurons (∼100 neurons/mouse) that guard the airways against assault. We used genetic tools that broadly cover a vagal/glossopharyngeal sensory neuron atlas to map, ablate, and control specific afferent populations. Optogenetic activation of vagal P2RY1 neurons evokes a coordinated airway defense program-apnea, vocal fold adduction, swallowing, and expiratory reflexes. Ablation of vagal P2RY1 neurons eliminates protective responses to laryngeal water and acid challenge. Anatomical mapping revealed numerous laryngeal terminal types, with P2RY1 neurons forming corpuscular endings that appose laryngeal taste buds. Epithelial cells are primary airway sentinels that communicate with second-order P2RY1 neurons through ATP. These findings provide mechanistic insights into airway defense and a general molecular/genetic roadmap for internal organ sensation by the vagus nerve.

Infectious and Inflammatory Pathways to Cough.

Coughing is a dynamic physiological process resulting from input of vagal sensory neurons innervating the airways and perceived airway irritation. Although cough serves to protect and clear the airways, it can also be exploited by respiratory pathogens to facilitate disease transmission. Microbial components or infection-induced inflammatory mediators can directly interact with sensory nerve receptors to induce a cough response. Analysis of cough-generated aerosols and transmission studies have further demonstrated how infectious disease is spread through coughing. This review summarizes the neurophysiology of cough, cough induction by respiratory pathogens and inflammation, and cough-mediated disease transmission.

Herb-CMap: a multimodal fusion framework for deciphering the mechanisms of action in traditional Chinese medicine using Suhuang antitussive capsule as a case study.

Herbal medicines, particularly traditional Chinese medicines (TCMs), are a rich source of natural products with significant therapeutic potential. However, understanding their mechanisms of action is challenging due to the complexity of their multi-ingredient compositions. We introduced Herb-CMap, a multimodal fusion framework leveraging protein-protein interactions and herb-perturbed gene expression signatures. Utilizing a network-based heat diffusion algorithm, Herb-CMap creates a connectivity map linking herb perturbations to their therapeutic targets, thereby facilitating the prioritization of active ingredients. As a case study, we applied Herb-CMap to Suhuang antitussive capsule (Suhuang), a TCM formula used for treating cough variant asthma (CVA). Using in vivo rat models, our analysis established the transcriptomic signatures of Suhuang and identified its key compounds, such as quercetin and luteolin, and their target genes, including IL17A, PIK3CB, PIK3CD, AKT1, and TNF. These drug-target interactions inhibit the IL-17 signaling pathway and deactivate PI3K, AKT, and NF-κB, effectively reducing lung inflammation and alleviating CVA. The study demonstrates the efficacy of Herb-CMap in elucidating the molecular mechanisms of herbal medicines, offering valuable insights for advancing drug discovery in TCM.

DAT, deacylating autotransporter toxin, from Bordetella parapertussis demyristoylates Gαi GTPases and contributes to cough.

The pathogenic bacteria Bordetella pertussis and Bordetella parapertussis cause pertussis (whooping cough) and pertussis-like disease, respectively, both of which are characterized by paroxysmal coughing. We previously reported that pertussis toxin (PTx), which inactivates heterotrimeric GTPases of the Gi family through ADP-ribosylation of their α subunits, causes coughing in combination with Vag8 and lipid A in B. pertussis infection. In contrast, the mechanism of cough induced by B. parapertussis, which produces Vag8 and lipopolysaccharide (LPS) containing lipid A, but not PTx, remained to be elucidated. Here, we show that a toxin we named deacylating autotransporter toxin (DAT) of B. parapertussis inactivates heterotrimeric Gi GTPases through demyristoylation of their α subunits and contributes to cough production along with Vag8 and LPS. These results indicate that DAT plays a role in B. parapertussis infection in place of PTx.

Epidemiology and Prognostic Significance of Cough in Fibrotic Interstitial Lung Disease.

Rationale: Cough is a key symptom in patients with fibrotic interstitial lung disease (ILD). Objectives: This study evaluated the prevalence, longitudinal change, associations, and prognostic significance of cough severity in patients with fibrotic ILD. Methods: We included consecutive patients with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic ILD who completed the 100-mm Cough Severity Visual Analog Scale from the prospective multicenter Canadian Registry for Pulmonary Fibrosis. Baseline cough severity and associations with patient demographics and clinical factors were determined. Relationships between baseline cough severity and health outcomes were evaluated. Measurements and Main Results: Patients with IPF (n = 1,061) had higher median baseline cough severity than those with non-IPF fibrotic ILD (n = 2,825) (24 vs. 20 mm; P < 0.001), with worse cough associated with gastroesophageal reflux disease for both cohorts. Worse cough severity was independently associated with worse health-related quality of life at baseline, larger annualized decline in DlCO, development of disease progression, and reduced transplant-free survival in both IPF and non-IPF fibrotic ILD cohorts. The IPF cohort (2.2 mm; 95% confidence interval, 1.6-2.9 mm) had larger annualized increments in cough severity than the non-IPF fibrotic ILD cohort (1.1 mm; 95% confidence interval, 0.8-1.4 mm; P = 0.004). There was no difference in worsening cough over time comparing those receiving and not receiving ILD-targeted therapy or with and without lung function decline. Conclusions: Cough is common in patients with IPF and non-IPF fibrotic ILD, with increasing cough severity over time irrespective of ILD-targeted therapy. Patient-reported cough severity has prognostic implications on health-related quality of life, disease progression, and survival in fibrotic ILD.

Childhood Air Pollution Exposure Associated with Self-reported Bronchitic Symptoms in Adulthood.

Rationale: Few studies have examined the effects of long-term childhood air pollution exposure on adult respiratory health, including whether childhood respiratory effects underlie this relation. Objectives: To evaluate associations between childhood air pollution exposure and self-reported adult bronchitic symptoms while considering child respiratory health in the Southern California Children's Health Study. Methods: Exposures to nitrogen dioxide (NO2), ozone, and particulate matter <2.5 µm and <10 µm in diameter (PM10) assessed using inverse-distance-squared spatial interpolation based on childhood (birth to age 17 yr) residential histories. Bronchitic symptoms (bronchitis, cough, or phlegm in the past 12 mo) were ascertained via a questionnaire in adulthood. Associations between mean air pollution exposure across childhood and self-reported adult bronchitic symptoms were estimated using logistic regression. We further adjusted for childhood bronchitic symptoms and asthma to understand whether associations operated beyond childhood respiratory health impacts. Effect modification was assessed for family history of asthma, childhood asthma, and adult allergies. Measurements and Main Results: A total of 1,308 participants were included (mostly non-Hispanic White [56%] or Hispanic [32%]). At adult assessment (mean age, 32.0 yr; standard deviation [SD], 4.7), 25% reported bronchitic symptoms. Adult bronchitic symptoms were associated with NO2 and PM10 childhood exposures. Odds ratios per 1-SD increase were 1.69 (95% confidence interval, 1.14-2.49) for NO2 (SD, 11.1 ppb) and 1.51 (95% confidence interval, 1.00-2.27) for PM10 (SD, 14.2 µg/m3). Adjusting for childhood bronchitic symptoms or asthma produced similar results. NO2 and PM10 associations were modified by childhood asthma, with greater associations among asthmatic individuals. Conclusions: Childhood NO2 and PM10 exposures were associated with adult bronchitic symptoms. Associations were not explained by childhood respiratory health impacts; however, participants with childhood asthma had stronger associations.

Cough and Itch: common mechanisms of irritation in the throat and skin.

Cough and itch are protective mechanisms in the body. Cough occurs as a reflex motor response to foreign body inhalation, while itch is a sensation that similarly evokes a scratch response to remove irritants from the skin. Both cough and itch can last for sustained periods, leading to debilitating chronic disorders that negatively impact quality of life. Understanding the parallels and differences between chronic cough and chronic itch may be paramount to developing novel therapeutic approaches. In this article, we identify connections in the mechanisms contributing to the complex cough and scratch reflexes and summarize potential shared therapeutic targets. An online search was performed using various search engines, including PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov from 1983 to 2024. Articles were assessed for quality, and those relevant to the objective were analyzed and summarized. The literature demonstrated similarities in the triggers, peripheral and central nervous system processing, feedback mechanisms, immunologic mediators, and receptors involved in the cough and itch responses, with the neuronal sensitization processes exhibiting the greatest parallels between cough and itch. Given the substantial impact on quality of life, novel therapies targeting similar neuroimmune pathways may apply to both itch and cough and provide new avenues for enhancing their management.

Key risk factors of asthma-like symptoms are mediated through infection burden in early childhood.

BACKGROUND: Risk factors of asthma-like symptoms in childhood may act through an increased infection burden because infections often trigger these symptoms. OBJECTIVE: We sought to investigate whether the effect of established risk factors of asthma-like episodes in early childhood is mediated through burden and subtypes of common infections. METHODS: The study included 662 children from the Copenhagen Prospective Studies on Asthma in Childhood 2010 mother-child cohort, in which infections were registered prospectively in daily diaries from age 0 to 3 years. The association between established risk factors of asthma-like episodes and infection burden was analyzed by quasi-Poisson regressions, and mediation analyses were performed for significant risk factors. RESULTS: In the first 3 years of life, the children experienced a median of 16 (interquartile range, 12-23) infectious episodes. We found that the infection burden significantly (PACME < .05) mediated the association of maternal asthma (36.6% mediated), antibiotics during pregnancy (47.3%), siblings at birth (57.7%), an asthma exacerbation polygenic risk score (30.6%), and a bacterial airway immune score (80.2%) with number of asthma-like episodes, whereas the higher number of episodes from male sex, low birth weight, low gestational age, and maternal antibiotic use after birth was not mediated through an increased infection burden. Subtypes of infections driving the mediation were primarily colds, pneumonia, gastroenteritis, and fever, but not acute otitis media or acute tonsillitis. CONCLUSIONS: Several risk factors of asthma-like symptoms in early childhood act through an increased infection burden in the first 3 years of life. Prevention of infectious episodes may therefore be beneficial to reduce the burden of asthma-like symptoms in early childhood.

Sputum Metabolomic Signature and Dynamic Change of Cough Variant Asthma.

Cough variant asthma (CVA), a common reason for chronic cough, is a globally prevalent and burdensome condition. The heterogeneity of CVA and a lack of knowledge concerning the exact molecular pathogenesis has hampered its clinical management. This study presented the first sputum metabolome of CVA patients, revealed the dynamic change during treatment, and explored biomarkers related to the occurrence and treatment response of CVA. We found arginine biosynthesis, purine metabolism, and pyrimidine metabolism pathways were enriched in CVA compared to healthy controls. Part of metabolic disturbances could be reversed by anti-asthmatic medication. The levels of dipeptides/tripeptides (alanyltyrosine, Gly-Tyr-Ala, Ala-Leu, and Thr-Leu) were significantly associated with sputum Neu% or Eos% of CVA patients. Differential metabolites pre-treatment between effective and ineffective groups enriched in purine metabolism, thiamine metabolism, and arginine metabolism. 2-isopropylmalate was down-regulated in CVA patients and increased after treatment, and effective group had a lower 2-isopropylmalate level pre-treatment. Random forest and logistic regression models identified glutathione, thiamine phosphate, alanyltyrosine, and 2'-deoxyadenosine as markers for distinguishing CVA from healthy controls (all AUC > 0.8). Thiamine phosphate might also be promising for predicting therapy responsiveness (AUC = 0.684). These findings implied that disturbed mitochondrial energy metabolism and imbalanced oxidation-reduction homeostasis probably underlay the metabolic pathogenesis of CVA.

Immunization with an mRNA DTP vaccine protects against pertussis in rats.

Bordetella pertussis is a Gram-negative bacterium that is the causative agent of the respiratory disease known as pertussis. Since the switch to the acellular vaccines of DTaP and Tap, pertussis cases in the US have risen and cyclically fallen. We have observed that mRNA pertussis vaccines are immunogenic and protective in mice. Here, we further evaluated the pertussis toxoid mRNA antigen and refined the formulation based on optimal pertussis toxin neutralization in vivo. We next evaluated the mRNA pertussis vaccine in Sprague-Dawley rats using an aerosol B. pertussis challenge model paired with whole-body plethysmography to monitor coughing and respiratory function. Female Sprague-Dawley rats were primed and boosted with either commercially available vaccines (DTaP or wP-DTP), an mRNA-DTP vaccine, or mock-vaccinated. The mRNA-DTP vaccine was immunogenic in rats and induced antigen-specific IgG antibodies comparable to DTaP. Rats were then aerosol challenged with a streptomycin-resistant emerging clinical isolate D420Sm1. Bacterial burden was assessed at days 1 and 9 post-challenge, and the mRNA vaccine reduced burden equal to both DTaP and wP-DTP. Whole-body plethysmography revealed that mRNA-DTP vaccinated rats were well protected against coughing which was comparable to the non-challenged group. These data suggest that an mRNA-DTP vaccine is immunogenic in rats and provides protection against aerosolized B. pertussis challenge in Sprague-Dawley rats.

Virus-like particles displaying the mature C-terminal domain of filamentous hemagglutinin are immunogenic and protective against Bordetella pertussis respiratory infection in mice.

Bordetella pertussis, the bacterium responsible for whooping cough, remains a significant public health challenge despite the existing licensed pertussis vaccines. Current acellular pertussis vaccines, though having favorable reactogenicity and efficacy profiles, involve complex and costly production processes. In addition, acellular vaccines have functional challenges such as short-lasting duration of immunity and limited antigen coverage. Filamentous hemagglutinin (FHA) is an adhesin of B. pertussis that is included in all multivalent pertussis vaccine formulations. Antibodies to FHA have been shown to prevent bacterial attachment to respiratory epithelial cells, and T cell responses to FHA facilitate cell-mediated immunity. In this study, FHA's mature C-terminal domain (MCD) was evaluated as a novel vaccine antigen. MCD was conjugated to virus-like particles via SpyTag-SpyCatcher technology. Prime-boost vaccine studies were performed in mice to characterize immunogenicity and protection against the intranasal B. pertussis challenge. MCD-SpyVLP was more immunogenic than SpyTag-MCD antigen alone, and in Tohama I strain challenge studies, improved protection against challenge was observed in the lungs at day 3 and in the trachea and nasal wash at day 7 post-challenge. Furthermore, a B. pertussis strain encoding genetically inactivated pertussis toxin was used to evaluate MCD-SpyVLP vaccine immunity. Mice vaccinated with MCD-SpyVLP had significantly lower respiratory bacterial burden at both days 3 and 7 post-challenge compared to mock-vaccinated animals. Overall, these data support the use of SpyTag-SpyCatcher VLPs as a platform for use in vaccine development against B. pertussis and other pathogens.

Eosinophils as drivers of bacterial immunomodulation and persistence.

Traditionally, eosinophils have been linked to parasitic infections and pathological disease states. However, emerging literature has unveiled a more nuanced and intricate role for these cells, demonstrating their key functions in maintaining mucosal homeostasis. Eosinophils exhibit diverse phenotypes and exert multifaceted effects during infections, ranging from promoting pathogen persistence to triggering allergic reactions. Our investigations primarily focus on Bordetella spp., with particular emphasis on Bordetella bronchiseptica, a natural murine pathogen that induces diseases in mice akin to pertussis in humans. Recent findings from our published work have unveiled a striking interaction between B. bronchiseptica and eosinophils, facilitated by the btrS-mediated mechanism. This interaction serves to enhance pathogen persistence while concurrently delaying adaptive immune responses. Notably, this role of eosinophils is only noted in the absence of a functional btrS signaling pathway, indicating that wild-type B. bronchiseptica, and possibly other Bordetella spp., possess such adeptness in manipulating eosinophils that the true function of these cells remains obscured during infection. In this review, we present the mounting evidence pointing toward eosinophils as targets of bacterial exploitation, facilitating pathogen persistence and fostering chronic infections in diverse mucosal sites, including the lungs, gut, and skin. We underscore the pivotal role of the master regulator of Bordetella pathogenesis, the sigma factor BtrS, in orchestrating eosinophil-dependent immunomodulation within the context of pulmonary infection. These putative convergent strategies of targeting eosinophils offer promising avenues for the development of novel therapeutics targeting respiratory and other mucosal pathogens.

BECC438b TLR4 agonist supports unique immune response profiles from nasal and muscular DTaP pertussis vaccines in murine challenge models.

The protection afforded by acellular pertussis vaccines wanes over time, and there is a need to develop improved vaccine formulations. Options to improve the vaccines involve the utilization of different adjuvants and administration via different routes. While intramuscular (IM) vaccination provides a robust systemic immune response, intranasal (IN) vaccination theoretically induces a localized immune response within the nasal cavity. In the case of a Bordetella pertussis infection, IN vaccination results in an immune response that is similar to natural infection, which provides the longest duration of protection. Current acellular formulations utilize an alum adjuvant, and antibody levels wane over time. To overcome the current limitations with the acellular vaccine, we incorporated a novel TLR4 agonist, BECC438b, into both IM and IN acellular formulations to determine its ability to protect against infection in a murine airway challenge model. Following immunization and challenge, we observed that DTaP + BECC438b reduced bacterial burden within the lung and trachea for both administration routes when compared with mock-vaccinated and challenged (MVC) mice. Interestingly, IN administration of DTaP + BECC438b induced a Th1-polarized immune response, while IM vaccination polarized toward a Th2 immune response. RNA sequencing analysis of the lung demonstrated that DTaP + BECC438b activates biological pathways similar to natural infection. Additionally, IN administration of DTaP + BECC438b activated the expression of genes involved in a multitude of pathways associated with the immune system. Overall, these data suggest that BECC438b adjuvant and the IN vaccination route can impact efficacy and responses of pertussis vaccines in pre-clinical mouse models.

Population-Based Study of Pertussis Incidence and Risk Factors among Persons >50 Years of Age, Australia.

Despite vaccination programs, pertussis has been poorly controlled, especially among older adults in Australia. This longitudinal, retrospective, observational study aimed to estimate the incidence and risk factors of pertussis among persons ≥50 years of age in Australia in the primary care setting, including those with underlying chronic obstructive pulmonary disease (COPD) or asthma. We used the IQVIA general practitioner electronic medical record database to identify patients ≥50 years of age with a clinical diagnosis of pertussis during 2015-2019. Pertussis incidence rates ranged from 57.6 to 91.4 per 100,000 persons and were higher among women and highest in those 50-64 years of age. Patients with COPD or asthma had higher incidence rates and an increased risk for pertussis compared with the overall population ≥50 years of age. Our findings suggest that persons ≥50 years of age in Australia with COPD or asthma have a higher incidence of and risk for pertussis diagnosis.

Reemergence of Bordetella parapertussis, United States, 2019-2023.

To determine changes in Bordetella pertussis and B. parapertussis detection rates, we analyzed 1.43 million respiratory multiplex PCR test results from US facilities from 2019 through mid-2023. From mid-2022 through mid-2023, Bordetella spp. detection increased 8.5-fold; 95% of detections were B. parapertussis. While B. parapertussis rates increased, B. pertussis rates decreased.

Phosphorylation chemistry of the Bordetella PlrSR TCS and its contribution to bacterial persistence in the lower respiratory tract.

Bordetella species cause lower respiratory tract infections in mammals. B. pertussis and B. bronchiseptica are the causative agents of whooping cough and kennel cough, respectively. The current acellular vaccine for B. pertussis protects against disease but does not prevent transmission or colonization. Cases of pertussis are on the rise even in areas of high vaccination. The PlrSR two-component system, is required for persistence in the mouse lung. A partial plrS deletion strain and a plrS H521Q strain cannot survive past 3 days in the lung, suggesting PlrSR works in a phosphorylation-dependent mechanism. We characterized the biochemistry of B. bronchiseptica PlrSR and found that both proteins function as a canonical two-component system. His521 was essential and Glu522 was critical for PlrS autophosphorylation. Asn525 was essential for phosphatase activity. The PAS domain was critical for both PlrS autophosphorylation and phosphatase activities. PlrS could both phosphotransfer to and exert phosphatase activity toward PlrR. Unexpectedly, PlrR formed a tetramer when unphosphorylated and a dimer upon phosphorylation. Finally, we demonstrated the importance of PlrS phosphatase activity for persistence within the murine lung. By characterizing PlrSR we hope to guide future in vivo investigation for development of new vaccines and therapeutics.

Efficacy of ensitrelvir for cough due to COVID-19 Omicron variant in medical healthcare workers.

We evaluated the efficacy of ensitrelvir for the treatment of cough due to coronavirus disease 2019 Omicron variant in medical healthcare workers. A total of 633 patients were registered in this study: 206 patients chose ensitrelvir and 427 patients chose symptomatic treatment. Difference in score changes using the Leicester Cough Questionnaire between groups was 3.17 on day 4, 3.24 on day 7, and 2.46 on day 14. The analysis demonstrated a significant difference at all time points.

Identifying vagal bronchopulmonary afferents mediating cough response to inhaled sulfur dioxide in mice.

Sulfur dioxide (SO2), a common environmental and industrial air pollutant, possesses a potent effect in eliciting cough reflex, but the primary type of airway sensory receptors involved in its tussive action has not been clearly identified. This study was carried out to determine the relative roles of three major types of vagal bronchopulmonary afferents [slowly adapting receptors (SARs), rapidly adapting receptors (RARs), and C-fibers] in regulating the cough response to inhaled SO2. Our results showed that inhalation of SO2 (300 or 600 ppm for 8 min) evoked an abrupt and intense stimulatory effect on bronchopulmonary C-fibers, which continued for the entire duration of inhalation challenge and returned toward the baseline in 1-2 min after resuming room air-breathing in anesthetized and mechanically ventilated mice. In stark contrast, the same SO2 inhalation challenge generated a distinct and consistent inhibitory effect on both SARs and phasic RARs; their phasic discharges synchronized with respiratory cycles during the baseline (breathing room air) began to decline progressively within 1-3 min after the onset of SO2 inhalation, ceased completely before termination of the 8-min inhalation challenge, and then slowly returned toward the baseline after >40 min. In a parallel study in awake mice, inhalation of SO2 at the same concentration and duration as that in the nerve recording experiments evoked cough responses in a pattern and time course similar to that observed in the C-fiber responses. Based on these results, we concluded that stimulation of vagal bronchopulmonary C-fibers is primarily responsible for triggering the cough response to inhaled SO2.NEW & NOTEWORTHY This study demonstrated that inhalation of a high concentration of sulfur dioxide, an irritant gas and common air pollutant, completely and reversibly inhibited the neural activities of both slowly adapting receptor and rapidly adapting receptor, two major types of mechanoreceptors in the lungs with their activities conducted by myelinated fibers. Furthermore, the results of this study suggested that stimulation of vagal bronchopulmonary C-fibers is primarily responsible for triggering the cough reflex responses to inhaled sulfur dioxide.

Analysis of the Trends and Influencing Factors for Postoperative Cough in Patients with Esophageal Cancer Based on Patient-Reported Outcomes.

BACKGROUND: Cough is a common symptom that affects patients' recovery and quality of life after esophagectomy. This study sought to investigate trends in postoperative cough and the factors that influence cough. METHODS: A total of 208 of 225 patients were enrolled in this study. The Mandarin Chinese version of the Leicester Cough Questionnaire was administered the day before surgery and at three time points (1 week, 1 month, and 3 months) after esophagectomy to assess patient-reported outcomes. RESULTS: All patients' LCQ-MC scores after surgery were lower than presurgery (P < 0.05), with the lowest score found 1 week after esophagectomy. Factors associated with a cough 1 week after surgery included clinical stage of cancer (OR 0.782, 95% CI 0.647-0.944, P = 0.011), anastomotic position (OR 1.241, 95% CI 1.069-1.441, P = 0.005), duration of surgery (OR 0.759, 95% CI 0.577-0.998, P = 0.049), and subcarinal lymph node dissection (OR 0.682, 95% CI 0.563-0.825, P < 0.001). Factors associated with a cough one month after surgery included clinical stage (OR 0.782, 95% CI 0.650-0.940, P = 0.009), anastomotic position (OR 1.293, 95% CI 1.113-1.503, P = 0.001), and maintaining a semi-reclining position (OR 1.440, 95% CI 1.175-1.766, P < 0.001). Factors associated with a cough 3 months after surgery were clinical stage (OR 0.741, 95% CI 0.591-0.928, P = 0.009) and anastomotic position (OR 1.220, 95% CI 1.037-1.435, P = 0.016). CONCLUSIONS: This study showed that the factors influencing postoperative cough differed over time following esophagectomy. These results may warrant prospective intervention to better manage patients undergoing surgery for esophageal cancer to prevent postoperative cough.