Airway Obstruction in Primary Care Patients: Need for Implementing Spirometry Use.

(1) Background: To detect early airway obstruction in an adult primary care setting. (2) Methods: Seventeen general practitioners (GP) were involved. A total of 912 patients consulting their GPs over 40 years were recruited: 583 of them (323M) agreed to perform/undergo all the procedures: respiratory questionnaire, mMRC questionnaire, and spirometry. We identified four subgroups: physician COPD patients; physician asthma patients; asthma-COPD overlap syndrome patients; and no respiratory diagnosis subjects, on the basis of physician diagnosis. For screening purposes, an FEV1/FVC < 70% was considered a marker of airway obstruction (AO). (3) Results: Prevalence rates of COPD, A, and ACOS were 12.5%, 7.8%, and 3.6%, respectively. In the overall sample 16.3% showed airway obstruction: 26% mild, 56% moderate, 17% severe, and 1% very severe. In obstructed subjects, those reporting neither respiratory symptoms nor a physician's respiratory diagnosis were 60% level I; 43% level II; 44% level III; and none level IV. Wheezing (p < 0.001), sputum (p = 0.01), older age (p < 0.0001), and male gender (p = 0.002) were the best predictors of airway obstruction. (4) Conclusions: A high prevalence of AO was found. In AO we found a high prevalence of subjects without respiratory symptoms or respiratory chronic diagnosis. Airway obstruction was predicted by the presence of wheezing, sputum, older age, and male gender.

High Mobility Group Box 1: Biological Functions and Relevance in Oxidative Stress Related Chronic Diseases.

In the early 1970s, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and named high-mobility group (HMG) proteins. High-mobility group box 1 (HMGB1) is the most studied HMG protein that detects and coordinates cellular stress response. The biological function of HMGB1 depends on its subcellular localization and expression. It plays a critical role in the nucleus and cytoplasm as DNA chaperone, chromosome gatekeeper, autophagy maintainer, and protector from apoptotic cell death. HMGB1 also functions as an extracellular alarmin acting as a damage-associated molecular pattern molecule (DAMP). Recent findings describe HMGB1 as a sophisticated signal of danger, with a pleiotropic function, which is useful as a clinical biomarker for several disorders. HMGB1 has emerged as a mediator in acute and chronic inflammation. Furthermore, HMGB1 targeting can induce beneficial effects on oxidative stress related diseases. This review focus on HMGB1 redox status, localization, mechanisms of release, binding with receptors, and its activities in different oxidative stress-related chronic diseases. Since a growing number of reports show the key role of HMGB1 in socially relevant pathological conditions, to our knowledge, for the first time, here we analyze the scientific literature, evaluating the number of publications focusing on HMGB1 in humans and animal models, per year, from 2006 to 2021 and the number of records published, yearly, per disease and category (studies on humans and animal models).

Relationship between Multimorbidity and Quality of Life in a Primary Care Setting: The Mediating Role of Dyspnea.

Multimorbidity is known to impair Quality of Life (QoL) in patients in a primary setting. Poor QoL is associated with higher dyspnea perception. How multimorbidity and dyspnea perception are related to QoL needs clarification. The aim of the present study is to evaluate the mediating role of dyspnea perception in the relationship between multimorbidity and QoL in adults with and without airflow obstruction in a primary care setting. Seventeen general practitioners participated in the study: a total of 912 adult patients attending the practitioner's surgery for a generic consultation completed a preliminary respiratory screening; 566 of them answered a respiratory questionnaire between January and June 2014, and 259 of the latter (148 M, aged 40-88) agreed to go through all the of procedures including spirometry, the IMCA and QoL (SF-36 through Physical Health "PCS" and Mental Health components) questionnaires, evaluation of comorbidities and the mMRC Dyspnea Scale. For screening purpose, a cut-off of FEV1/FVC < 70% was considered a marker of airflow obstruction (AO). Of the sample, 25% showed airflow obstruction (AO). No significant difference in mMRC score regarding the number of comorbidities and the PCS was found between subjects with and without AO. Multimorbidity and PCS were inversely related in subjects with (p < 0.001) and without AO (p < 0.001); mMRC and PCS were inversely related in subjects with (p = 0.001) and without AO (p < 0.001). A mediation analysis showed that the relation between number of comorbidities and PCS was totally mediated by mMRC in subjects with AO and partially in subjects without AO. We conclude that the effect of multimorbidity on PCS is totally mediated by mMRC only in AO. Detecting and monitoring mMRC in a primary care setting may be a useful indicator for evaluating a patient's global health.

Relationship among Body Composition, Adipocytokines, and Irisin on Exercise Capacity and Quality of Life in COPD: A Pilot Study.

Adipose tissue is an endocrine organ that interferes with the severity of chronic obstructive pulmonary disease (COPD). Although inflammatory markers, body composition, and nutritional status have a significant impact on pulmonary function, the real contribution of adipocytokines and myokines in COPD is still controversial. We aimed to evaluate the role played by the body composition, leptin, adiponectin, haptoglobin, and irisin on the functional exercise capacity, respiratory function, and quality of life (QoL) in COPD. In 25 COPD (20% GOLD-1; 60% GOLD-2; 20% GOLD-3) patients and 26 matched control subjects, we find that leptin, total adiponectin and haptoglobin are significantly increased whereas the 6 min walk test (6MWT) and physical functioning scores are significantly decreased in COPD versus controls. A significant positive relationship is found between leptin and fat mass and between 6MWT and the good health indicators of nutritional status. A significant inverse relationship is found between 6MWT and leptin and fat mass, FEV1 and haptoglobin, and irisin and haptoglobin. Phase angle and leptin level are significant predictors for functional exercise capacity assessed with 6MWT. Taken altogether, the results of this pilot study further support the role played by body composition and adipocytokines on exercise capacity respiratory function and QoL in COPD.

Lung Function Decline in Adult Asthmatics-A 10-Year Follow-Up Retrospective and Prospective Study.

Asthma may have an impact on lung function decline but conflicting results are reported in forced expiratory volume in one second (FEV1) decline. We aimed to describe the changes in FEV1 in lifelong non-smoking adult asthmatic outpatients during a 10-year follow-up comparing years 1-5 (1st period) with years 6-10 (2nd period) to assess factors affecting these changes. A total of 100 outpatients performed spirometry every 3 months during a 10-year survey. FEV1/Ht3 slope values of the 2nd period reduced significantly respect to the 1st period (p < 0.0001). FEV1 slopes of years 1-5 and 6-10 were inversely associated with FEV1 at enrolment (p = 0.02, p = 0.01, respectively). Reversibility and variability FEV1 showed a significant effect on the 1st period slopes (p = 0.01 and p < 0.04, respectively). Frequent exacerbators in the 1st year had steeper FEV1/Ht3 slopes in the 1st period (p = 0.01). The number of subjects using higher doses of ICS was significantly lower at the 10th years respect to the 5th and the 1st year (p < 0.001, p = 0.003, respectively). This study shows that FEV1 decline in treated adult asthmatics non-smokers, over 10-year follow-up, is not constant. In particular, it slows down over time, and is influenced by FEV1 at enrolment, reversibility, variability FEV1 and exacerbation score in the 1st year.

Relationship between domestic smoking and metals and rare earth elements concentration in indoor PM2.5.

Cigarette smoke is the main source of indoor chemical and toxic elements. Cadmium (Cd), Thallium (Tl), Lead (Pb) and Antimony (Sb) are important contributors to smoke-related health risks. Data on the association between Rare Earth Elements (REE) Cerium (Ce) and Lanthanum (La) and domestic smoking are scanty. To evaluate the relationship between cigarette smoke, indoor levels of PM2.5 and heavy metals, 73 children were investigated by parental questionnaire and skin prick tests. The houses of residence of 41 "cases" and 32 "controls" (children with and without respiratory symptoms, respectively) were evaluated by 48-h PM2.5 indoor/outdoor monitoring. PM2.5 mass concentration was determined by gravimetry; the extracted and mineralized fractions of elements (As, Cd, Ce, La, Mn, Pb, Sb, Sr, Tl) were evaluated by ICP-MS. PM2.5 and Ce, La, Cd, and Tl indoor concentrations were higher in smoker dwellings. When corrected for confounding factors, PM2.5, Ce, La, Cd, and Tl were associated with more likely presence of respiratory symptoms in adolescents. We found that: i) indoor smoking is associated with increased levels of PM2.5, Ce, La, Cd, and Tl and ii) the latter with increased presence of respiratory symptoms in children.

An elevated body mass index increases lung volume but reduces airflow in Italian schoolchildren.

BACKGROUND: Asthma and obesity are important and growing health issues worldwide. Obesity is considered a risk factor for asthma, due to the induction of changes in airway mechanics and altered airway inflammation. METHODS: We cross-sectionally investigated the effect of increased weight on pulmonary function in a large population sample of healthy children, aged 10-17 yrs living in Palermo, Italy. Explanatory effect of weight on lung function variables were evaluated by multiple linear regression models, taking into account height, gender, and age-class. RESULTS: Among the 2,393 subjects, FVC and FEV1 were positively correlated to weight. Multiple regression models showed that the weight beta coefficient for FEV1 was significantly lower with respect to that for FVC (0.005 and 0.009 l/kg, respectively), indicating a different magnitude in explanatory effect of weight on FVC and FEV1. Both FEV1/FVC and FEF25-75%/FVC ratios were negatively correlated to weight, while FEF25-75% was not significantly correlated. Similar results were obtained also when 807 symptomatic subjects were introduced in the model through a sensitivity analysis. CONCLUSION: In healthy children, the disproportionate increase of FEV1 and FVC with weight produces airflow decrease and consequently apparent poorer lung function independently from respiratory disease status.

Effect of indoor nitrogen dioxide on lung function in urban environment.

BACKGROUND: High levels of indoor NO2 are associated with increased asthma symptoms and decreased expiratory peak flows in children. We investigated the association of exposure to domestic indoor NO2, objectively measured in winter and spring, with respiratory symptoms and lung function in a sample of adolescents from a southern Mediterranean area. METHODS: From a large school population sample (n=2150) participating in an epidemiological survey in the urban area of the City of Palermo (southern Italy), a sub-sample of 303 adolescents was selected which furnished an enriched sample for cases of current asthma. All subjects were evaluated by a health questionnaire, skin prick tests and spirometry. One-week indoor NO2 monitoring of their homes was performed by diffusive sampling during spring and again during winter. RESULTS: We found that about 25% of subjects were exposed to indoor NO2 levels higher than the 40µg/m(3) World Health Organization limit, during both spring and winter. Moreover, subjects exposed to the highest indoor NO2 concentrations had increased frequency of current asthma (p=0.005), wheeze episodes in the last 12 months (p<0.001), chronic phlegm (p=0.013), and rhinoconjunctivitis (p=0.008). Finally, subjects with a personal history of wheeze ever had poorer respiratory function (FEF25-75%, p=0.01) when exposed to higher indoor NO2 concentrations. CONCLUSIONS: Home exposure to high indoor NO2 levels frequently occurs in adolescents living in a southern Mediterranean urban area and is significantly associated with the risks for increased frequency of both respiratory symptoms and reduced lung function.

The burden of rhinitis and rhinoconjunctivitis in adolescents.

PURPOSE: Rhinitis and conjunctivitis are common diseases worldwide that are frequently associated. Nevertheless, the risk factors for rhinoconjunctivitis are not well-described and the impact of conjunctivitis on rhinitis and asthma in children remains unknown. This study explored the different risk factors and evaluated the burden of rhinoconjunctivitis among adolescents. METHODS: This was a cross-sectional study conducted on a random sample of schoolchildren, aged 10-17 years, using skin prick tests and a self-administered questionnaire on respiratory health investigating the impact of rhinitis and rhinoconjunctivitis on daily activities. RESULTS: A complete evaluation was obtained for 2,150 children. The prevalence of rhinitis alone was 18.2% and rhinitis associated with conjunctivitis was 20.5%. Rhinoconjunctivitis was more frequently associated with females, a parental history of atopy, domestic exposure to mold/dampness, passive smoke exposure, and reported truck traffic in residential streets. Moreover, rhinoconjunctivitis was associated with a higher level of allergic sensitization. The prevalence of current asthma was 1.7% in subjects without rhinitis or rhinoconjunctivitis, 5.1% in rhinitis and 10.7% in rhinoconjunctivitis. In a logistic model, rhinoconjunctivitis yielded a 2-fold risk for current asthma with respect to rhinitis. Subjects with rhinoconjunctivitis had poorer quality of life (QoL); there was an impact on daily activities in 4.6% of rhinitis and 10.7% of rhinoconjunctivitis. CONCLUSIONS: Ocular symptoms increase the role of rhinitis as a risk factor for asthma and its impact on daily activities in children.

Rhinitis as a risk factor for depressive mood in pre-adolescents: a new approach to this relationship.

BACKGROUND: Respiratory allergic symptoms impact on social life and school activities, influencing the patient's mood states. We evaluated the relationships between allergic respiratory diseases and depressive/anxious mood in a large sample of Italian middle school students, using the partial directed acyclic graph (P-DAG). METHODS: We studied 1283 subjects aged 10-13. A health respiratory questionnaire including questions relevant to socioeconomic status (HCI) and a test for depression and anxiety were administered. All subjects performed spirometry and skin prick tests. RESULTS: A causal role of rhinitis on depression was found: the likelihood of being depressed increased from 11.2 to 17.7%, when rhinitis was present. Moreover, a direct effect of low HCI on depressive mood was shown (p < 0.0001) as well as the correlation between anxiety and depression (p < 0.0001). Gender was not a direct causal factor for depressive mood, but their relation was mediated through anxious mood. Anxiety appeared to have a stronger association with depression than gender. Allergic sensitization was significantly related to both asthma and rhinitis (p < 0.0001, respectively). Asthma and rhinitis were also directly associated (p < 0.0001). Conversely, asthma was not directly associated with depressive mood, but their relation was mediated through rhinitis. Body mass index (BMI) and impaired lung function (IPF) were not associated with the other variables. CONCLUSIONS: The use of this novel approach to analyzing the dynamic relationships allowed us to find a causal role of rhinitis on depressive state. Moreover, anxious condition and low socioeconomic status contributed to induce depressive mood.

A cross-sectional study assessing the relationship between BMI, asthma, atopy, and eNO among schoolchildren.

BACKGROUND: Increased body weight may influence airway inflammatory mechanisms. OBJECTIVE: To assess whether overweight-obesity (OW-O), evaluated as increased body mass index, is associated either with exhaled nitric oxide (eNO), a marker of airway inflammation, or with allergic sensitization in a large sample of children and adolescents. METHODS: A cross-sectional, epidemiological study was performed on a population sample of schoolchildren evaluating 708 subjects (age 10-16 years; BMI 13-39 kg/m(2)) by respiratory health questionnaire, skin prick tests, spirometry, and eNO measure. RESULTS: Prevalence rates were: OW-O 16.4%, asthma ever (A) 11.9%, and rhinoconjunctivitis (RC) 14.8%. Asthma ever and allergic sensitization were significantly more frequent among OW-O (21.0 and 51.6%) than in non-OW-O (10.2 and 37.0%, respectively). The forced expiratory volume in 1 second (FEV(1))/forced vital capacity (FVC) ratio was not significantly different between OW-O and non-OW-O. Exhaled NO (median and interquartile range) was 15.3 (11.2-23.1) ppb in the overall sample, 20.3 (12.9-35.8) ppb among allergic subjects, and 13.9 (10.6-18.3) ppb among nonallergic subjects (P<.0001). No significant difference between OW-O and non OW-O subjects was found in eNO levels. Similarly, OW-O subjects with A or RC did not show significantly higher eNO levels than non-OW-O. In a logistic regression model, presence of allergic sensitization, A, and RC, and not OW-O, were significant predictors of increased eNO. CONCLUSIONS: In children, OW-O was not associated with increased eNO levels, but it was an independent risk factor for asthma and allergic sensitization.

Proportional Venn diagram and determinants of allergic respiratory diseases in Italian adolescents.

Large variations in prevalence of atopy and allergic diseases are reported worldwide in children, but in epidemiological studies the use of skin prick tests (SPT) and spirometry along with questionnaires is not common in the Mediterranean Area. The present work was aimed at evaluating the prevalence of current asthma (CA), rhinoconjunctivitis (RC), and eczema (E), with atopy and respiratory function, and the role of risk factors for allergic respiratory diseases. A total of 2150 Italian schoolchildren were cross-sectionally investigated through respiratory questionnaire, SPT, and spirometry. A proportional Venn diagram quantified the distribution of CA, RC, and E, stratifying for allergic sensitization to show differences in prevalence of allergic diseases among subjects with and without positive SPT. CA prevalence was 4.2%, RC 17.9%, and E 5.3%. CA and RC increased, while E decreased, with respect to previous local studies. Allergic sensitization prevalence (evaluated as positive response to at least one SPT) was 39.2%. A double Venn diagram identified 15 categories. Atopic CA was threefold more frequent than non-atopic CA. Atopic vs non-atopic RC and E were 9.6% vs 10.3% and 2.0% vs 3.3%, respectively. Atopic vs non-atopic RC associated with CA were 1.6% vs 0.5%; the same figures for RC associated with E were 0.8% vs 1.3%. Asymptomatic atopic subjects were 27.0%. Atopy, RC, parental asthma, and environmental risk factors were associated with CA. Atopy and environmental factors were risk factors also for RC. Asthma and traffic exposure were linked to reduced lung function. Respiratory allergic diseases are still increasing and largely concomitant in Italian adolescents. Atopy is more important for CA than RC. Avoiding exposures to measured environmental risk factors would prevent 41% of current asthma and 34% of rhinoconjunctivitis.

The Val432Leu polymorphism of the CYP1B1 gene is associated with differences in estrogen metabolism and bone density.

Polymorphisms of the CYP450 genes that encode for the enzymes that metabolize estrogen are linked to hormone-related cancers. We investigated the impact of two polymorphisms of the CYP1B1 gene previously reported to be associated with hormone-related disorders on estrogen metabolism and bone mineral density (BMD), another hormone-dependent condition, in women from different ethnic backgrounds. Four hundred sixty-eight postmenopausal Caucasian women, 220 from St. Louis, MO, USA (mean age=63.5+/-0.53 years) and 248 from Palermo, Italy (mean age=72.9+/-0.44 years) participated in the study. Measurements of urinary estrogen metabolites by enzyme-linked immunoassay, serum estradiol by ultrasensitive radioimmnunoassay, and serum sex hormone-binding globulin by immunoradiometric assay were performed only in the American women, while BMD by dual energy X-ray absorptiometry and genotyping by pyrosequencing were performed in both American and Italian women. Differences in the levels of metabolites, free estradiol index and BMD were analyzed by analysis of covariance. Analysis among the American participants for the Valine432Leucine polymorphism showed that, compared to women with the Val/Val genotype, women with the Leu allele (Val/Leu and Leu/Leu) had significantly higher log-transformed values of total urinary estrogen metabolite (ng/mg-creatinine) levels (1.23+/-0.04, 1.35+/-0.02, and 1.34+/-0.03; p=0.03), and significantly lower BMD (gm/cm(2)) in the lumbar spine (1.009+/-0.02, 0.955+/-0.01 and 0.931+/-0.02; p=0.03) and the femoral neck (0.748+/-0.02, 0.717+/-0.01 and 0.693+/-001, p=0.03) for the Val/Val, Val/Leu and Leu/Leu genotypes respectively. There were no significant differences in the urinary metabolites and BMD in the different genotypes for the Alanine119Serine polymorphism among the American women. Meanwhile, a separate analysis among the Italian women revealed no significant differences in BMD among the different genotypes for the two polymorphisms investigated. In conclusion, women with the Leu allele for the CYP1B1 Val432polymorphism have increased estrogen catabolism, as indicated by higher urinary estrogen metabolites, compared to those with Val/Val genotype. This may lead to relative hypoestrogenism and lower BMD in the lumbar spine and femoral neck in these women. Our data suggest that through its effect on the rate of estrogen catabolism, the Val432Leu polymorphism of the CYP1B1 gene may represent as a possible genetic risk factor for osteoporosis in American women.

Low serum levels of 25-hydroxy vitamin D in adults affected by thalassemia major or intermedia.

Adult thalassemic patients have reduced bone mass due to disturbances in several different mechanisms affecting bone turnover. To determine if vitamin D deficiency contributes to the low bone mass of adult thalassemic subjects, we studied serum 25-OH-vitamin D levels in 90 patients (age ranging between 21 and 48 years) affected with thalassemia major (TM) and 35 (age 21-56 years) with thalassemia intermedia (TI). TM patients had been receiving regular transfusions from the age of 2 years and had increased serum ferritin, glutamic oxalacetic transaminase, glutamic piruvic transaminase as well as low bone density (L1-L4 Z score -2.07 +/- 0.2). TI patients did not receive transfusions, but their ferritin levels were increased as well (520.3 +/- 138,1). 8 TM patients (10.1%) and 4 TI (11.4%) had serum 25-OH-vitamin D less than 10.4 ng/ml and were considered presenting an absolute deficiency of vitamin D. Mean 25-OH-vitamin D was significantly (P < 0.01) lower in both TM and TI patients (20.3 +/- 0.7 ng/ml and 20.9 +/- 2.3 ng/ml, respectively) than in 100 healthy control subjects of similar age (25.2 +/- 1 ng/ml). 1,25-OH-vitamin D levels were in the normal-lower levels (45.15 +/- 1.5 mg/dl), while 24 H urinary calcium was below the normal range (15.75 mg/dl). In TM patients, the 25-OH-vitamin D levels correlated negatively with age (P < 0.05) and with serum ferritin (P < 0.05). TM and TI patients with low 25-OH-vitamin D levels (<17.8 ng/ml) presented higher serum ferritin levels (P < 0.01) and higher PTH (P < 0.05) compared to those with normal vitamin D. Moreover, TM patients with low 25-OH-vitamin D levels were significantly older (P < 0.05) and had higher GPT (P < 0.05) than patients with normal vitamin D. In conclusion, calcium metabolism is frequently impaired in adult thalassemic patients. An early and effective medical treatment should be taken in consideration by the clinician in order to improve the bone health in these patients.

Non-specific bronchial hyper-responsiveness in children with allergic rhinitis: relationship with the atopic status.

An increased prevalence of bronchial hyper-responsiveness (BHR) has been demonstrated in children from a general population, and in non-asthmatic adults with allergic rhinitis. Thus, also children with allergic rhinitis are expected to be at higher risk of BHR. We evaluated the prevalence of BHR in a sample of non-asthmatic children with allergic rhinitis by means of the methacholine (Mch) bronchial challenge, and by monitorizing the airway patency using the daily peak expiratory flow variability (PEFv). Fifty-one children (ranged 6-15 years of age) with allergic rhinitis, ascertained by skin prick test to inhalant allergens, underwent a 14-day peak expiratory flow monitoring, and a Mch bronchial provocation challenge. Thirty healthy children matched for age, and sex served as control group. Thirty-one children in the rhinitis group (61%), and six (20%) in the control group were Mch+ (Mch provocative dose causing a 20% fall of forced expiratory volume in 1 s respect to baseline <2250 microg, equivalent to 11.50 micromol). In rhinitic children the PEFv did not significantly differ between Mch+ and Mch- subjects, but the total serum immunoglobulin E (IgE) were higher among Mch+. The persistent form of rhinitis was significantly associated to Mch positivity. Non-asthmatic children with allergic rhinitis displayed a high prevalence of BHR. The BHR was significantly associated with persistent rhinitis and with higher total IgE levels. Nevertheless, the spontaneous changes in airway patency, as expressed by PEFv, were within normal limits both in Mch+ and Mch- children.

Lung function decline in bronchial asthma.

STUDY OBJECTIVE: We evaluated the longitudinal changes in lung function and the factors associated with FEV(1) changes over time in a sample of asthmatic subjects. SETTING: FEV(1) measures were recorded every 3 months over a 5-year follow-up period. To compare all subjects independently of body size, FEV(1) values were normalized for the subject's height at the third power. We evaluated the possible effect of age, baseline FEV(1), disease duration, and FEV(1) variability on the rate of change of FEV(1). PATIENTS: We studied 142 subjects with asthma diagnosed on the basis of validated clinical and functional criteria. RESULTS: FEV(1) showed a linear decay with aging in each subject. For a subject 1.65 m in height, the median overall FEV(1) decay was 40.9 mL/yr. FEV(1) decay slopes were significantly influenced by age and sex, being steeper in younger male subjects. A significant interaction was found between age and baseline FEV(1): the FEV(1) decay was significantly higher among younger asthmatics with a poorer baseline functional condition. A longer disease duration was associated with a lower FEV(1) slope. FEV(1) variability was strongly associated with an increased rate of FEV(1) decline. CONCLUSIONS: FEV(1) decline in patients with bronchial asthma is significantly influenced by baseline FEV(1), disease duration, and FEV(1) variability. Moreover, the rate of FEV(1) decline seems to increase in younger subjects only when the baseline function is poorer.