Effects of treatment with montelukast alone, budesonide/formoterol alone and a combination of both in cough variant asthma.

BACKGROUND: Whether cysteinyl-leukotriene receptor antagonists (LTRAs) have a similar antitussive effect to inhaled corticosteroids and long-acting ß2-agonist (ICS/LABA), and that LTRA plus ICS/LABA is superior to LTRAs alone or ICS/LABA alone in treating cough variant asthma (CVA) remain unclear. This study aimed to investigate and compare the efficacy of montelukast alone, budesonide/formoterol alone and the combination of both in the treatment of CVA. METHODS: Ninety-nine CVA patients were assigned randomly in a 1:1:1 ratio to receive montelukast (M group: 10 mg, once daily), budesonide/formoterol (BF group: 160/4.5 µg, one puff, twice daily), or montelukast plus budesonide/formoterol (MBF group) for 8 weeks. The primary outcomes were changes in the cough visual analogue scale (VAS) score, daytime cough symptom score (CSS) and night-time CSS, and the secondary outcomes comprised changes in cough reflex sensitivity (CRS), the percentage of sputum eosinophils (sputum Eos%) and fractional exhaled nitric oxide (FeNO). CRS was presented with the lowest concentration of capsaicin that induced at least 5 coughs (C5). The repeated measure was used in data analysis. RESULTS: The median cough VAS score (median from 6.0 to 2.0 in the M group, 5.0 to 1.0 in the BF group and 6.0 to 1.0 in the MBF group, all p < 0.001), daytime CSS (all p < 0.01) and night-time CSS (all p < 0.001) decreased significantly in all three groups after treatment for 8 weeks. Meanwhile, the LogC5 and sputum Eos% improved significantly in all three groups after 8 weeks treatment (all p < 0.05). No significant differences were found in the changes of the VAS score, daytime and night-time CSSs, LogC5 and sputum Eos% among the three groups from baseline to week 8 (all p > 0.05). The BF and MBF groups also showed significant decreases in FeNO after 8 weeks treatment (p = 0.001 and p = 0.008, respectively), while no significant change was found in the M group (p = 0.457). Treatment with MBF for 8 weeks significantly improved the FEV1/FVC as well as the MMEF% pred and decreased the blood Eos% (all p < 0.05). CONCLUSIONS: Montelukast alone, budesonide/formoterol alone and a combination of both were effective in improving cough symptom, decreasing cough reflex sensitivity and alleviating eosinophilic airway inflammation in patients with CVA, and the antitussive effect and anti-eosinophilic airway inflammation were similar. Trial registration ClinicalTrials.gov, number NCT01404013.

Characteristics of different asthma phenotypes associated with cough: a prospective, multicenter survey in China.

BACKGROUND: Asthma is a heterogeneous disease with variable symptoms, which presents with cough either as the sole or predominant symptom with or without wheezing. We compared the clinical and pathophysiological characteristics of cough predominant asthma (CPA), cough variant asthma (CVA) and classic asthma (CA) in order to determine any differential phenotypic traits. METHODS: In 20 clinics across China, a total of 2088 patients were finally recruited, including 327 CVA, 1041 CPA and 720 CA patients. We recorded cough and wheezing visual analogue scale, Leicester cough questionnaire (LCQ) and asthma control test scores. Fractional exhaled nitric oxide (FeNO), induced sputum cell counts, and capsaicin cough challenge were also measured and compared. RESULTS: CPA patients more frequently presented with cough as the initial symptom, and laryngeal symptoms (p < 0.001), had less symptoms related with rhinitis/sinusitis and gastroesophageal reflux (p < 0.05) than CA patients. Comorbidities including rhinitis and gastroesophageal reflux were similar, while the proportion of COPD and bronchiectasis was higher in CA patients. There were no differences in FeNO levels, sputum eosinophil and neutrophil counts, FEV1 (%pred) decreased from CVA to CPA to CA patients (p < 0.001). Cough sensitivity was higher in CVA and CPA compared to CA (p < 0.001), and was positively correlated with LCQ scores. CONCLUSIONS: CVA, CPA and CA can be distinguished by the presence of laryngeal symptoms, cough sensitivity and airflow obstruction. Asthma-associated chronic cough was not associated with airway inflammation or comorbidities in our cohort. Trial registration The Chinese Clinical Trial Registration Center, ChiCTR-POC-17011646, 13 June 2017.

Efficacy of convalescent plasma for the treatment of severe influenza.

BACKGROUND: Convalescent plasma administration may be of clinical benefit in patients with severe influenza, but reports on the efficacy of this therapy vary. METHODS: We conducted a systematic review and meta-analysis assessing randomized controlled trials (RCTs) involving the administration of convalescent plasma to treat severe influenza. Healthcare databases were searched in February 2020. All records were screened against eligibility criteria, and the risks of bias were assessed. The primary outcome was the fatality rate. RESULTS: A total of 2861 studies were retrieved and screened. Five eligible RCTs were identified. Pooled analyses yielded no evidence that using convalescent plasma to treat severe influenza resulted in significant reductions in mortality (odds ratio, 1.06; 95% CI, 0.51-2·23; P = 0.87; I2 = 35%), number of days in the intensive care unit, or number of days on mechanical ventilation. This treatment may have the possible benefits of increasing hemagglutination inhibition titers and reducing influenza B viral loads and cytokine levels. No serious adverse events were reported. The included studies were generally of high quality with a low risk of bias. CONCLUSIONS: The administration of convalescent plasma appears safe but may not reduce the mortality, number of days in the intensive care unit, or number of days on mechanical ventilation in patients with severe influenza.

High-flow nasal cannula in adults with acute respiratory failure and after extubation: a systematic review and meta-analysis.

BACKGROUND: High-flow nasal cannula (HFNC) can be used as an initial support strategy for patients with acute respiratory failure (ARF) and after extubation. However, no clear evidence exists to support or oppose HFNC use in clinical practice. We summarized the effects of HFNC, compared to conventional oxygen therapy (COT) and noninvasive ventilation (NIV), on important outcomes including treatment failure and intubation/reintubation rates in adult patients with ARF and after extubation. METHODS: We searched 4 electronic databases (Pubmed, EMBASE, Scopus, and Web of Science) to identify randomized controlled trials (RCTs) comparing the effects of HFNC with either COT or NIV on rates of 1) treatment failure and 2) intubation/reintubation in adult critically ill patients. RESULTS: We identified 18 RCTs (n = 4251 patients) in pooled analyses. As a primary mode of support, HFNC treatment reduced the risk of treatment failure [Odds Ratio (OR) 0.65; 95% confidence interval (CI) 0.43-0.98; p = 0.04; I2 = 32%] but had no effect on preventing intubation (OR, 0.74; 95%CI 0.45-1.21; p = 0.23; I2 = 0%) compared to COT. When used after extubation, HFNC (vs. COT) treatment significantly decreased reintubation rate (OR 0.46; 95%CI 0.33-0.63; p < 0.00001; I2 = 30%) and extubation failure (OR 0.43; 95%CI 0.25-0.73; p = 0.002; I2 = 66%). Compared to NIV, HFNC significantly reduced intubation rate (OR 0.57; 95%CI 0.36-0.92; p = 0.02; I2 = 0%) when used as initial support, but did no favorably impact clinical outcomes post extubation in few trials. CONCLUSIONS: HFNC was superior to COT in reducing treatment failure when used as a primary support strategy and in reducing rates of extubation failure and reintubation when used after extubation. In few trials, HFNC reduced intubation rate compared to NIV when used as initial support but demonstrated no beneficial effects after extubation.

Clinical characteristics of protracted bacterial bronchitis in adults.

There are few data regarding adult protracted bacterial bronchitis (PBB). This study aimed to delineate the clinical features of PBB and evaluate their potential diagnostic value in adults. We recruited 55 adult patients with PBB and selected randomly 220 patients with non-PBB as control. A diagnosis of PBB was considered if patients had a cough lasting ≥3 weeks, no abnormalities of chest computed tomography, positive bacterial culture in sputum and/or response well to oral moxifloxacin for 1-4 weeks. The clinical manifestations and laboratory investigations were compared between PBB patients and non-PBB patients. Of the 55 patients with PBB, approximately three-fifths (34, 61.8%) were females with a median age of 46.0 years, which were similar to that of patients with non-PBB. We observed a shorter cough duration in PBB than non-PBB (median 3.0 versus 24.0 months, p < 0.001). Compared to non-PBB patients, PBB patients had higher incidences of productive cough, yellow phlegm and a sensation of mucus in the throat (SMIT) (all p < 0.001). Sputum neutrophils and lymphocytes were markedly elevated in PBB patients than non-PBB patients (both p = 0.004). Bacterial pathogens were detected in eight (28.6%) of 28 cases with PBB. The multivariate analyses showed yellow phlegm, productive cough, SMIT, increased sputum lymphocytes (≥2.3%) and cough duration ≤8.5 months with moderate sensitivity (50.9-81.8%) and moderate-high specificity (60.5-94.4%) for determining PBB. In summary, adults with PBB are characterized by productive cough, yellow phlegm, SMIT and neutrophilic airway inflammation. These cough features and increased sputum lymphocytes may be useful to indicate PBB.

Genetic Risk and Chronic Obstructive Pulmonary Disease Independently Predict the Risk of Incident Severe COVID-19.

Rationale: Both genetic variants and chronic obstructive pulmonary disease (COPD) contribute to the risk of incident severe coronavirus disease (COVID-19). Whether genetic risk of incident severe COVID-19 is the same regardless of preexisting COPD is unknown. Objectives: In this study, we aimed to investigate the potential interaction between genetic risk and COPD in relation to severe COVID-19. Methods: We constructed a polygenic risk score for severe COVID-19 by using 112 single-nucleotide polymorphisms in 430,582 participants from the UK Biobank study. We examined the associations of genetic risk and COPD with severe COVID-19 by using logistic regression models. Results: Of 430,582 participants, 712 developed severe COVID-19 as of February 22, 2021, of whom 19.8% had preexisting COPD. Compared with participants at low genetic risk, those at intermediate genetic risk (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.09-1.66) and high genetic risk (OR, 1.50; 95% CI, 1.18-1.92) had higher risk of severe COVID-19 (P for trend = 0.001), and the association was independent of COPD (P for interaction = 0.76). COPD was associated with a higher risk of incident severe COVID-19 (OR, 1.37; 95% CI, 1.12-1.67; P = 0.002). Participants at high genetic risk and with COPD had a higher risk of severe COVID-19 (OR, 2.05; 95% CI, 1.35-3.04; P < 0.001) than those at low genetic risk and without COPD. Conclusions: The polygenic risk score, which combines multiple risk alleles, can be effectively used in screening for high-risk populations of severe COVID-19. High genetic risk correlates with a higher risk of severe COVID-19, regardless of preexisting COPD.

Habitual fish oil supplementation and incident chronic obstructive pulmonary disease: Data from a prospective cohort study.

BACKGROUND: Fish oil is one of the most popular supplements in the UK and other developed countries. However, the relationship between fish oil use and chronic obstructive pulmonary disease (COPD) is unclear. OBJECTIVE: To prospectively examine the association of habitual fish oil supplementation with incident COPD risk and to evaluate potential effect modification by genetic predisposition. METHODS: This study included 484,414 participants (mean and standard deviation [SD] age: 56.5 [8.1] years) from the UK Biobank who completed a touchscreen questionnaire on habitual fish oil supplement use between 2006 and 2010 and were followed up through 2018. Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) with adjustment for sociodemographic and lifestyle behaviours, health conditions, and other potential confounding factors. A weighted genetic risk score (GRS) for COPD was derived from 112 validated single nucleotide polymorphisms. RESULTS: During a median follow-up of 9.0 years, 8860 incident COPD events were recorded. A total of 31.4% (152,230) of the study participants reported habitual fish oil supplementation at baseline. Habitual fish oil supplementation was significantly associated with a lower risk of incident COPD (adjusted HR: 0.88; 95% CI: 0.84-0.93). The association with COPD did not differ by GRS strata (P for interaction = 0.880). The results from subgroup and sensitivity analyses supported the robustness of our findings. CONCLUSIONS: Our findings suggest that habitual fish oil supplementation is associated with a lower risk of incident COPD, irrespective of genetic predisposition.

Current Status of Cell-Based Therapies for COVID-19: Evidence From Mesenchymal Stromal Cells in Sepsis and ARDS.

The severe respiratory consequences of the coronavirus disease 2019 (COVID-19) pandemic have prompted the urgent need for novel therapies. Cell-based therapies, primarily using mesenchymal stromal cells (MSCs), have demonstrated safety and potential efficacy in the treatment of critical illness, particularly sepsis and acute respiratory distress syndrome (ARDS). However, there are limited preclinical data for MSCs in COVID-19. Recent studies have shown that MSCs could decrease inflammation, improve lung permeability, enhance microbe and alveolar fluid clearance, and promote lung epithelial and endothelial repair. In addition, MSC-based therapy has shown promising effects in preclinical studies and phase 1 clinical trials in sepsis and ARDS. Here, we review recent advances related to MSC-based therapy in the context of sepsis and ARDS and evaluate the potential value of MSCs as a therapeutic strategy for COVID-19.

Is Hemoglobin Concentration a Linear Predictor of Mortality in Older Adults From Chinese Longevity Regions?

Introduction: The association patterns of hemoglobin (HB) concentrations with mortality among the longevity older adults are unclear. We aimed to evaluate the relationship among older adults form Chinese longevity regions. Methods: We included 1,785 older adults aged ≥65 years (mean age, 86.7 years; 1,002 women, 783 men) from the community-based Chinese Longitudinal Healthy Longevity Survey. We estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality using multivariable Cox proportional hazards models and Cox models with restricted cubic spline. Results: In total, 999 deaths occurred during a median follow-up of 5.4 years from 2011 to 2017. Restricted cubic spline analysis found no non-linear association between HB concentrations and all-cause mortality after a full adjustment for covariates among the older adults form longevity regions (p > 0.05 for non-linearity). The risk for all-cause mortality was significantly higher in the groups with HB concentration of <11.0 g/dL (HR: 1.37, 95% CI: 1.10-1.70) and 11.0-12.0 g/dL (HR: 1.25, 95% CI: 1.01-1.54); the risk of all-cause mortality was significantly lower in the groups with HB concentration ≥14.0 g/dL (HR: 0.76, 95% CI: 0.60-0.97) compared with the reference group (13.0-13.9 g/dL). Conclusions: Among older adults form Chinese longevity regions, HB concentrations were found to be inversely and linearly associated with all-cause mortality. Further prospective intervention trials are needed to confirm whether higher HB concentrations had a lower risk of mortality in these older adults.

The Predicative Clinical Features Associated with Chronic Cough That Has a Single Underlying Cause.

BACKGROUND: Few studies have investigated the usefulness of the clinical characteristics of cough in the diagnosis of chronic cough. OBJECTIVE: To evaluate the diagnostic value of clinical characteristics and concomitant symptoms of chronic cough in predicting its cause. METHODS: We recruited adult patients with chronic cough as a primary presenting symptom and identified those with a single underlying cause. Clinical features of cough were recorded with a custom-designed questionnaire and the relationships between clinical features and cause of cough were analyzed. RESULTS: A total of 1162 patients with a single underlying cause were enrolled. Nocturnal cough alone was a predictor of cough variant asthma (odds ratio [OR], 2.037; 95% CI, 1.003-4.139) with high specificity (97.6%) and low sensitivity (8.1%). Heartburn (OR, 2.671; 95% CI, 1.544-4.620), belching (OR, 2.536; 95% CI, 1.620-3.971), and acid regurgitation (OR, 2.043; 95% CI, 1.299-3.212) indicated gastroesophageal reflux-related cough with high specificity (85.5%-94.9%) and low sensitivity (22.8%-40.7%). Cough after meals had a high specificity (91.2%) and a low sensitivity (24.8%) for gastroesophageal reflux-related cough. Postnasal dripping (OR, 2.317; 95% CI, 1.425-3.767) and history of sinusitis (OR, 4.137; 95% CI, 2.483-6.892) were indicators for upper airway cough syndrome with high specificity (80.8% and 90.2%, respectively). Rhinitis/sinusitis-related symptoms showed moderate sensitivity (72.9%); however, they showed mild specificity (46.1%) for upper airway cough syndrome. CONCLUSIONS: Cough timing, several concomitant symptoms associated with gastroesophageal reflux or rhinitis/sinusitis, and medical history are useful to indicate common causes of chronic cough.

The spectrum, clinical features and diagnosis of chronic cough due to rare causes.

BACKGROUND: Chronic cough has many diverse causes, including common and uncommon causes. There are few comprehensive reports on rare causes of chronic cough. The purpose of this study is to determine the etiological distribution, clinical features, and diagnostic value of special examinations in patients with rare causes of chronic cough. METHODS: A retrospective analysis of patients with chronic cough who underwent medical history taking, full examination, and etiological treatment over a 13-year period was conducted. Causes of chronic cough with a prevalence of less than 3% were defined as rare causes. RESULTS: A total of 1,554 patients were enrolled, and 39 causes of chronic cough were identified. Among them, 1,055 cases were due to common causes, whereas 235 cases were due to rare causes; the causes involved 7 bodily systems. The top five rare causes were protracted bacterial bronchitis, somatic cough syndrome, diffuse panbronchiolitis, obstructive sleep apnea syndrome (OSAS), and interstitial lung disease, accounting for 67.2% of all rare causes. Among 235 patients with rare causes, causes in 90 (38.3%) patients were detected by chest high-resolution computed tomography (HRCT), in 44 (18.7%) patients by bronchoscopy/nasopharyngoscopy, and in 21 (8.9%) patients by pulmonary spirometry and diffusing capacity testing. CONCLUSIONS: Among the 31 rare causes of chronic cough in this cohort, the top five were protracted bacterial bronchitis, somatic cough syndrome, diffuse panbronchiolitis, OSAS, and interstitial lung disease. Special examinations, such as chest HRCT and bronchoscopy, should be considered after excluding common causes of chronic cough.

The efficacy and safety of azithromycin in chronic respiratory diseases related cough.

BACKGROUND: Azithromycin is potential for preventing exacerbations in chronic respiratory diseases. However, rare attention was paid to the cough symptom of such airway diseases by azithromycin intervention. We summarized the efficacy and safety of azithromycin in chronic respiratory diseases related cough. METHODS: We searched 4 electronic databases (PubMed, EMBASE, Cochrane, and Web of Science) to identify randomized controlled trials (RCTs) comparing the change of Leicester Cough Questionnaire (LCQ) score, cough visual analogue scale (VAS) and side effects of azithromycin in patients of chronic respiratory diseases with cough. RESULTS: We identified 5 RCTs (n=879 patients) in pooled analyses. Compared to placebo, azithromycin intervention had no effect in reducing cough [mean difference (MD) 0.73; 95% CI: -0.78 to 2.24; P=0.34] with significant heterogeneity (P=0.03, I2 =71%). However, heterogeneity is caused by one study. After removal of this study, azithromycin administration had shown clinically important improvement in LCQ score (MD 1.30; 95% CI: 1.15-1.46; P<0.00001; I2 =0%). In addition, no significant difference was detected in adverse events and azithromycin administration probably had less central nervous system side effects for chronic respiratory diseases with cough. CONCLUSIONS: The addition of oral azithromycin may result in significant benefit for chronic respiratory diseases related cough. Azithromycin was safe for those patients with cough.

Role of Plasma Calreticulin in the Prediction of Severity in Septic Patients.

BACKGROUND: Calreticulin has been identified to play a critical role in innate and adaptive immune responses. However, little is known about the role of calreticulin in sepsis with a characteristic of immune disorder. This study was aimed at investigating whether plasma calreticulin level increases in sepsis and its association with sepsis severity. METHODS: This retrospective analysis evaluated sepsis patients who were admitted to the intensive care unit (ICU). Healthy subjects were also included as controls. Plasma samples were collected from the patients within 48 h after ICU admission as well as the healthy subjects. Plasma calreticulin levels were measured via the enzyme-linked immunosorbent assay. RESULTS: In total, 127 sepsis patients and 40 healthy controls were included. Calreticulin was significantly increased in sepsis patients than in healthy controls. Furthermore, the level of plasma calreticulin was significantly higher in nonsurvivors than in survivors. Patients with calreticulin levels > 343.5 pg/ml showed lower cumulative survival than those with levels < 343.5 pg/ml. CONCLUSION: Calreticulin level was positively correlated with the severity of sepsis. High calreticulin level indicated poor prognosis of sepsis patients.

Age and Sex Distribution of Chinese Chronic Cough Patients and Their Relationship With Capsaicin Cough Sensitivity.

PURPOSE: An older female predominance has been reported among chronic cough patients in Western countries, which is considered to be associated with a higher cough sensitivity in females. However, the characteristics of Chinese chronic cough patients remain unclear. This study aimed to explore the age and sex distribution as well as their relationship with cough reflex sensitivity to capsaicin in Chinese chronic cough patients. METHODS: We analyzed the demographic features of 1,882 consecutive chronic cough patients who attended our cough clinic in Guangzhou, China. Cough sensitivity to capsaicin, which was defined as the lowest concentration of capsaicin causing 5 coughs or more (C5), was measured in 539 of the 1,882 patients and 68 healthy volunteers. RESULTS: The mean age of the patients was 43.0 ± 13.7 years and patients aged <50 years accounted for more than two-thirds of the study population. Around 87% of the patients were never-smokers. The proportion of females (51.5%) was almost equal to that of males (48.5%). The pattern of the age and sex distribution was consistently reflected within most common causes of chronic cough, while a female predominance was shown in patients with cough-variant asthma and patients aged ≥50 years. Female patients had higher cough sensitivity to capsaicin than male patients (log C5: 1.58 ± 0.84 vs. 2.04 ± 0.84 µmol/L, P = 0.001), and patients aged ≥50 years had higher cough sensitivity to capsaicin than patients aged <50 years. CONCLUSIONS: In China, patients with chronic cough have a roughly equal sex distribution and a middle-aged predominance, irrespective of a higher cough sensitivity to capsaicin in females and older patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02591550.

[Study on the relationship between breast cancer resistance protein expression and 5-fluorouracil resistance].

OBJECTIVE: To screen breast cancer resistance protein BCRP-mediated resistance agents and to investigate the relations between BCRP expression and drug resistance. METHODS: MT assay was performed to screen BCRP-mediated resistant agents with established BCRP expression cell model. While, the high performance liquid chromatography (HPLC) assay was administrated to measure the related dosage of intracellular retention resistant agents. The BCRP expression was investigated by both real-time RT-PCR and immunohistochemistry (IHC) assay in 140 clinical breast cancer tissue specimens. Chemosensitivity to resistant agents for clinical breast cancer tissue specimens was analyzed by MT assay. The Nonparametric variance statistics method was used to analyze the correlations between clinical breast cancer tissue of BCRP expression and drug resistance. RESULTS: MT assay showed that increasing resistance of 5-fluorouracil (5-Fu) climbed with the increases of the BCRP expressions by 10.58 times (P < 0.05, n = 3) in cell model. HPLC assay also proved that a significant negative correlation between the intracellular retention dose of 5-Fu with different expression of BCRP (r = -0.897, P < 0.05, n = 3). Forty-seven tissue specimens of BCRP-positive expression were rapidly determined by using both real-time RT-PCR and IHC in 140 clinical breast cancer tissue specimens. Subsequently, the resistance index (RI) for 47 BCRP-positive clinical breast cancer tissues to 5-Fu was shown from 7 to 12 times compared with normal cancer-side tissues through MT assay. The statistical correlation between BCRP expression and 5-Fu resistance was observed in clinical breast cancer tissue specimens (R2 = 0.8124, P < 0.01). CONCLUSION: This study results showed that there is a significant relationship between BCRP expression and 5-Fu resistance. Moreover, the results suggest that the chemotherapy scheme could be optimized on BCRP-positive expression breast cancer patients.