Multiple respiratory abnormalities can be found in anxiety disorders, especially in panic disorder (PD). Individuals with PD experience unexpected panic attacks, characterized by anxiety and fear, resulting in a number of autonomic and respiratory symptoms. Respiratory stimulation is a common event during panic attacks. The respiratory abnormality most often reported in PD patients is increased CO2 sensitivity, which has given rise to the hypothesis of fundamental abnormalities in the physiological mechanisms that control breathing in PD. There is evidence that PD patients with dominant respiratory symptoms are more sensitive to respiratory tests than are those who do not manifest such symptoms, and that the former group constitutes a distinct subtype. Patients with PD tend to hyperventilate and to panic in response to respiratory stimulants such as CO2, triggering the activation of a hypersensitive fear network. Although respiratory physiology seems to remain normal in these subjects, recent evidence supports the idea that they present subclinical abnormalities in respiration and in other functions related to body homeostasis. The fear network, composed of the hippocampus, the medial prefrontal cortex, the amygdala and its brain stem projections, might be oversensitive in PD patients. This theory might explain why medication and cognitive-behavioral therapy are both clearly effective. Our aim was to review the relationship between respiration and PD, addressing the respiratory subtype of PD and the hyperventilation syndrome, with a focus on respiratory challenge tests, as well as on the current mechanistic concepts and the pharmacological implications of this relationship.

Keywords: Panic disorder; Anxiety; Respiration; Hyperventilation; Carbon dioxide.

Nitric oxide (NO) is an endogenous vasoactive compound that contributes to pulmonary vascular homeostasis and is produced by three nitric oxide synthase (NOS) isoforms-neuronal NOS (nNOS); inducible NOS (iNOS); and endothelial NOS (eNOS)-all three of which are present in the lung. Studies using pharmacological inhibitors or knockout mice have shown that eNOS-derived NO plays an important role in modulating pulmonary vascular tone and attenuating pulmonary hypertension. However, studies focusing on the role of iNOS have shown that this isoform contributes to the pathophysiology of acute lung injury and acute respiratory distress syndrome. This review aimed at outlining the role played by NO in the control of pulmonary circulation, both under physiological and pathophysiological conditions. In addition, we review the evidence that the L-arginine-NO-cyclic guanosine monophosphate pathway is a major pharmacological target in the treatment of pulmonary vascular diseases.

Keywords: Nitric oxide; Arginine; Nitric oxide synthase; Cyclic GMP; Pulmonary circulation.

Objective: To describe the prevalence of signs and symptoms of respiratory disease among pig farmers in Braço do Norte, Santa Catarina, Brazil, evaluating the characteristics of swine confinement buildings and identifying potential risk factors. Methods: An exploratory, cross-sectional, observational study involving interviews and pulmonary function tests (spirometry). Aspects related to job history, work conditions, and environment, as well as to respiratory status and smoking, were evaluated. Odds ratios were used to estimate the chances of exposure when comparing pig farmers according to the signs and symptoms of respiratory disease. Results: The prevalence of clinical signs and symptoms of respiratory disease was 84.3%, clinical manifestations of bronchial asthma were detected in 5.6% of the farmers evaluated, and chronic bronchitis was diagnosed in 5.1% of the workers over the age of 40. Only 2.6% used specific individual respiratory protection devices. Respiratory disease was positively associated with low socioeconomic level, low level of education, smoking, the use of wood stoves, and the use of disinfectants. Work load and length of employment were both apparently associated with a lower prevalence of respiratory disease. Conclusion: The association between duration of employment and lower prevalence of respiratory disease can be attributed to the healthy worker effect. However, the evident respiratory impairment among pig farmers and the limited use of personal protective equipment draw attention to the need to implement a program to monitor exposure and regulate environmental factors.

Keywords: Occupational Exposure; Occupational Diseases/epidemiology; Swine; Animal husbandry; Respiratory tract diseases.

Objective: To report demographic and clinical characteristics of patients with asthma who evolved to death, as well as to describe the conditions related to this outcome in a subgroup of patients admitted to the Program for the Control of Asthma and Rhinitis in Bahia (ProAR). Methods: A descriptive, retrospective, observational study. Data from clinical charts and death certificates of 16 patients of 930 subjects with severe asthma monitored at the ProAR Central Reference Center from December 2003 to June 2006 were reviewed. Results: Of the 930 patients participating in the program, 16 (1.72%) died. Of these, there were 10 males and 6 females, ranging in age from 39 to 74 years (median, 55 years); 12 (75%) of the patients were black. Time since diagnosis ranged from 1 to 68 years (median, 30 years). In 43.8 and 53.8%, respectively, there was a personal or family history of atopy. Ex-smokers (<10 pack-years) accounted for 37.5% of the cases. Causes of death listed on the death certificates were as follows: asthma or asthma exacerbations in 8 (50%); respiratory failure in 3 (18.75%); acute heart infarction in 2 (12.5%); hepatitis in 1 (6.25%); hypovolemic shock in 1 (6.25%); and cardiorespiratory arrest in 1 (6.25%). Of the 16 deaths, 13 (81.25%) occurred inside hospitals. Conclusion: Asphyxia and cardiovascular diseases were the most common atributed causes of mortality in this subgroup of patients with severe asthma. Hospital-based mortality, male gender, advanced age, long-term disease and fixed airflow obstruction were the aspects most frequently observed in the cases studied.

Keywords: Mortality; Rhinitis/treatment; Asthma/treatment; Cardiovascular diseases.

Objective: To evaluate deaths attributed to multiple causes in which tuberculosis was one of the causes listed. Methods: All deaths among residents of the state of Rio de Janeiro, Brazil, occurring between 1999 and 2001 and for which the death certificate mentioned tuberculosis, were investigated. The World Health Organization guidelines were used in characterizing the underlying and associated (non-underlying) causes of death. Results: In deaths from tuberculosis, conditions related to its natural history were the principal associated causes, together with alcoholism and diabetes. In approximately three-fifths of all deaths for which tuberculosis was listed as an associated cause, the underlying cause of death was acquired immunodeficiency syndrome. High proportion of ill-defined causes of death, low values found for the number of causes informed per death certificate and for TB as an associated cause point towards a certain degree of underestimation of the actual number of TB-related deaths in Rio de Janeiro State. Conclusion: The study shows that the rates of tuberculosis-related mortality in the state of Rio de Janeiro, calculated based on the number of times tuberculosis was listed as a cause of death (underlying or associated), are the highest in the country. Epidemiological studies of mortality are recommended as a means of guiding the activities of the tuberculosis control program.

Keywords: Tuberculosis/mortality; Acquired immunodeficiency syndrome; Multipe cause of death; Brazil

Objective: To analyze and compare the transport properties of respiratory secretions, classified by selected parameters, in individuals with bronchiectasis unrelated to cystic fibrosis. Methods: We collected mucus samples from 35 individuals with bronchiectasis unrelated to cystic fibrosis. The samples were first classified by their surface properties (adhesive or nonadhesive), as well as by their aspect (mucoid or purulent). We then tested the samples regarding relative transport velocity (RTV), displacement in a simulated cough machine (SCM), and contact angle (CA). For the proposed comparisons, we used ANOVA models, with a level of significance set at 5%. Results: In comparison with nonadhesive samples, adhesive samples showed significantly less displacement in the SCM, as well as a significantly higher CA (6.52 ± 1.88 cm vs. 8.93 ± 2.81 cm and 27.08 ± 6.13° vs. 22.53 ± 5.92°, respectively; p < 0.05 for both). The same was true in the comparison between purulent and mucoid samples (7.57 ± 0.22 cm vs. 9.04 ± 2.48 cm and 25.61 ± 6.12° vs. 21.71 ± 5.89°; p < 0.05 for both). There were no significant differences in RTV among the groups of samples, although the values were low regardless of the surface properties (adhesive: 0.81 ± 0.20; nonadhesive: 0.68 ± 0.24) or the aspect (purulent: 0.74 ± 0.22; mucoid: 0.82 ± 0.22). Conclusions: The respiratory secretions of patients with bronchiectasis showed decreased mucociliary transport. Increased adhesiveness and purulence cause the worsening of transport properties, as demonstrated by the lesser displacement in the SCM and the higher CA.

Keywords: Bronchiectasis; Mucus; Mucociliary clearance; Adhesiveness.

Gastroesophageal reflux disease often presents as heartburn and acid reflux, the so-called "typical" symptoms. However, a subgroup of patients presents a collection of signs and symptoms that are not directly related to esophageal damage. These are known collectively as the extraesophageal manifestations of gastroesophageal reflux disease. Principal among such manifestations are bronchospasm, chronic cough and laryngitis, which are classified as atypical symptoms. These manifestations comprise a heterogeneous group. However, some generalizations can be made regarding all of the subgroups. First, although the correlation between gastroesophageal reflux disease and the extraesophageal manifestations has been well established, a cause-and-effect relationship has yet to be definitively elucidated. In addition, the main proposed pathogenic mechanisms of extraesophageal reflux are direct injury of the extraesophageal tissue (caused by contact with gastric acid) and the esophagobronchial reflex, which is mediated by the vagus nerve. Furthermore, gastroesophageal reflux disease might not be considered in the differential diagnosis of patients presenting only the atypical symptoms. In this article, we review the extraesophageal manifestations of gastroesophageal reflux disease, discussing its epidemiology, pathogenesis, diagnosis and treatment. We focus on the most extensively studied and well-established presentations.

Keywords: Gastroesophageal reflux/complications; Asthma; Laryngitis; Cough; Fundoplication; Respiration disorders/etiology

Tuberculosis continues to be a public health priority in many countries. In 2015, tuberculosis killed 1.4 million people, including 210,000 children. Despite the recent progress made in the control of tuberculosis in Brazil, it is still one of the countries with the highest tuberculosis burdens. In 2015, there were 69,000 reported cases of tuberculosis in Brazil and tuberculosis was the cause of 4,500 deaths in the country. In 2014, the World Health Organization approved the End TB Strategy, which set a target date of 2035 for meeting its goals of reducing the tuberculosis incidence by 90% and reducing the number of tuberculosis deaths by 95%. However, to achieve those goals in Brazil, there is a need for collaboration among the various sectors involved in tuberculosis control and for the prioritization of activities, including control measures targeting the most vulnerable populations. Children are highly vulnerable to tuberculosis, and there are particularities specific to pediatric patients regarding tuberculosis development (rapid progression from infection to active disease), prevention (low effectiveness of vaccination against the pulmonary forms and limited availability of preventive treatment of latent tuberculosis infection), diagnosis (a low rate of bacteriologically confirmed diagnosis), and treatment (poor availability of child-friendly anti-tuberculosis drugs). In this review, we discuss the epidemiology, clinical manifestations, and prevention of tuberculosis in childhood and adolescence, highlighting the peculiarities of active and latent tuberculosis in those age groups, in order to prompt reflection on new approaches to the management of pediatric tuberculosis within the framework of the End TB Strategy.

Keywords: Tuberculosis, pulmonary/prevention & control; Mycobacterium tuberculosis; Lung diseases/etiology; Child; Adolescent.

Objective: To describe respiratory function in a series of patients with late-onset Pompe disease after the definitive diagnosis and before enzyme replacement therapy. Methods: This was a cross-sectional study involving patients with a definitive molecular diagnosis of late-onset Pompe disease. The data analyzed included age at symptom onset; age at definitive diagnosis; type of initial symptoms; time from symptom onset to diagnosis; FVC in the sitting and supine positions; six-minute walk distance; and locomotor ability. Analyses were carried out using frequencies, medians, minimum values, and maximum values. Results: Six patients were included in the study. The median age at symptom onset was 15 years (range, 13-50 years), and the median age at diagnosis was 39.5 years (range, 10-64 years). The median time from symptom onset to diagnosis was 8 years (range, 0-45 years). In all cases, the initial manifestation of the disease had been motor weakness. The median FVC in percentage of the predicted value (FVC%) in the sitting and supine positions was 71.0% (range, 22.9-104.6%) and 58.0% (range, 10.9-106.9%), respectively. The median ΔFVC% was 24.5% (range, −4.59 to 52.40%).The median six-minute walk distance was 391.7 m (range, 97-702 m). Conclusions: In this case series, the time from symptom onset to diagnosis was long. Although respiratory signs or symptoms were not the initial manifestations of the disease, 66.7% of the patients showed reduced FVC% in the sitting and supine positions at diagnosis.

Keywords: Glycogen storage disease type II; Respiratory function tests; Respiratory muscles/pathology.

Objective: Lymphangioleiomyomatosis (LAM) is a rare disease that is currently considered a low-grade neoplasm with metastatic potential and variable progression. Mammalian target of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus, have recently become a treatment option for LAM patients, especially those with extrapulmonary manifestations. The objective of the present study was to describe a case series of four patients with LAM in Brazil who showed significant improvement, particularly in their extrapulmonary manifestations, after treatment with sirolimus (at 1-4 mg/day). Methods: We describe four cases of LAM patients with different extrapulmonary manifestations who were treated with sirolimus. Results: After treatment with sirolimus for 12 months, one patient presented resolution of severe chylothorax; one had a significant reduction in renal angiomyolipoma volume; and one showed significant regression of retroperitoneal lymphangioleiomyomas and abdominal lymph node enlargement. After treatment with sirolimus for 6 months, the remaining patient had a significant reduction in the volume of a massive retroperitoneal lymphangioleiomyoma. Conclusions: Our findings confirm that mTOR inhibitors are beneficial for patients with LAM, especially those with extrapulmonary manifestations, such as renal angiomyolipoma, lymphangioleiomyomas, and chylous effusions. However, certain aspects, such as the optimal dose, duration of treatment, and long-term adverse effects, have yet to be sufficiently clarified for mTOR inhibitors to be incorporated into LAM management protocols.

Keywords: Neoplasms; Lymphangioleiomyomatosis/therapy; TOR serine-threonine kinases; Sirolimus.

Objective: The present study attempted to determine whether patients with chronic obstructive pulmonary disease (COPD) get the minimum daily amount of physical activity recommended in the guidelines established by the American College of Sports Medicine (ACSM), as well as to characterize the consequences of noncompliance with those guidelines. Methods: This study involved 23 patients (median age: 61 - range, 59-69 years; FEV1: 39% of predicted - range, 34-53%; BMI: 24 kg/m2 - range, 21-27 kg/m2). The following parameters were evaluated: daily physical activity (DynaPort activity monitor); pulmonary function; muscle force; exercise tolerance; quality of life; functional status; and various indices of disease severity (GOLD, BODE and MRC). Results: Based on compliance with the guidelines (minimum of 30 minutes of walking per day), 12 patients were considered "physically active", and 11 were considered "physically inactive". No significant differences were observed between the two groups in terms of age, gender, BMI, muscle force, ventilatory reserve, hyperinflation or quality of life. The inactive group presented more impaired pulmonary function and lower exercise tolerance, as well as lower MRC and BODE scores (p < 0.05). In their daily life, patients in the inactive group also walked for less time and more slowly than did those in the active group (p < 0.05). The MRC and BODE indices were superior to the GOLD index in predicting compliance with the guidelines, both presenting a specificity of 0.83, compared with 0.50 for the GOLD index. The BODE index score increased significantly with each day of inactivity. Conclusion: A large number of COPD patients do not walk more than 30 minutes per day and are therefore not getting the minimum daily amount of physical activity recommended by the ACSM. Inactivity correlates with a higher mortality rate. The MRC and BODE indices proved superior to the GOLD index in predicting whether patients are physically inactive in their daily lives.

Keywords: Pulmonary disease, chronic obstructive; Body mass index; Exercise tolerance; Exercise; Guidelines; Severity of illness index

Lung cancer is the leading cause of cancer-related deaths worldwide. Promising new therapies have recently emerged from the development of molecular targeted drugs; particularly promising are those blocking the signal transduction machinery of cancer cells. One of the most widely studied cell signaling pathways is that of EGFR, which leads to uncontrolled cell proliferation, increased cell angiogenesis, and greater cell invasiveness. Activating mutations in the EGFR gene (deletions in exon 19 and mutation L858R in exon 21), first described in 2004, have been detected in approximately 10% of all non-squamous non-small cell lung cancer (NSCLC) patients in Western countries and are the most important predictors of a response to EGFR tyrosine-kinase inhibitors (EGFR-TKIs). Studies of the EGFR-TKIs gefitinib, erlotinib, and afatinib, in comparison with platinum-based regimens, as first-line treatments in chemotherapy-naïve patients have shown that the EGFR-TKIs produce gains in progression-free survival and overall response rates, although only in patients whose tumors harbor activating mutations in the EGFR gene. Clinical trials have also shown EGFR-TKIs to be effective as second- and third-line therapies in advanced NSCLC. Here, we review the main aspects of EGFR pathway activation in NSCLC, underscore the importance of correctly identifying activating mutations in the EGFR gene, and discuss the main outcomes of EGFR-TKI treatment in NSCLC.

Keywords: Molecular targeted therapy; Receptor, epidermal growth factor; Lung neoplasms/drug therapy; Mutation; Oncogenes.

Background: Bronchiectasis is a frequently found disease in medical practice in Brazil leading to significant morbidity and decrease in quality of life of the affected individuals. Objectives: To study diagnostic and therapeutic aspects in a series of hospitalized patients with bronchiectasis in a department of pulmonary diseases. Methods: Signs, symptoms, microbiological and radiographic data, and therapeutic results were studied in 170 hospitalized patients between 1978 and 2001 - females 62.4%, males 37.6%, and aged from 12 to 88 years (mean age 36.8 yrs). Previous history of pneumonia in childhood was detected in 52.5% of the patients, tuberculosis in 19.8%; 8.8% had bronchial asthma, and 2 had Kartagener's syndrome. Results: The most common symptoms were cough (100.0%), expectoration (96.0%) and pulmonary rales (66.0%). The pulmonary lesions were unilateral in 46.5% of the cases. Pneumococcus, H. influenzae or mixed flora were found in 85.0% of the examined sputa. All 170 patients received antibiotics and postural drainage, and 88 of them (younger and with a higher functional reserve) were also submitted to pulmonary resections (82 unilateral and 6 bilateral). Two deaths occurred, and repetitive hospitalizations were more frequent among the clinically treated patients. The follow up showed that most of the surgically treated patients had significant symptoms improvement and rarely needed to be re-hospitalized. Conclusions: In the majority of the patients, lung resection surgery improved permanently the prolonged bronchopulmonary symptoms of patients with bronchiectasis, differently from the patients who received only clinical treatment.

Keywords: Bronchiectasis/diagnosis. Bronchiectasis/therapy. Bronchiectasis/surgery. Bronchiectasis/complications. Tomography X-ray computed/methods. Inpatients. Retrospective studies.