20S-Ginsenoside Rh2, the major bioactive saponin in Panax notoginseng flowers, ameliorates cough by inhibition of NaV1.7 and TRPV1 channel currents and downregulation of TRPV1 expression.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng flowers, which are the buds of the traditional Chinese medicinal herb Sanqi, are widely used in China for their cough-ameliorating properties, with demonstrated therapeutic effects in the treatment of both acute and chronic coughs. However, both the antitussive mechanism and active compound basis of P. notoginseng flowers remain poorly understood. AIM OF THE STUDY: We investigated the antitussive effects of P. notoginseng flowers, identified the bioactive constituents responsible for alleviating cough symptoms, and elucidated the underlying pharmacological mechanisms. MATERIALS AND METHODS: We analyzed the major chemical constituents of aqueous extracts of P. notoginseng flowers using liquid chromatography-mass spectrometry and quantitatively analyzed the key component, 20S-ginsenoside Rh2, using high-performance liquid chromatography. Using a cough reflex model in healthy mice and an ovalbumin-induced, highly sensitive guinea pig cough model, we verified the suppressive effects of P. notoginseng flowers and their saponin constituents on coughing. Furthermore, we explored the mechanisms of action of the key ion channels, NaV1.7 and TRPV1, using whole-cell patch-clamp techniques and molecular docking. Finally, the therapeutic mechanisms of P. notoginseng flowers on pathological cough were revealed using hematoxylin and eosin staining, immunohistochemistry, and western blotting. RESULTS: The active components of P. notoginseng flowers were primarily protopanaxadiol-type saponins, among which 20S-ginsenoside Rh2 had the highest content (51.46 mg/g). In the mouse model, P. notoginseng flowers exhibited antitussive effects comparable to those of pentoxyverine citrate. Although its main saponin component, 20S-ginsenoside Rh2, showed slightly weaker effects, it still demonstrated concentration-dependent inhibition of channel activity. The whole-cell patch-clamp technique and virtual molecular docking showed that Rh2 might exert its effects by directly binding to the NaV1.7 and TRPV1 channels. In the guinea pig model, P. notoginseng flowers and their saponin components not only reduced cough frequency and prolonged the latency period before cough onset, but also significantly inhibited tracheal and pulmonary inflammation and the overexpression of TRPV1. CONCLUSIONS: 20S-Ginsenoside Rh2, the major bioactive saponin in P. notoginseng flowers, exhibits potent antitussive effects. The potential mechanism of action of 20S-Ginsenoside Rh2 in the treatment of cough may involve inhibiting NaV1.7 and TRPV1 channel currents through direct binding to core protein active sites and downregulating TRPV1 expression.

Amygdalar involvement in respiratory dysfunction.

The brainstem has long been recognized as the major respiratory control center, but it has become increasingly appreciated that areas upstream of the brainstem modulate respiration and airway defensive behaviors. This review aims to define the role of the amygdala, a key temporal brain region essential for limbic function, in respiration and airway defenses. We summarize literature describing roles for the amygdala in control of respiration, swallow, cough, airway smooth muscle contraction, and mucus secretion. We emphasize the need to understand how the amygdala regulates these functions both at a local scale and network scale and identify knowledge gaps for current and future investigations. Lastly, we highlight literature suggesting that amygdala dysfunction may contribute to respiratory dysfunction.

Laryngopharyngeal Reflux Pathophysiology, Clinical Presentation, and Management: A Narrative Review.

Laryngopharyngeal reflux (LPR) is a common and often misinterpreted clinical entity responsible for various symptoms affecting the upper aerodigestive tract. This narrative literature review aims to review the pathophysiology, symptoms, and management of LPR, emphasizing the emerging understanding of gastric content reflux in aerodigestive tissue irritation. Understanding the pathophysiology of LPR will allow general practitioners and specialists to accurately recognize and treat a condition that causes substantial morbidity in the affected patients. Using evidence-based findings from randomized controlled trials, clinical studies, and meta-analyses, the present investigation aims to outline and unify previous research into LPR. A review of anatomical structures, pathogenic mechanisms, endoscopic findings in LPR, and clinical manifestations and treatment options are also discussed. Though controversy around the diagnosis and management of LPR persists, emerging research in cellular damage and diagnostic tools promises to provide increasingly accurate and reliable modalities for characterizing LPR. Hopefully, future research will unify the field and provide overarching guidelines for both primary care and specialists. The present investigation provides an integrated perspective on LPR, a clinically prevalent and complex disease.

A rare case of foreign body inhalation masquerading as calcification in the right upper lobe suggestive of tuberculosis.

Airway foreign bodies are a common clinical emergency, predominantly occurring in children, with adults less frequently affected. Airway foreign bodies can cause a variety of symptoms, with adults more commonly presenting with cough, a factor that often leads to misdiagnosis or missed diagnosis. Due to anatomical features, most foreign bodies are more likely to be aspirated into the right bronchus, especially the right lower and middle bronchi, with the right upper lung less commonly involved. Here, we report a case where a small, sharp foreign body (a chicken bone) became lodged at the opening of the right upper lobe bronchus in a healthy middle-aged male. Initially, the foreign body was mistaken for an old tuberculous calcification due to recurrent coughing and shortness of breath over two years, misdiagnosed as chronic obstructive pulmonary disease. Eventually, the foreign body was successfully removed. Therefore, the possibility of foreign body inhalation should not be overlooked in adult patients presenting with recurrent cough symptoms.

Co-Existing Fungi: An Unforeseen Combo Creating a Dilemma in Diagnostic Morale.

Mucormycosis is a rare fungal infection belonging to Mucorales order fungi. Rhino-cerebral form is more noted in patients with diabetes mellitus, but pulmonary mucormycosis is a rare manifestation with hematological malignancy, malignant tumors, and transplant recipient patients. Aspergillus species are also known to cause allergic bronchopulmonary aspergillosis, aspergilloma, chronic pulmonary aspergillosis, and invasive aspergillosis in immunocompromised individuals. We report a case of pulmonary mucormycosis superimposed with aspergillus infection presenting in an immunocompromised patient with metastatic prostate cancer on chemotherapy, initially misdiagnosed as aspergillus infection.

Association of SLCO1B1 gene variants with angiotensin-converting enzyme inhibitor-induced cough in a Pakistani hypertensive cohort.

Background: Angiotensin-converting enzyme inhibitors (ACEIs) are prescribed for individuals with high cardiovascular (CV) risk; however, persistent cough limits the use of ACEIs in a large number of patients. The current study aimed to identify the genetic variants in the SLCO1B1 gene that might be associated with ACEI-related cough in a Pakistani hypertensive population. Methods: A prospective cohort study was conducted at a tertiary care hospital in Pakistan. A total of 74 patients who had been treated with ACEIs were recruited through a convenient sampling method. The study was approved by the Institutional Review Board & Ethics Committee of the Shifa International Hospital, Islamabad. Patients provided 2 ml of blood for sequencing after signing informed consent. Partial gene sequencing of SLCO1B1 was carried out to find single nucleotide polymorphisms (SNPs) and haplotypes. Results: It was found, through a structured questionnaire, that thirty-eight (38) patients experienced cough within 2 weeks of ACEI administration and were considered as a case group (cough), and thirty-six (36) patients were considered as a control group (no cough). The incidence of cough was 51%. We found six different SNPs and 9 haplotypes in the partial gene sequences of SLCO1B1. Haplotype H4 was associated significantly with cough after adjusting for sex and smoking status. Other SNPs and haplotypes were not significantly associated with ACE-Is-induced cough. Conclusion: These findings emphasize the significance of SLCO1B1 genetic variants, specifically H4, as a potential predictor of ACEI-induced cough. It could be included in clinical practice as a possible risk factor for ACEI-induced cough once confirmed in larger clinical trials with bigger sample sizes. The replication of these findings in larger and more diverse populations is likely to contribute to the therapeutic use of ACEIs by predicting ACEI-induced cough.

Pertussis Epidemiology in Children: The Role of Maternal Immunization.

In the last twelve months, a significant global increase in pertussis cases has been observed, particularly among infants under three months of age. This age group is at the highest risk for severe disease, hospitalization, and death. Maternal immunization with the Tdap vaccine during pregnancy has been recommended to protect newborns by transferring maternal antibodies transplacentally. This review examines the current epidemiology of pertussis, the importance of preventing it in young children, and the effectiveness of maternal immunization. Despite the proven benefits of maternal vaccination, which has been found effective in pertussis prevention in up to 90% of cases, coverage remains suboptimal in many countries. Factors contributing to low vaccination rates include vaccine hesitancy due to low trust in health authority assessments, safety concerns, practical barriers to vaccine access, and the impact of the COVID-19 pandemic, which disrupted routine vaccination services. The recent increase in pertussis cases may also be influenced by the natural cyclic nature of the disease, increased Bordetella pertussis (Bp) activity in older children and adults, and the genetic divergence of circulating Bp strains from vaccine antigens. Given the high efficacy of maternal vaccination in preventing pertussis in infants, increasing coverage rates is crucial. Efforts to improve vaccine uptake should address barriers to access and vaccine hesitancy, ensuring consistent immune protection for the youngest and most vulnerable populations. Enhanced maternal vaccination could significantly reduce the incidence of whooping cough in infants, decreasing related hospitalizations and deaths.

Choosing the optimal combination of lungs lobe evaluation during focused pulmonary ultrasonography in calves.

Bovine respiratory disease (BRD) poses significant challenges on beef and dairy farms, impacting mortality rates, animal welfare, and production efficiency. Although pulmonary ultrasonography is highly sensitive and specific for monitoring lung lesions and diagnosing BRD, its practical application could be optimized by focusing on the most commonly affected lung lobes. This study first evaluated the efficacy of focused lung ultrasonography for diagnosing BRD in calves, examining individual lung lobes and their associations versus the extensive lung scanning under various disease prevalence scenarios. Then, the relationship between individual and combined clinical respiratory signs vs lung consolidation was analyzed. In a combined analysis, 193 Holstein calves from a longitudinal study and 112 Angus calves from a cross-sectional study underwent a total of 1265 complete bilateral thoracic ultrasonographic evaluations from 1 to 6 mo of age. Then, it was assessed the agreement and sensitivity of specific lung lobe combinations compared with the findings from total lung ultrasonography. The Classification and Regression Tree (CART) algorithm was used to suggest an optimal examination sequence, and logistic regression was applied to associate specific clinical signs with the presence of lung consolidation adjusting for breed and calf age. Findings reveal that the most sensitive areas are cranial (K: 0.867; Se: 84.7%) and the caudal (K: 0.433; Se: 40.3%) portions of the right cranial lobe, the caudal portion (K: 0.235; Se: 20.6%) of the left cranial lobe, and the middle lobe (K: 0.25; Se: 22%). The optimal lobe combinations for focused lung ultrasonography were identified as the right cranial lobe paired with either the left cranial lobe or the middle lobe. Focused techniques achieved sensitivity over 94% and maintained good agreement. Using these focused techniques were relatively robust to various true lung consolidation scenarios. CART analysis recommended initiating examinations with the right cranial lobe, proceeding to the left cranial lobe, and concluding with the middle lobe. While spontaneous cough was linked to pneumonia presence, reliance on a single clinical sign is not advised due to low sensitivity (26.8%) and high specificity (85.4%); it should merely prompt further ultrasound assessment. In conclusion, focused lung ultrasonography, especially utilizing the right cranial lobe in conjunction with the left cranial lobe or the middle lobe, emerged as effective strategies for focused pulmonary ultrasonography, preserving the accuracy of the results.

Effects of Azithromycin on Blood Inflammatory Gene Expression and Cytokine Production in Sarcoidosis.

INTRODUCTION: In sarcoidosis granulomas, monocyte-derived macrophages are activated by pro-inflammatory cytokines including TNF and IL-6. Current drug treatment for sarcoidosis aims to suppress inflammation but disabling side effects can ensue. The macrolide azithromycin may be anti-inflammatory. We aimed to determine whether treatment with azithromycin affects blood inflammatory gene expression and monocyte functions in sarcoidosis. METHODS: Blood samples were collected from patients with chronic pulmonary sarcoidosis enrolled in a single arm, open label clinical trial who received oral azithromycin 250 mg once daily for 3 months. Whole blood inflammatory gene expression with or without LPS stimulation was measured using a 770-mRNA panel. Phenotypic analysis and cytokine production were conducted by flow cytometry and ELISA after 24h stimulation with growth factors and TLR ligands. mTOR activity was assessed by measuring phosphorylated S6RP. RESULTS: Differential gene expression analysis indicated a state of heightened myeloid cell activation in sarcoidosis. Compared with controls, sarcoidosis patients showed increased LPS responses for several cytokines and chemokines. Treatment with azithromycin had minimal effect on blood gene expression overall, but supervised clustering analysis identified several chemokine genes that were upregulated. At the protein level, azithromycin treatment increased LPS-stimulated TNF and unstimulated IL-8 production. No other cytokines showed significant changes following azithromycin. Blood neutrophil counts fell during azithromycin treatment whereas mononuclear cells remained stable. Azithromycin had no detectable effects on mTOR activity or activation markers. CONCLUSION: Blood myeloid cells are activated in sarcoidosis, but azithromycin therapy did not suppress inflammatory gene expression or cytokine production in blood. TRIAL REGISTRATION: EudraCT 2019-000580-24 (17 May 2019).

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.

Are Otolaryngologists Seeing More Cough? Longitudinal Trends and Patterns.

OBJECTIVE: Otolaryngologists play an increasing role in managing cough, but little data exists examining the demographics of this patient population and the referral patterns that influence their access to care. This study sought to elucidate these factors using a longitudinal, nationwide database to minimize sampling bias and identify trends representative of the national population. STUDY DESIGN: Nationally representative survey. SETTING: National Ambulatory Medical Care Survey (NAMCS). METHODS: Visits with a diagnosis and chief complaint of cough between 2005 and 2019 in NAMCS were examined. Univariable and multivariable analyses were performed to compare patient demographics between visits to surgical specialists, medical specialists, and primary care physicians. RESULTS: Otolaryngologists made up more than 84% of surgical specialist visits. There was a 0.52% [0.20%-0.84%] increase per year in the proportion of visits attributed to surgical specialists. Based on a sensitivity analysis of the multivariable model, Hispanic patients (adjusted odds ratio, aOR: 0.88 [0.78-0.99] vs White) and patients living outside of metropolitan areas (aOR: 0.77 [0.61-0.99] vs living within) were less likely to see surgical specialists than primary care doctors for their cough. Patients who were referred (aOR: 1.47 [1.28-1.72] vs not referred) and with chronic cough (aOR: 1.47 [1.23-1.75] vs acute/subacute) were more likely to see a surgical specialist. CONCLUSION: Otolaryngologists are increasingly called upon to evaluate and consider treatment for cough. Identifying patient groups with limited access underscores the need for enhanced education about otolaryngologists' roles and integrated care approaches to improve access to specialized cough treatment. LEVEL OF EVIDENCE: Level 4.

Chronic Cough Related to Thyroid Cartilage Superior Cornu Abnormality.

Chronic cough is a common troublesome symptom in otolaryngology head and neck surgery practice. In rare cases, chronic cough may be related to anatomical abnormalities. In this article, we report the history of a 64-year-old female with a chronic course due to a curved superior cornu of the thyroid cartilage and related irritation of the laryngeal superior nerve. The cough was atypical and resolved after the surgical resection of the abnormal cornu. There was no recurrence at 9 months post-surgery. The findings of the present case report highlight the need to explore the laryngeal anatomy in patients with chronic cough to identify potential abnormalities, which may be treated surgically.

Diagnosed and undiagnosed cough-related stress urinary incontinence in women with refractory or unexplained chronic cough: Its impact on general health status and quality of life.

Background: Stress urinary incontinence (SUI) is common in women with chronic cough but may be overlooked. Objective: To determine the frequency of underdiagnosis of cough-related SUI and its impact on women's general health status and quality of life (QoL). Methods: Data were analyzed for 147 women with refractory/unexplained chronic cough. Relevant details were collected from clinical charts and a patient-completed survey. General health status was assessed using the EuroQoL visual analogue scale (EQ-VAS) and QoL with the cough-specific Leicester Cough Questionnaire (LCQ). Results: Women were classified into diagnosed (n = 32; 21.8%) or undiagnosed (n = 33; 22.4%) cough-related SUI, and no SUI (n = 82; 55.6%) groups. Women with versus without cough-related SUI perceived poorer health status and greater impact of cough on everyday lives. Mean LCQ scores were significantly lower in cough-related SUI groups versus no SUI group. In multivariate analysis, the presence of cough-related SUI was significantly associated with lower EQ-VAS and LCQ scores. Conclusion: In our cohort, 44% of women had cough-related SUI, and half were undiagnosed. Irrespective of diagnosis, impairment to everyday lives and QoL was similar. Diagnosing cough-related SUI may identify additional patients who can benefit from therapies to suppress cough and improve QoL.

The impact of expiratory muscle strength training on voluntary cough effectiveness in Huntington's disease.

BACKGROUND AND PURPOSE: Dysfunction of the airway defence system in Huntington's disease (HD) is a significant but often overlooked problem. Although expiratory muscle strength training (EMST) is frequently utilized in cough effectiveness treatment, its specific impact in HD patients has not yet been explored. This study investigated the effects of EMST on voluntary peak cough flow (vPCF) in HD patients and evaluated the retention of potential gains post-intervention. METHODS: In this prospective case-controlled trial, 29 HD patients completed an 8-week wait-to-start period, which served to identify the natural development of expiratory muscle strength and vPCF. This was followed by 8 weeks of EMST training and an additional 8 weeks of follow-up. The study's outcome parameters, vPCF and maximum expiratory pressure (MEP), were measured against those of age- and sex-matched healthy controls. RESULTS: Huntington's disease patients had significantly lower MEP (p < 0.001) and vPCF (p = 0.012) compared to healthy controls at baseline. Following the EMST, significant improvements in MEP (d = 1.39, p < 0.001) and vPCF (d = 0.77, p = 0.001) were observed, with HD patients reaching the cough performance levels of healthy subjects. However, these gains diminished during the follow-up, with a significant decline in vPCF (d = -0.451, p = 0.03) and in MEP (d = -0.71; p = 0.002). CONCLUSIONS: Expiratory muscle strength training improves expiratory muscle strength and voluntary cough effectiveness in HD patients, but an ongoing maintenance programme is necessary to sustain the improvements.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): a family with five affected sibs from Turkey.

BACKGROUND: Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), a relatively common cause of late-onset progressive ataxia, is a genetic disease characterised by biallelic pentanucleotide AAGGG repeat expansion in intron 2 of the replication factor complex subunit 1 gene. Herein, we describe the first molecularly confirmed CANVAS family with five affected siblings from Turkey. CASE PRESENTATION: The family comprised seven siblings born from healthy non-consanguineous parents. CANVAS phenotype was present in five of them; two were healthy and asymptomatic. Chronic cough was the first symptom reported in all five siblings, followed by the development of sensory symptoms, oscillopsia and imbalance. Clinical head impulse test (HIT) was positive in all cases and video HIT performed on three patients revealed very low vestibulo-ocular reflex gains bilaterally. Magnetic resonance imaging and nerve conduction studies revealed cerebellar atrophy and sensory neuronopathy, respectively. RP-PCR confirmed the homozygous presence of the AAGGG repeat expansion in all five cases. CONCLUSION: Genetic screening for CANVAS should be considered in all patients with late-onset ataxia, sensory disturbances and vestibular involvement, especially in the presence of chronic cough.

Postoperative exacerbated cough hypersensitivity syndrome induces dramatic respiratory alkalosis, lactatemia, and electrolyte imbalance.

BACKGROUND: The perioperative management of patients with chronic cough or cough hypersensitivity syndrome and its sometimes severe effects is currently under-researched and under-reported. CASE PRESENTATION: A 46-year-old female patient with a history of chronic cough and Cough Hypersensitivity Syndrome. After laparoscopic hiatoplasty and anterior fundoplication under general anesthesia, experienced a pronounced exacerbation of coughing symptoms. Despite prompt and extensive treatment involving antitussives, inhalants, anxiolytics, and sedatives, the symptoms remained uncontrollable. Within a few hours, the patient developed a respiratory alkalosis with severe and life-threatening electrolyte shift (pH 7.705, pCO2 1.72 kPa, K+ 2.1 mmol/l). Lactatemia lasted for more than 12 hours with values up to 6.6 mmol/l. Acute bleeding, pneumothorax, and an acute cardiac event were ruled out. Deep analgosedation and inhalation of high-percentage local anesthetics were necessary to manage the clinical symptoms. CONCLUSIONS: This case highlights the challenging nature of chronic cough and hypersensitivity syndrome perioperatively. A tailored anesthesiologic approach, exclusion of other provoking medical problems, and knowledge of possible management and treatment options are key.

Small airway inflammation in atypical asthma.

Background: Less attention has been paid to the pathophysiological changes in atypical asthma such as cough variant asthma (CVA) and chest tightness variant asthma (CTVA). The obstruction of large and small airways is the important component in the development of asthma. We investigated whether small airway inflammation (SAI) induced small airway dysfunction (SAD) in these atypical asthmatics. Methods: Six hundred and eighty-six patients were enrolled and analyzed in the study. The partitioned airway inflammation was assessed by fractional exhaled nitric oxide (FeNO), such as FnNO, FeNO50, FeNO200, and calculated alveolar fraction of exhaled NO (CaNOdual). Correlations between exhaled NOs and SAD-related variables were assessed, whereas cell classification was evaluated by Spearman's rank tests. Classic asthma, CVA, and CTVA about potential risk were conducted using binary logistic regression models. Results: The whole airway inflammation increased in classic and atypical asthma than controls, whereas the central and peripheral airway inflammation in the CVA and CTVA groups increased compared with the classic asthma group. Smoking exposure was found to increase the central and peripheral airway inflammation in patients with asthma. The exhaled NO of FeNO50 and FeNO200 was associated with SAD in classic asthma, but not in CVA and CTVA. FeNO200 was the main risk (adjusted odds ratio [OR], 1.591; 95 % CI, 1.121-2.259; P = .009) in classic asthma and (adjusted OR, 1.456; 95 % CI, 1.247-1.700; P = .000) in CVA. The blood eosinophil levels were correlated with FeNO50 and FeNO200 in classic asthma and atypical asthma. Conclusion: More severe inflammatory process was present in central and peripheral airways in CVA and CTVA, which might reflect a pre-asthmatic state. SAI was the predominant risk factor in the development of asthma before SAD.

Pulmonary infection by Mycobacterium riyadhense: first case report in United Arab Emirates.

Mycobacterium riyadhense is an emerging slowly growing species that belongs to the group of nontuberculous mycobacteria (NTM) with approximately 20 cases reported worldwide. We highlight the first case of pulmonary infection by Mycobacterium riyadhense in United Arab Emirates (UAE). A 44-year-old female presented with chronic productive cough; a bronchial breathing pattern was appreciated on auscultation of her right upper lung. She was treated multiple times with allergic medications and antibiotics. Thorough investigations revealed Mycobacterium riyadhense and antitubercular drugs were started, eventually she was cured, however she had multiple relapses later. This case report holds a significant potential to make considerable contribution to the diagnosis of NTM, primarily because it presents the first documented case in UAE, as well as insights on how to address possible similar cases in the future.