Tobacco Smoke Exposure, Urban and Environmental Factors as Respiratory Disease Predictors in Italian Adolescents.

Risk monitoring in childhood is useful to estimate harmful health effects at later stages of life. Thus, here we have assessed the effects of tobacco smoke exposure and environmental pollution on the respiratory health of Italian children and adolescents using spirometry and the forced oscillation technique (FOT). For this purpose, we recruited 188 students aged 6-19 years living in Chivasso, Italy, and collected from them the following data: (1) one filled out questionnaire; (2) two respiratory measurements (i.e., spirometry and FOT); and (3) two urine tests for Cotinine (Cot) and 15-F2t-Isoprostane (15-F2t-IsoP) levels. We found a V-shape distribution for both Cotinine and 15-F2t-IsoP values, according to age groups, as well as a direct correlation (p = 0.000) between Cotinine and tobacco smoke exposure. These models demonstrate that tobacco smoke exposure, traffic, and the living environment play a fundamental role in the modulation of asthma-like symptoms (p = 0.020) and respiratory function (p = 0.007). Furthermore, the results from the 11-15-year group indicate that the growth process is a protective factor against the risk of respiratory disease later in life. Lastly, the FOT findings highlight the detrimental effects of tobacco smoke exposure and urbanization and traffic on respiratory health and asthma-like symptoms, respectively. Overall, monitoring environmental and behavioral factors in childhood can provide valuable information for preventing respiratory diseases in adulthood.

Bisphenol A, Tobacco Smoke, and Age as Predictors of Oxidative Stress in Children and Adolescents.

OBJECTIVES: The purpose of this study was to investigate bisphenol A (BPA) and its role in the induction of oxidative stress and confirm the same for tobacco smoke. METHODS: A total of 223 young, healthy students (7-19 years old) were recruited in Chivasso, Italy. A spot of urine of each subject was analyzed to quantify BPA, cotinine, and 15F2t-isoprostane. RESULTS: BPA showed a slight increase of concentration proportional with increasing age, even though the 11-14 years age group had slightly lower results, inducing a V-shape. The same trend was observed for 15F2t-isoprostane and cotinine. The result of piecewise linear robust regression shows a break point of the effect of BPA on 15F2t-isoprostane at 6 ng/mg CREA (p < 0.001). At higher levels, 15F2t-isoprostane shows an exponential increase by more than threefold for each one-log unit of BPA. An increase of oxidative stress due to BPA was observed, but only from 6 ng/mg of CREA up. Passive tobacco smoke is also able to induce an increase in oxidative stress. CONCLUSION: Prevention against BPA and passive tobacco smoke represents an important tool for promoting the highest health standard.

Correction: Seventy Years of Asthma in Italy: Age, Period and Cohort Effects on Incidence and Remission of Self-Reported Asthma from 1940 to 2010.

[This corrects the article DOI: 10.1371/journal.pone.0138570.].

Towards a formalin-free hospital. Levels of 15-F2t-isoprostane and malondialdehyde to monitor exposure to formaldehyde in nurses from operating theatres.

Purpose: nurses are exposed to formaldehyde when managing surgical samples that are to be later transferred to histopathology. We evaluated the conditions favouring the risk of exposure to this toxic reagent and the effect of measures to prevent it. Methods: we conducted a cross-sectional study where 94 female workers were enrolled as being potentially exposed to formaldehyde. From each nurse were collected: (1) personal air-formaldehyde by a personal dosimeter (8 hours), (2) a standardized questionnaire, (3) a urine sample to test 15-F2t-isoprostane, malondialdehyde, cotinine. Results: the results indicate a marked difference related to the adoption of the under vacuum sealing procedure, as an alternative to formaldehyde for preserving tissues. Nurses using the under vacuum sealing system in the operating rooms are exposed to levels of formaldehyde 75% lower than those who do not use that system. Oxidative stress biomarkers (15-F2t-isoprostane, malondialdehyde) are significantly higher in nurses using formaldehyde (p < 0.001) and in the absence of the under vacuum sealing system (p = 0.027), in particular in those workers who use liquid formaldehyde in the operating theatre (p = 0.012). Conclusions: analysis of the biological biomarkers confirms a direct responsibility of air formaldehyde on the onset of oxidative stress while the use of the under vacuum sealing technique is associated with a significant reduction of the exposure to air-formaldehyde and redox status. Our findings can be useful to characterize the environmental health risk in operating theatres and to plan preventive measures such as the under vacuum sealing procedure.

Seventy Years of Asthma in Italy: Age, Period and Cohort Effects on Incidence and Remission of Self-Reported Asthma from 1940 to 2010.

BACKGROUND: It is well known that asthma prevalence has been increasing all over the world in the last decades. However, few data are available on temporal trends of incidence and remission of asthma. OBJECTIVE: To evaluate the rates of asthma incidence and remission in Italy from 1940 to 2010. METHODS: The subjects were randomly sampled from the general Italian population between 1991 and 2010 in the three population-based multicentre studies: ECRHS, ISAYA, and GEIRD. Individual information on the history of asthma (age at onset, age at the last attack, use of drugs for asthma control, co-presence of hay-fever) was collected on 35,495 subjects aged 20-84 and born between 1925-1989. Temporal changes in rates of asthma incidence and remission in relation to age, birth cohort and calendar period (APC) were modelled using Poisson regression and APC models. RESULTS: The average yearly rate of asthma incidence was 2.6/1000 (3,297 new cases among 1,263,885 person-years). The incidence rates have been linearly increasing, with a percentage increase of +3.9% (95%CI: 3.1-4.5), from 1940 up to the year 1995, when the rates begun to level off. The stabilization of asthma incidence was mainly due to a decrease in the rates of atopic asthma after 1995, while non-atopic asthma has continued to increase. The overall rate of remission was 43.2/1000person-years, and it did not vary significantly across generations, but was associated with atopy, age at asthma onset and duration of the disease. CONCLUSIONS: After 50 years of a continuous upward trend, the rates of asthma incidence underwent a substantial stabilization in the late 90s. Despite remarkable improvements in the treatment of asthma, the rate of remission did not change significantly in the last seventy years. Some caveats are required in interpreting our results, given that our estimates are based on self-reported events that could be affected by the recall bias.

Lung function changes from childhood to adolescence: a seven-year follow-up study.

BACKGROUND: As part of an investigation into the respiratory health in children conducted in Torino, northwestern Italy, our aim was to assess development in lung function from childhood to adolescence, and to assess changes or persistence of asthma symptoms on the change of lung function parameters. Furthermore, the observed lung function data were compared with the Global Lung Function Initiative (GLI) reference values. METHODS: We conducted a longitudinal study, which lasted 7 years, composed by first survey of 4-5 year-old children in 2003 and a follow-up in 2010. Both surveys consisted in collecting information on health by standardized SIDRIA questionnaire and spirometry testing with FVC, FEV1, FEV1/FVC% and FEF25-75 measurements. RESULTS: 242 subjects successfully completed both surveys. In terms of asthma symptoms (AS = asthma attacks or wheezing in the previous 12 months), 191/242 were asymptomatic, 13 reported AS only in the first survey (early transient), 23 had AS only in the second survey (late onset), and 15 had AS in both surveys (persistent). Comparing the lung function parameters observed with the predicted by GLI only small differences were detected, except for FVC and FEF25-75, for which more than 5% of subjects had Z-score values beyond the Z-score normal limits. Furthermore, as well as did not significantly affect developmental changes in FVC and FEV1, the decrease in FEV1/FVC ratio was significantly higher in subjects with AS at the time of follow-up (late onset and persistent phenotypes) while the increase in FEF25-75 was significantly smaller in subjects with persistent AS (p < 0.05). CONCLUSIONS: The GLI equations are valid in evaluating lung function during development, at least in terms of lung volume measurements. Findings also suggest that the FEF25-75 may be a useful tool for clinical and epidemiological studies of childhood asthma.

Urban air and tobacco smoke as conditions that increase the risk of oxidative stress and respiratory response in youth.

BACKGROUND: Air pollution and tobacco smoke can induce negative effects on the human health and often leads to the formation of oxidative stress. OBJECTIVE: The purpose of this study was to clarify the role of the urbanization degree and of passive exposure to tobacco smoke in the formation of oxidative stress. Thus, a group of non-smoking adolescents was recruited among those who live and attend school in areas with three different population densities. To each subject a spot of urine was collected to quantify 15-F2t isoprostane as a marker of oxidative stress and cotinine as a marker of passive exposure to tobacco smoke. Furthermore, respiratory functionality was also measured. RESULTS: Multiple linear regression analysis results showed a direct correlation (p<0.0001) of 15-F2t isoprostane with both the urbanization and passive smoke. Lung function parameters proved significantly lower for the subjects living in the most populous city of Torino. CONCLUSION: This remarks the negative effect that urbanization has on the respiratory conditions. Lastly, lung functionality presented a low inverse correlation with 15-F2t isoprostane, suggesting an independent mechanism than that of the urban factor.

The course of asthma in young adults: a population-based nine-year follow-up on asthma remission and control.

BACKGROUND: Only few longitudinal studies on the course of asthma among adults have been carried out. OBJECTIVE: The aim of the present prospective study, carried out between 2000 and 2009 in Italy, is to assess asthma remission and control in adults with asthma, as well as their determinants. METHODS: All the subjects with current asthma (21-47 years) identified in 2000 in the Italian Study on Asthma in Young Adults in 6 Italian centres were followed up. Asthma remission was assessed at follow-up in 2008-2009 (n = 214), asthma control at baseline and follow-up. Asthma remission and control were related to potential determinants by a binomial logistic and a multinomial logistic model. Separate models for remission were used for men and women. RESULTS: The estimate of the proportion of subjects who were in remission was 29.7% (95%CI: 14.4%;44.9%). Men who were not under control at baseline had a very low probability of being in remission at follow-up (OR = 0.06; 95%CI:0.01;0.33) when compared to women (OR = 0.40; 95%CI:0.17;0.94). The estimates of the proportion of subjects who were under control, partial control or who were not under control in our sample were 26.3% (95%CI: 21.2;31.3%), 51.6% (95%CI: 44.6;58.7%) and 22.1% (95%CI: 16.6;27.6%), respectively. Female gender, increasing age, the presence of chronic cough and phlegm and partial or absent asthma control at baseline increased the risk of uncontrolled asthma at follow-up. CONCLUSION: Asthma remission was achieved in nearly 1/3 of the subjects with active asthma in the Italian adult population, whereas the proportion of the subjects with controlled asthma among the remaining subjects was still low.

Yield of tuberculosis contact investigation in a low-incidence country.

BACKGROUND: Tuberculosis (TB) contact tracing is a valid public health measure to control the spread of TB infection in low-burden settings. The aim of this study was to assess the yield of the Piedmont TB contact investigation program and to evaluate the role of its main determinants. METHODS: The Piedmont TB notification systems were used to identify index TB cases. All cases were classified by contagiousness (sputum-smear-positive, AFB+; culture-positive, CULT+; other-than-defined). TB contacts were screened for active and latent TB infection by clinical manifestations and Tuberculin Skin Test (TST). RESULTS: 833 index TB cases with at least one contact were identified; 4441 contacts were screened, and 3942 (82.8%) were evaluated. TB contacts aged ≤ 35 years, regular and household contacts had a higher probability of being evaluated; foreign-born TB contacts were the least traceable. Higher rates of TB infection were observed in contacts at 35 years of age or younger who also lived in the same household with index cases or exposed to AFB+ or CULT+ index cases. CONCLUSION: More efforts should be focused on young TB contacts, since they are likely to be new infections. An early identification and treatment of TB Infection in this group contributes to the prevention and control of TB transmission. The program should also be extended to the contacts of CULT+ cases.

Acute urticaria presenting in the emergency room of a general hospital.

BACKGROUND: Acute urticaria is a common disorder that often prompts patients to seek treatment in the emergency room (ER). There are few data on acute urticaria presenting in ER. OBJECTIVES: This study aimed to provide demographic and clinical data of patients presenting with acute urticaria at an ER of an Italian general hospital covering an area of about 90,000 inhabitants. The predictive factors of the length of stay in the ER had also been investigated. METHODS: The database of ER patients was searched for urticaria by ICD-9 code and by keywords in the diagnosis description. All the medical records of the identified patients were reviewed and the length of stay in ER was noted. RESULTS: A total of 459 patients were admitted to ER with acute urticaria in a 1-year period corresponding to 1.01% of total ER visits and to 1.2 admission per day. Angioedema was present in 139 cases (30.3%), fever in 55 (12%). Twenty-nine patients fulfilled the criteria of anaphylaxis. Triggers could be identified in 193 cases (42%): drugs in 20.7%, insects bites (10.2%), foods (7.4%) and contact urticaria in 3.7%. Anaphylaxis (p<0.001), food (p<0.05) and drugs (p<0.05) as triggers were significant and independent predictive factors of the length of stay in ER. CONCLUSIONS: Patients with acute urticaria are frequently referred to the emergency room, but only in a few cases urticaria is associated with severe allergic manifestations. Drug and food hypersensitivity, together with anaphylaxis, are the best predictors of the length of stay in ER.

Oxidative stress in adolescent passive smokers living in urban and rural environments.

Purpose of this study was to study the oxidative stress status through the urinary 15-F(2t)-isoprostane (15-F(2t)-isoP) among a group of 168 adolescents, differently exposed to passive tobacco smoke. Subjects were enrolled, with written informed consent, between two populations of students living and attending school in two areas with different levels of urbanization in Piedmont Region, North-Western Italy. A general linear model (GLM) analysis was performed to evaluate the role of air pollution, dependent from selected degree of urbanization and of passive exposure to tobacco smoke, quantified through cotinine, in the synthesis of 15-F(2t)-isoP, measured with ELISA technique. Formaldehyde (FA) concentration in air was also evaluated as a primary confounding factor in oxidative stress but no significant differences between the two sites were found. Conversely, direct relationship between oxidative stress status and residence of adolescents was found: oxidative stress level was 31% higher for adolescents living in Chivasso (urban site) than for those living in Casalborgone (countryside area). Furthermore, also passive tobacco smoke exposure proved to play another important direct role in the distribution of 15-F(2t)-isoP levels (p<0.0001). Lastly, an inversely proportional relationship was found between the age of adolescents and 15-F(2t)-isoP (p<0.0001). Finally, the detection of such a sensitive biological response as a consequence of limited differences of environmental pollution and exposure to tobacco smoke passively breathed could provide new and useful knowledge for the appraisal of preventive strategies, particularly for young subjects.

High rates of Mycobacterium tuberculosis among socially marginalized immigrants in low-incidence area, 1991-2010, Italy.

Migration from low- and middle-income countries to high-income countries increasingly determines the severity of tuberculosis (TB) cases in the adopted country. Socially marginalized groups, about whom little is known, may account for a reservoir of TB among the immigrant populations. We investigated the rates of and risk factors for Mycobacterium tuberculosis transmission, infection, and disease in a cohort of 27,358 socially marginalized immigrants who were systematically screened (1991-2010) in an area of Italy with low TB incidence. Overall TB and latent TB infection prevalence and annual tuberculin skin testing conversion rates (i.e., incidence of new infection) were 2.7%, 34.6%, and 1.7%, respectively. Prevalence of both TB and latent TB infection and incidence of infection increased as a function of the estimated TB incidence in the immigrants' countries of origin. Annual infection incidence decreased with time elapsed since immigration. These findings have implications for control policy and immigrant screening in countries with a low prevalence of TB.

The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.

BACKGROUND: The joint distribution of asthma and chronic obstructive pulmonary disease (COPD) has not been well described. This study aims at determining the prevalence of self-reported physician diagnoses of asthma, COPD and of the asthma-COPD overlap syndrome and to assess whether these conditions share a common set of risk factors. METHODS: A screening questionnaire on respiratory symptoms, diagnoses and risk factors was administered by mail or phone to random samples of the general Italian population aged 20-44 (n = 5163) 45-64 (n = 2167) and 65-84 (n = 1030) in the frame of the multicentre Gene Environment Interactions in Respiratory Diseases (GEIRD) study. RESULTS: A physician diagnosis of asthma or COPD (emphysema/chronic bronchitis/COPD) was reported by 13% and 21% of subjects aged <65 and 65-84 years respectively. Aging was associated with a marked decrease in the prevalence of diagnosed asthma (from 8.2% to 1.6%) and with a marked increase in the prevalence of diagnosed COPD (from 3.3% to 13.3%). The prevalence of the overlap of asthma and COPD was 1.6% (1.3%-2.0%), 2.1% (1.5%-2.8%) and 4.5% (3.2%-5.9%) in the 20-44, 45-64 and 65-84 age groups. Subjects with both asthma and COPD diagnoses were more likely to have respiratory symptoms, physical impairment, and to report hospital admissions compared to asthma or COPD alone (p<0.01). Age, sex, education and smoking showed different and sometimes opposite associations with the three conditions. CONCLUSION: Asthma and COPD are common in the general population, and they coexist in a substantial proportion of subjects. The asthma-COPD overlap syndrome represents an important clinical phenotype that deserves more medical attention and further research.

The cost of persistent asthma in Europe: an international population-based study in adults.

BACKGROUND: This study is aimed at providing a real-world evaluation of the economic cost of persistent asthma among European adults according to the degree of disease control [as defined by the 2006 Global Initiative for Asthma (GINA) guidelines]. METHODS: A prevalence-based cost-of-illness study was carried out on 462 patients aged 30-54 years with persistent asthma (according to the 2002 GINA definition), who were identified in general population samples from 11 European countries and examined in clinical settings in the European Community Respiratory Health Survey II between 1999 and 2002. The cost estimates were computed from the societal perspective following the bottom-up approach on the basis of rates, wages and prices in 2004 (obtained at the national level from official sources), and were then converted to the 2010 values. RESULTS: The mean total cost per patient was EUR 1,583 and was largely driven by indirect costs (i.e. lost working days and days with limited, not work-related activities 62.5%). The expected total cost in the population aged 30-54 years of the 11 European countries was EUR 4.3 billion (EUR 19.3 billion when extended to the whole European population aged from 15 to 64 years). The mean total cost per patient ranged from EUR 509 (controlled asthma) to EUR 2,281 (uncontrolled disease). Chronic cough or phlegm and having a high BMI significantly increased the individual total cost. CONCLUSIONS: Among European adults, the cost of persistent asthma drastically increases as disease control decreases. Therefore, substantial cost savings could be obtained through the proper management of adult patients in Europe.

15-F2t isoprostane as biomarker of oxidative stress induced by tobacco smoke and occupational exposure to formaldehyde in workers of plastic laminates.

BACKGROUND: Formaldehyde (FA) is a suspected human carcinogen capable of inducing oxidative stress through different metabolic ways. FA may originate from tobacco smoke, several environmental sources, as well as occupational sources, like furnishing industries specialized in the production of pressed-wood and laminate products. OBJECT: Our aim was to investigate the role of tobacco smoke and occupational exposure to air-FA in the induction of oxidative stress status by comparing FA-exposed with non-exposed subjects who smoked or did not. METHODS: Enrollment of 105 subjects was made in an industry of plastic laminates, including both workers directly exposed to FA and non-exposed office personnel, as control group. 15-F(2t) isoprostane (15-F(2t) IsoP), detected by ELISA technique and urinary cotinine, detected by GC-MS, were used for evaluating oxidative stress and tobacco smoke exposure, respectively. Air-FA levels were detected by GC-MS. RESULTS: FA concentrations were significantly higher in subjects occupationally exposed than the controls. Smoking habits and air-FA exposures independently induce the formation of 15-F(2t) IsoP and increase the oxidative stress level. CONCLUSIONS: Our findings show, for the first time, that 15-F(2t) IsoP presents a dependency from both the smoking habit and air-FA exposures, and consequently, that these breathable pollutants could be considered as two important independent risk factors in increasing the oxidative stress in human beings.

Tuberculosis among health care workers.

To assess the annual risk for latent tuberculosis infection (LTBI) among health care workers (HCWs), the incidence rate ratio for tuberculosis (TB) among HCWs worldwide, and the population-attributable fraction of TB to exposure of HCWs in their work settings, we reviewed the literature. Stratified pooled estimates for the LTBI rate for countries with low (<50 cases/100,000 population), intermediate (50-100/100,000 population), and high (>100/100,000 population) TB incidence were 3.8% (95% confidence interval [CI] 3.0%-4.6%), 6.9% (95% CI 3.4%-10.3%), and 8.4% (95% CI 2.7%-14.0%), respectively. For TB, estimated incident rate ratios were 2.4 (95% CI 1.2-3.6), 2.4 (95% CI 1.0-3.8), and 3.7 (95% CI 2.9-4.5), respectively. Median estimated population-attributable fraction for TB was as high as 0.4%. HCWs are at higher than average risk for TB. Sound TB infection control measures should be implemented in all health care facilities with patients suspected of having infectious TB.

The impact of diagnosed and undiagnosed current asthma in the general adult population.

BACKGROUND: Restrictive definitions of current asthma are used in epidemiological studies to achieve a highly specific classification of subjects. However, undiagnosed asthmatics should be taken into account to correctly evaluate the impact of the disease in the general population. METHODS: In an Italian multi-centre cross-sectional survey carried out in 1998-2000, 18,647 responders (20-44 years old) to a screening questionnaire were classified as having physician-diagnosed current asthma or current respiratory symptoms. Similarities in the risk factor profile and in the socioeconomic burden were considered suggestive of undiagnosed current asthma. RESULTS: In Italy, the prevalence of physician-diagnosed current asthma was 4.9% (95% CI 4.4-5.4), while that of 'asthma attacks and/or use of anti-asthmatic drugs in the past 12 months without a diagnosis of asthma' (ADWD) was 1.5% (95% CI 1.3-1.7). Allergic rhinitis was highly associated with diagnosed current asthma [relative risk ratio (RRR) 12.48; 95% CI 9.12-17.07; reference category: neither asthma during lifetime nor current respiratory symptoms] and with ADWD (RRR 8.42; 95% CI 6.33-11.19). Chronic cough/phlegm was homogeneously associated with all the respiratory conditions, and the strongest relationship was with ADWD (RRR 7.79; 95% CI 4.95-12.25). Subjects with ADWD and diagnosed current asthmatics were characterised by high and homogeneous percentages of individuals who reported productivity losses (19.0 and 15.1%) and hospitalisations (9.2 and 6.2%) because of respiratory problems in the past year. CONCLUSIONS: The impact of current asthma seems to be largely underestimated among Italian adults, since the individuals with ADWD may be undiagnosed current asthmatics.

Asthma in childhood reduces smoking initiation in subsequent teens among males.

BACKGROUND: The association between smoking habits and asthma is complex because subjects with asthma could avoid smoking, whereas smoking could increase asthma severity or incidence. PURPOSE: The relation between asthma in childhood (0-10 years) and smoking initiation in the second decade (11-20 years) was investigated using the database of the Italian Study on Asthma in Young Adults, performed in 1998-2000 on people aged 20-45 years. METHODS: The cumulative incidence of smoking initiation was compared among (1) subjects not reporting asthma attacks in the first 20 years of life (n = 17,384), (2) subjects reporting asthma onset in the first decade and no disease remission by the age of 20 years (n = 305), (3) subjects reporting asthma onset in the first decade and remission in the first and second decades (n = 573). RESULTS: Among men, the cumulative incidence of smoking onset was higher among nonasthmatics (49%) than among asthmatics (35.6%), and intermediate among asthmatics with disease remission (44.2%) (p = .001). These differences were larger in males born between 1953 and 1965, and tended to decrease in males born between 1966 and 1979: cumulative incidence of smoking onset decreased from 54.3% to 43.8% in nonasthmatics, whereas it remained stable in asthmatics (from 36.8% to 35%). Women, instead, had similar cumulative incidence of smoking initiation, irrespective of asthma onset or remission (p = .849). CONCLUSION: Asthma in childhood reduces smoking initiation during the subsequent teenage in men, but not in women. This protective effect tends to fade when asthma remission occurs. In the last decades, smoking initiation has decreased among nonasthmatic males, but not among asthmatic males.

Unexplained chronic cough and vitamin B-12 deficiency.

BACKGROUND: Chronic cough is characterized by sensory neuropathy. Vitamin B-12 (cobalamin) deficiency (Cbl-D) causes central and peripheral nervous system damage and has been implicated in sensory neuropathy and autonomic nervous system dysfunction. OBJECTIVE: We evaluated whether Cbl-D has a role in chronic, unexplained cough. DESIGN: Laryngeal threshold (histamine concentration that provokes a 25% decrease in the midinspiratory flow), bronchial threshold (histamine concentration that provokes a 20% decrease in the forced expiratory volume in 1 s), and cough threshold (histamine concentration that causes ≥5 coughs) in response to an inhaled histamine were assessed in 42 patients with chronic, unexplained cough [27 Cbl-D patients and 15 patients without Cbl-D (Cbl-N)] before and after intramuscular injections of cobalamin for 2 mo. Laryngeal, bronchial, and cough hyperresponsiveness was diagnosed when histamine concentration thresholds were ≤8 mg/mL. Seven Clb-D and 3 Cbl-N patients underwent an oropharyngeal biopsy before treatment. RESULTS: Cbl-D patients had a higher prevalence of laryngeal hyperresponsiveness than did Cbl-N patients (92.6% compared with 66.7%; P = 0.03), a thinner oropharyngeal epithelium [133.7 µm (95% CI: 95, 172 µm) compared with 230.8 µm (95% CI: 224, 237 µm); P = 0.002], a lower number of myelinated nerve fibers [2.25/mm(2) (95% CI: 1.8, 2.7/mm(2)) compared with 3.44/mm(2) (95% CI: 3, 3.8/mm(2)); P = 0.05], and a higher immunoreactive score for nerve growth factor (NGF) [6.7 (95% CI: 6, 7.3) compared with 2.8 (95% CI: 2.5, 3.1); P = 0.02]. After cobalamin supplementation, symptoms and laryngeal, bronchial, and cough thresholds were significantly improved in Cbl-D but not in Cbl-N patients. CONCLUSIONS: This study suggests that Cbl-D may contribute to chronic cough by favoring sensory neuropathy as indicated by laryngeal hyperresponsiveness and increased NGF expression in pharyngeal biopsies of Cbl-D patients. Cbl-D should be considered among factors that sustain chronic cough, particularly when cough triggers cannot be identified.