Alpha-1 deficiency in severe asthma patients.

Alpha-1 antitrypsin (AAT) deficiency, an autosomal co-dominant condition, decreases protein concentration and activity at both serum and tissue levels. Few studies investigated whether the type of SERPINA1 gene phenotype in patients with severe asthma can influence symptoms and disease control during follow-up.To assess whether the presence of a non-MM genotype of SERPINA1 in patients with severe asthma is associated with disease control, systemic and airway inflammation, lung function and comorbidities prevalence compared to severe asthma patients with a homozygous genotype (MM).Asthmatic patients belonging to Global Initiative for Asthma (GINA) step 5 were retrospectively analysed in an Italian reference asthma clinic. We collected clinical, biological and functional variables at baseline and for the three following years.Out of 73 patients enrolled, 14 (19.18%) were non-MM and 59 (80.8%) were MM. Asthmatics with non-MM genotype had lower serum AAT concentration (P = 0.004) and higher emphysema prevalence than the MM group (P = 0.003) at baseline. During follow up, only MM patients showed a significant improvement of both ACQ-6 score (P < 0.0001) and eosinophilic systemic inflammation (P < 0.0001).Our findings emphasise the importance of a screening for AAT deficiency in severe asthma, as alleles mutation may influence patient's follow-up..

Lung consolidation in a young-age active smoker: An unexpected diagnosis.

A 29-year-old man presented to Emergency Department with nonspecific symptoms. Through a series of radiological and invasive diagnostic studies we finally reach an unexpected diagnosis of hypersentivity pneumonitis; this is a complex and heterogeneous disease which diagnosis can be challenging as its clinical, radiologic and histopathologic features overlap with those of other interstitial lung diseases (ILDs). Diagnosing an ILD is a dynamic process, and that is the reason why complex cases discussed in a multidisciplinary team may need to be reconsidered in light of evolution of the disease and the results of the performed exams with a flexible approach.

Where are we with the use of N-acetylcysteine as a preventive and adjuvant treatment for COVID-19?

OBJECTIVE: As N-acetylcysteine (NAC) is promising as a re-purposed drug for the adjunctive or supportive treatment of serious COVID-19, this article aimed to describe current evidence. MATERIALS AND METHODS: A search was performed in PubMed/Medline for "NAC", "viral Infection", COVID-19", oxidative stress", "inflammation", retrieving preclinical and clinical studies. RESULTS: NAC is a pleiotropic molecule with a dual antioxidant mechanism; it may neutralize free radicals and acts as a donor of cysteine, restoring the physiological pool of GSH. Serious COVID-19 patients have increased levels of reactive oxygen species (ROS) and free radicals and often present with glutathione depletion, which prompts a cytokine storm. NAC, which acts as a precursor of GSH inside cells, has been currently used in many conditions to restore or protect against GSH depletion and has a wide safety margin. In addition, NAC has anti-inflammatory activity independently of its antioxidant activity. CONCLUSIONS: Clinical and experimental data suggest that NAC may act on the mechanisms leading to the prothrombotic state observed in severe COVID-19.

COVID-19 infection in severe Alpha 1-antitrypsin deficiency: Looking for a rationale.

The clinical manifestations of COVID-19 are heterogeneous: 46.4% of patients admitted into hospital reported to have at least one comorbidity. Comorbidities such as COPD, diabetes, hypertension and malignancy predispose patients with Covid-19 to adverse clinical outcomes. Alpha 1-antitrypsin deficiency (AATD) is a genetic disorder caused by pathological mutation(s) in the SERPINA1 gene resulting in an imbalance in proteinase activity which may lead to premature emphysema and COPD. Our aim was to investigate whether people with severe AAT deficiency (AATD) have an increased risk of (severe) COVID-19 infection. We collected data on COVID-19 symptoms, laboratory-confirmed infection, hospitalization and treatment by means of a telephone survey, directly administered to Italian severe AATD subjects in May 2020. We then compared our findings with data collected by the Istituto Superiore di Sanità on the total population in Italy during the same period. We found an higher frequency of SARS-CoV-2 infection in our cohort (3.8%) compared to national data regarding infection, thus giving severe AATD a relative risk of 8. 8 (95%CI 5.1-20,0; p<0.0001) for symptomatic SARS-CoV-2 infection. Moreover, the relative risk (RR) was higher in AATD patients with pre-existing lung diseases (RR 13.9; 95%CI 8.0-33.6; p<0.001), but with a similar death rate (1 in 8, 12.5%) compared to the general population (13.9%; RR 0.9). These preliminary findings highlight the importance of close surveillance in the spread of COVID-19 in patients with severe AATD and underlines the need for further studies into the role of the antiprotease shield in preventing SARS-Cov-2 infection.

The prevalence of sleep impairments and predictors of sleep quality among patients with asthma.

BACKGROUND: Sleep is a significant dimension of daily life. However, only a few studies have examined the sleep quality of asthmatics in a real-world clinical settings. OBJECTIVE: This study is aimed to estimate the prevalence of sleep impairments among asthmatic patients and examine the relationship between sleep quality, asthma control, rhinitis symptoms, and sociodemographic characteristics. METHODS: The present study adopted the observational cross-sectional research design that has been designed by the Italian Respiratory Society and used valid assessments to measure the study variables. RESULTS: Data from 1150 asthmatic patients (mean age 51.01 years ± 16.03) were subjected to analysis. 58.3% of the patients had impaired sleep quality (Pittsburgh Sleep Quality Index [PSQI] total scores > 5), and their mean PSQI score was 5.68 (SD = 3.4). A significant correlation emerged between sleep quality and asthma control (p = 0.0001) and a significant albeit weak correlation emerged between PSQI total scores and Total 5 Symptoms Score (r = 0.24, p = 0.0001). Sleep quality was significantly associated health-related quality of life [HRQoL]. (r = 0.50, p < 0.001). After exclusion of patients at risk for Obstructive Sleep Apnea Syndrome (OSAS) and Gastro Esophageal Reflux Disease (GERD), the most important determinants of PSQI score were HRQoL, In the entire sample asthma control is the strongest predictor of both sleep quality and HRQoL. CONCLUSIONS: The results of this real-world study highlight the prevalence, impact and predictors of sleep disturbances in asthmatic patients and suggest the need for physicians to detect poor sleep quality.

What drives inhaler prescription for asthma patients? Results from a real-life retrospective analysis.

BACKGROUND: The choice of inhaler device for asthma patients depends upon multiple attributes. We investigated factors that may drive general practitioners (GPs) and respiratory specialists in the prescription of inhaler devices for asthma patients who initiated inhalation therapy. METHODS: We retrospectively analysed prescriptions by GPs and respiratory specialists to asthma patients commencing inhaled corticosteroid/long-acting ß2-agonist combination therapy available as both pressurised metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs). Patient characteristics were compared by device and multivariate analysis was used to model the likelihood of receiving a pMDI as opposed to a DPI in order to identify drivers for prescription. A sample of the respiratory specialists completed an ad-hoc survey of their perceived success in achieving asthma control in their patients and barriers to attaining full control. RESULTS: Prescription of a particular inhaler device was unrelated to the characteristics of the patients. Multivariate analysis revealed that the main driver for the choice of inhaler device was the medication (Odds Ratio and 95% Confidence Interval, respectively for GPs and specialists: 0.19 [0.16-0.23]; 0.17 [0.08-0.37]). Specialists perceived asthma as being inadequately controlled in 41% of their patients, and considered patients' difficulties in using DPIs and pMDIs as instrumental in this, citing a need for a novel, more effective inhaler technology. CONCLUSION: Physicians choose inhaler devices according to the prescribed drugs and not to the characteristics of the individual patient. This may reflect a lack of confidence in existing inhaler devices and underlines the need for technologies, which are more reliable and easier to use by patients.

The course of asthma during pregnancy in a recent, multicase-control study on respiratory health.

BACKGROUND: Over the years it has been widely stated that approximately one-third of asthmatic women experience worsening of the disease during pregnancy. However, the literature has not been reviewed systematically and the meta-analytic reviews include old studies. This study aimed to examine whether the prevalence of worsening asthma during pregnancy is still consistent with prior estimate or it has been reduced. METHODS: A detailed Clinical Questionnaire on respiratory symptoms, medical history, medication, use of services, occupation, social status, home environment and lifestyle was administered to random samples of the Italian population in the frame of the Gene Environment Interactions in Respiratory Diseases (GEIRD) study. Only clinical data belong to 2.606 subjects that completed the clinical stage of the GEIRD study, were used for the present study. RESULTS: Out of 1.351 women, 284 self-reported asthma and 92 of them had at least one pregnancy. When we considered the asthma course during pregnancy, we found that 16 women worsened, 31 remained unchanged, 25 improved. Seven women had not the same course in the different pregnancies and 13 did not know. The starting age of ICS use almost overlaps with that of asthma onset in women with worsening asthma during pregnancy (19 years ± 1.4), unlike the other women who started to use ICS much later (30.3 years ± 12). In addition, the worsening of asthma was more frequent in women with an older age of onset of asthma (18 years ± 9 vs 13 years ± 10). Among women who completed the ACT during the clinical interview, the 50% of women who experienced worsening asthma during pregnancy (6/12) had an ACT score below 20. CONCLUSION: Asthma was observed to worsen during pregnancy in a percentage much lower to that generally reported in all the previous studies. There is still room in clinical practice to further reduce worsening of asthma during pregnancy by improving asthma control, with a more structured approach to asthma education and management prepregnancy.

Pulmonary endarterectomy: the lancet first, tears for pills.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease due to the incomplete resolution of pulmonary emboli, leading to right heart failure, with a poor survival. Pulmonary endarterectomy (PEA) is the operation of choice for CTEPH. As there are no well-defined criteria to discriminate surgically accessible from inaccessible obstructive lesions, the operability assessment relies on the surgeon's experience. The recommended algorithms to perform a correct diagnosis of CTEPH still suggest the lung ventilation/perfusion scan, despite advances in computed tomography with 3-D reconstruction and magnetic resonance imaging. Selective pulmonary angiography is the gold standard to assess operability in CTEPH. Medical therapy should not be considered an alternative to PEA, as it should be reserved to patients with either peripheral disease, deemed inoperable by an experienced PEA surgeon, or persistent/recurrent pulmonary hypertension after PEA. Lung transplantation, when indicated, still represents a viable option for patients with either inoperable CTEPH or CTEPH with concomitant severe parenchymal lung disease that contraindicates PEA. The outcome of operable CTEPH is still best predicted after surgery. Remarkably, the recovery of exercise capacity is not as immediate as hemodynamic improvement, underlining the importance of early identification of surgical candidates before physical deconditioning.

Pulmonary involvement in patients with Marfan Syndrome.

AIM: Pulmonary involvement is not generally considered a main feature of Marfan syndrome, an autosomal connective tissue disorder caused by mutations in fibrillin 1. Thanks to the substantial progress in treatments, life expectation of these patients has been dramatically improved determining changes in different organ systems. The number of patients with pulmonary pathology may be higher than expected. Objective of the study was to evaluate the pulmonary involvement in all the patients referring to the largest Italian center for Marfan syndrome, assessing clinical examination and lung function tests. METHODS: Clinical history, spirometry, lung volumes and diffusing capacity have been assessed in 64 patients of our national referral center. RESULTS: None of the patients reported chronic respiratory symptoms. Fourteen percent reported a previous pneumothorax and 3 blebs and 45% had moderate to severe rib cage abnormalities. Twenty-three percent had cardiothoracic surgery. Two of the 19 patients with chest TC performed at our hospital were diagnosed with emphysema and were both non smoker; 7 had subpleural apical blebs. Only 37% of patients had normal lung function; 19% showed a restrictive pattern and 44% an obstructive pattern or an isolated diffusion impairment or an isolated hyperinflation. All patients with pneumothorax showed an obstructive pattern and diffusion impairment. CONCLUSION: In the absence of early respiratory symptoms, pulmonary abnormalities should be detected and monitored before they aggravate. Particular attention should be paid to prevent pneumothorax. Our results support the importance of lung volume determination to identify patients in which pulmonary parenchyma require a careful chest CT evaluation.

Asthma control in elderly asthmatics. An Italian observational study.

BACKGROUND: The exponential increase of individuals aged >64 yrs is expected to impact the burden of asthma. We aimed to explore the level of asthma control in elderly subjects, and factors influencing it. METHODS: A multicenter observational study was performed on consecutive patients >64 years old with a documented physician-diagnosis of asthma. Sixteen Italian centers were involved in this 6-month project. FINDINGS: A total of 350 patients were enrolled in the study. More than one-third of elderly asthmatic patients, despite receiving GINA step 3-4 antiasthmatic therapy, had an Asthma Control Test score ≤19, with a quarter experiencing at least one severe asthma exacerbation in the previous year. Twenty-nine percent of patients (n = 101) were classified as having Asthma-COPD Overlap Syndrome (ACOS) due to the presence of chronic bronchitis and/or CO lung diffusion impairment. This subgroup of patients had lower mean Asthma Control Test scores and more exacerbations compared to the asthmatic patients (18 ± 4 compared to 20 ± 4, p < 0.01, and 43% compared to 18%, p < 0.01, respectively). Modified Medical Research Council dyspnea mMRC scores and airway obstruction, assessed on the basis of a FEV(1)/FVC ratio below the lower limit of normal, were more severe in ACOS than in asthma, without any difference in responses to salbutamol. In a multivariate analysis, the mMRC dyspnea score, FEV(1)% of predicted and the coexistence of COPD were the only variables to enter the model. INTERPRETATION: Our results highlight the need to specifically evaluate the coexistence of features of COPD in elderly asthmatics, a factor that worsens asthma control.

Spirometric criteria to diagnose airway obstruction in the elderly: fixed ratio vs lower limit of normal.

COPD is the most common chronic lung disease. It becomes more prevalent with increasing age but remains under-diagnosed in the elderly. A heated debate concerns the most suitable way to diagnose airway obstruction in this age group. Most COPD guidelines recommend to use a FEV1/FVC of 0.70 as threshold to define an obstructive ventilatory defect. While the use of a 0.70 ratio may be simple, it may result in under-diagnosis of airflow obstruction in young people and over-diagnosis in the elderly due to an age-related decline in pulmonary volumes, especially in FEV1. This might lead to unnecessary use of medications and increased risk of adverse effects. A proposed strategy for reducing the misclassification of airway obstruction include the use of the statistically derived lower limit of normal (LLN) for FEV1/FVC, calculated as the fifth percentile of the normal distribution in a healthy population. Some authors addressed the possibility to evaluate lung function through high-resolution CT. In contrast to spirometry, CT imaging may allow for regional assessment of the compartments involved (airways, parenchyma, vasculature), and may enable a phenotype-driven characterization of COPD. Bhatt et al. recently observed that a small proportion (7%) of subjects with CT-defined emphysema were identified by the 0.70 threshold for FEV1/FVC but not by the LLN. However, there is no evidence that CT-emphysema corresponds to a clinical entity that can benefit by inhaled therapy. Further studies are needed to assess the classificatory and prognostic value of the different proposed criteria to diagnose airway obstruction in the elderly.

COPD classification methods and informativeness on mortality: contrasting evidences.

Understanding whether the ABCD GOLD classification method is informative with respect to the spirometric classification of severity in predicting mortality of patients with chronic obstructive pulmonary disease (COPD) is subject of debate. The results of a study performed on a sample of the Norwegian population (HUNT2) were recently published. Such data showed the inferiority of ABCD classification in predicting mortality compared to the spirometric classification, which was considered the gold standard up to the 2011 version of GOLD guidelines. This result is not in line with the results of other studies that have shown the equivalence of the two classifications. The new GOLD classification seemed to be a step forward for what concerns understanding patient's needs, but it seems clear that the insertion of a single clinical variable to the spirometric data may not be exhaustive in describing all the phenomena related to a heterogeneous disease such as COPD. The publication of the HUNT study provides an opportunity to analyze how the evidence has been produced, which scientific speculations it offers, what considerations could be drawn and what further research would be appropriate.

New life for macrolides.

This article is an attempt to analyze and discuss the role and the purported mechanisms of azithromycin (AZM) in non-eosinophilic severe asthma, including antineutrophil activity, an effect on gastroesophageal reflux or antibacterial activity against an underlying chronic infection, such as Chlamydia pneumoniae. Macrolides have an expanding role in the therapy of chronic inflammatory diseases based on their additional anti-inflammatory and immunosuppressive properties. Many studies have been performed in lung transplantation field and maintenance treatment has been proved to be effective in cystic fibrosis, bronchiectasis, diffuse panbronchiolitis, and in bronchiolitis obliterans syndrome and in the prevention of exacerbations in patients with chronic obstructive pulmonary disease. Pathobiological studies of people with severe, refractory asthma focused on its heterogeneity encouraging more targeted and personalized approaches to asthma therapy. In neutrophilic asthma corticosteroids are not very effective, while the immunomodulatory action of macrolides is particularly relevant on neutrophils. Recently, The AZIthromycin in Severe ASThma (AZISAST) study, published on the April number of Thorax, provided evidences on the efficacy and safety of long-term add-on treatment with AZM in severe non-eosinophilic asthma. Despite concerns about an increased proportion of macrolide-resistant organism and about the effects of macrolides on cardiovascular events, there was no evidence of an increased risk of pneumonia or other adverse events. Because the AZISAST study was not able to demonstrate significant improvement in lung function and use of rescue medication, there is still a need for new data confirming the efficacy of AZM in severe non-eosinophilic asthma.

ADRB2 Gly16Arg polymorphism, asthma control and lung function decline.

Arg/Arg homozygotes for the Gly16Arg polymorphism in the ß2-adrenoreceptor gene (ADRB2) have a reduced response to short-acting ß2-agonists but no effect has been associated with long-acting ß2-agonists (LABAs). We selected 604 subjects with current asthma from the European Community Respiratory Health Study to evaluate whether asthma control and lung function decline were associated with Gly16Arg polymorphism, and to test whether LABA or inhaled corticosteroid (ICS) use modified these effects. There was an increased risk of noncontrolled asthma (OR 1.33, 95% CI 1.01-1.75; p = 0.046) for each Arg allele. Among nonusers of ICS, the odds ratio of noncontrolled asthma among Arg/Arg versus Gly/Gly subjects was 2.73 (95% CI 1.28-5.82; p = 0.009). No increased risk of noncontrolled asthma associated with the Arg allele was observed among ICS and/or LABA users. For each Arg allele, a mean ± se decrease in decline in forced expiratory volume in 1 s of 7.7 ± 2.5 mL·yr⁻¹ was found (p-value for trend 0.003), irrespective of ICS or LABA use. Arg/Arg subjects had an increased risk of bronchial hyperresponsiveness (BHR) versus Gly/Gly subjects, with an odds ratio of 2.51 (95% CI 1.12-5.63; p = 0.025) if they did not use ICS. The Arg allele was associated with poorer asthma control, a steeper lung function decline and BHR. Absence of genotypic effects on asthma control among ICS users may be due to reversed ß2-adrenoreceptor desensitisation.

The Gene-Environment Interactions in Respiratory Diseases (GEIRD) Project.

The role of genetic and environmental factors, as well as their interaction, in the natural history of asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD) is largely unknown. This is mainly due to the lack of large-scale analytical epidemiological/genetic studies aimed at investigating these 3 respiratory conditions simultaneously. The GEIRD project is a collaborative initiative designed to collect information on biomarkers of inflammation and oxidative stress, individual and ecological exposures, diet, early-life factors, smoking habits, genetic traits and medication use in large and accurately defined series of asthma, allergic rhinitis and COPD phenotypes. It is a population-based multicase-control design, where cases and controls are identified through a 2-stage screening process (postal questionnaire and clinical examination) in pre-existing cohorts or new samples of subjects. It is aimed at elucidating the role that modifiable and genetic factors play in the occurrence, persistence, severity and control of inflammatory airway diseases, by way of the establishment of a historical multicentre standardized databank of phenotypes, contributed by and openly available to international epidemiologists. Researchers conducting population-based surveys with standardized methods may contribute to the public-domain case-control database, and use the resulting increased power to answer their own scientific questions.

What defines airflow obstruction in asthma?

Asthma guidelines from the Global Initiative for Asthma (GINA) and from the National Heart, Lung, and Blood Institute provide conflicting definitions of airflow obstruction, suggesting a fixed forced expiratory volume in 1 s (FEV(1))/forced vital capacity (FVC) cut-off point and the lower limit of normality (LLN), respectively. The LLN was recommended by the recent American Thoracic Society/European Respiratory Society guidelines on lung function testing. The problem in using fixed cut-off points is that they are set regardless of age and sex in an attempt to simplify diagnosis at the expense of misclassification. The sensitivity and specificity of fixed FEV(1)/FVC ratios of 0.70, 0.75 and 0.80 versus the LLN were evaluated in 815 subjects (aged 20-44 yrs) with a diagnosis of asthma within the framework of the European Community Respiratory Health Survey. In males, the 0.70 ratio showed 76.5% sensitivity and 100.0% specificity, the 0.75 ratio 100.0% sensitivity and 92.4% specificity, and the 0.80 ratio 100.0% sensitivity but 58.1% specificity. In females, the 0.70 ratio showed 57.3% sensitivity and 100.0% specificity, the 0.75 ratio 91.5% sensitivity and 95.9% specificity, and the 0.80 ratio 100.0% sensitivity but 72.9% specificity. The fixed cut-off points cause a lot of misidentification of airflow obstruction in young adults, with overestimation with the 0.80 ratio and underestimation with the 0.70 ratio. In conclusion, the GINA guidelines should change their criteria for defining airflow obstruction.

Underestimation of airflow obstruction among young adults using FEV1/FVC <70% as a fixed cut-off: a longitudinal evaluation of clinical and functional outcomes.

BACKGROUND: Early detection of airflow obstruction is particularly important among young adults because they are more likely to benefit from intervention. Using the forced expiratory volume in 1 s (FEV(1)) to forced vital capacity (FVC) (FEV(1)/FVC) <70% fixed ratio, airflow obstruction may be underdiagnosed. The lower limit of normal (LLN), which is statistically defined by the lower fifth percentile of a reference population, is physiologically appropriate but it still needs a clinical validation. METHODS: To evaluate the characteristics and longitudinal outcomes of subjects misidentified as normal by the fixed ratio with respect to the LLN, 6249 participants (aged 20-44 years) in the European Community Respiratory Health Survey were examined and divided into three groups (absence of airflow obstruction by the LLN and the fixed ratio; presence of airflow obstruction only by the LLN; presence of airflow obstruction by the two criteria) for 1991-1993. LLN equations were obtained from normal non-smoking participants. A set of clinical and functional outcomes was evaluated in 1999-2002. RESULTS: The misidentified subjects were 318 (5.1%); only 45.6% of the subjects with airflow obstruction by the LLN were also identified by the fixed cut-off. At baseline, FEV(1) (107%, 97%, 85%) progressively decreased and bronchial hyperresponsiveness (slope 7.84, 6.32, 5.57) progressively increased across the three groups. During follow-up, misidentified subjects had a significantly higher risk of developing chronic obstructive pulmonary disease and a significantly higher use of health resources (medicines, emergency department visits/hospital admissions) because of breathing problems than subjects without airflow obstruction (p<0.001). CONCLUSIONS: Our findings show the importance of using statistically derived spirometric criteria to identify airflow obstruction.

Chronic productive cough in young adults is very often due to chronic rhino-sinusitis.

BACKGROUND: Chronic productive cough is a common clinical problem; often potential causes outside the lower respiratory tract are forgotten or ignored. The aim of this study was to make a precise etiopathogenetic diagnosis of chronic productive cough in young adults. METHODS: In a clinical setting, 212 subjects (mean age 41+/-5 years) who had reported chronic productive cough in a previous postal survey of a young adult population underwent within two years clinical and functional investigations following a rational diagnostic approach. Two pulmonologists independently established the diagnosis using a clinically structured interview on nasal and respiratory symptoms, spirometry and other tests when appropriate (bronchodilator test or methacholine bronchial challenge, chest radiography); if rhino-sinusitis was suspected, subjects underwent an ENT examination with nasal endoscopy and/or sinus computed tomography. RESULTS: At the end of the diagnostic procedure, 87 subjects (41%) no longer had chronic productive cough and had normal function. Fifty-eight subjects (27%) had chronic rhino-sinusitis; seventeen subjects (8%) had asthma, and of these fourteen also had chronic rhino-sinusitis; 50 subjects (24%) had COPD stage 0+, of these seven also had chronic rhino-sinusitis. Chronic rhino-sinusitis was more frequent in females than in males (p<0.05). CONCLUSIONS: Both in clinical practice and in epidemiological studies, it is important to consider that the origin of chronic productive cough could be frequently outside the lower respiratory tract; a consistent percentage of young adults with persistent productive cough has indeed chronic rhino-sinusitis.