Addressing influenza's underestimated burden - Iberian experts call to action.

Having a proper understanding of the impact of influenza is a fundamental step towards improved preventive action. This paper reviews findings from the Burden of Acute Respiratory Infections study on the burden of influenza in Iberia, and its potential underestimation, and proposes specific measures to lessen influenza's impact.

Diagnosis of Fibrotic Hypersensitivity Pneumonitis: Is There a Role for Biomarkers?

Hypersensitivity pneumonitis is a complex interstitial lung syndrome and is associated with significant morbimortality, particularly for fibrotic disease. This condition is characterized by sensitization to a specific antigen, whose early identification is associated with improved outcomes. Biomarkers measure objectively biologic processes and may support clinical decisions. These tools evolved to play a crucial role in the diagnosis and management of a wide range of human diseases. This is not the case, however, with hypersensitivity pneumonitis, where there is still great room for research in the path to find consensual diagnostic biomarkers. Gaps in the current evidence include lack of validation, validation against healthy controls alone, small sampling and heterogeneity in diagnostic and classification criteria. Furthermore, discriminatory accuracy is currently limited by overlapping mechanisms of inflammation, damage and fibrogenesis between ILDs. Still, biomarkers such as BAL lymphocyte counts and specific serum IgGs made their way into clinical guidelines, while others including KL-6, SP-D, YKL-40 and apolipoproteins have shown promising results in leading centers and have potential to translate into daily practice. As research proceeds, it is expected that the emergence of novel categories of biomarkers will offer new and thriving tools that could complement those currently available.

Excess hospitalizations and mortality associated with seasonal influenza in Portugal, 2008-2018.

BACKGROUND: Influenza can have a domino effect, triggering severe conditions and leading to hospitalization or even death. Since influenza testing is not routinely performed, statistical modeling techniques are increasingly being used to estimate annual hospitalizations and deaths associated with influenza, to overcome the known underestimation from registers coded with influenza-specific diagnosis. The aim of this study was to estimate the clinical and economic burden of severe influenza in Portugal. METHODS: The study comprised ten epidemic seasons (2008/09-2017/18) and used two approaches: (i) a direct method of estimating the seasonal influenza hospitalization incidence, based on the number of National Health Service hospitalizations with influenza-specific International Classification of Diseases (ICD) codes (ICD-9: 487-488; ICD-10: J09-J11), as primary or secondary diagnosis; (ii) an indirect method of estimating excess hospitalizations and deaths using broader groups of ICD codes in time-series models, computed for six age groups and four groups of diagnoses: pneumonia or influenza (ICD-9: 480-488, 517.1; ICD-10: J09-J18), respiratory (ICD-9: 460-519; ICD-10: J00-J99), respiratory or cardiovascular (R&C, ICD-9: 390-459, 460-519; ICD-10: I00-I99, J00-J99), and all-cause. Means are reported excluding the H1N1pdm09 pandemic (2009/10). RESULTS: The mean number of hospitalizations coded as due to influenza per season was 1,207, resulting in 11.6 cases per 100,000 people. The mean direct annual cost of these hospitalizations was €3.9 million, of which 78.6% was generated by patients with comorbidities. Mean annual influenza-associated R&C hospitalizations were estimated at 5356 (min: 456; max: 8776), corresponding to 51.5 cases per 100,000 (95% CI: 40.9-62.0) for all age groups and 199.6 (95% CI: 163.9-235.8) for the population aged ≥ 65 years. The mean direct annual cost of the estimated excess R&C hospitalizations was €15.2 million for all age groups and €12.8 million for the population aged ≥ 65 years. Mean annual influenza-associated all-cause deaths per 100,000 people were estimated at 22.7 for all age groups. CONCLUSIONS: The study findings suggest that there is an under-detection of influenza in the Portuguese population. A high burden of severe influenza remains to be addressed, not only in the elderly population but also in younger people.

Clinical and Genetic Risk Factors for Drug-Induced Liver Injury Associated with Anti-Tuberculosis Treatment-A Study from Patients of Portuguese Health Centers.

Drug-induced liver injury (DILI) is an unpredictable and feared side effect of antituberculosis treatment (AT). The present study aimed to identify clinical and genetic variables associated with susceptibility to AT-associated hepatotoxicity in patients with pulmonary tuberculosis treated with a standard protocol. Of 233 patients enrolled, 90% prospectively, 103 developed liver injury: 37 with mild and 66 with severe phenotype (DILI). All patients with mild hepatitis had a RUCAM score ≥4 and all patients with DILI had a RUCAM score ≥ 6. Eight clinical variables and variants in six candidate genes were assessed. A logistic multivariate regression analysis identified four risk factors for AT-DILI: age ≥ 55 years (OR:3.67; 95% CI:1.82−7.41; p < 0.001), concomitant medication with other hepatotoxic drugs (OR:2.54; 95% CI:1.23−5.26; p = 0.012), NAT2 slow acetylator status (OR:2.46; 95% CI:1.25−4.84; p = 0.009), and carriers of p.Val444Ala variant for ABCB11 gene (OR:2.06; 95%CI:1.02−4.17; p = 0.044). The statistical model explains 24.9% of the susceptibility to AT-DILI, with an 8.9 times difference between patients in the highest and in the lowest quartiles of risk scores. This study sustains the complex architecture of AT-DILI. Prospective studies should evaluate the benefit of NAT2 and ABCB11 genotyping in AT personalization, particularly in patients over 55 years.

Pharmacogenetics of advanced lung cancer: Predictive value of functional genetic polymorphism AGXT Pro11Leu in clinical outcome?

INTRODUCTION: AGXT gene codes for the enzyme alanine glyoxylate aminotransferase, which is involved in hepatic peroxisomal metabolism of platinum-based chemotherapeutic agents. The association of genetic variant AGXT rs34116584 on the clinical outcome and response to chemotherapy of patients with non-small cell lung cancer (NSCLC) remains to be established. Our aim was to evaluate the association of functional AGXT gene polymorphism in NSCLC progression, considering as primary and secondary endpoint, progression free survival (PFS) and overall survival (OS), respectively. METHODS: Genotyping of theAGXT rs34116584 genetic polymorphism was performed by mass spectrometry on 168 DNA samples from patients with NSCLC (stages IIIA-IVB). Univariate survival analysis included the study of Kaplan-Meier curves with the Log-Rank test, while Cox regression was used as a multivariate analysis. RESULTS: Multivariate analysis showed shorter PFS for T carriers [HR=2.0, 95% CI, 1.4-3.0, p<0.0001] and shorter OS [HR=1.8, 95% CI, 1.1-3.0, p=0.017] globally, as well as in a subgroup of patients (n=144) treated with first line platinum-based chemotherapy [HR=2.0, 95% CI, 1.3-3.1, p=0.001] and [HR=1.8, 95% CI, 1.1-3.1, p=0.026], respectively. CONCLUSION: This polymorphism seems to have an impact on NSCLC progression, opening new perspectives for its inclusion as a pharmacogenetic predictor of response to platinum-based chemotherapy.

Asthma management with breath-triggered inhalers: innovation through design.

BACKGROUND: Asthma affects the lives of hundred million people around the World. Despite notable progresses in disease management, asthma control remains largely insufficient worldwide, influencing patients' wellbeing and quality of life. Poor patient handling of inhaling devices has been identified as a major persistent problem that significantly reduces inhaled drugs' efficacy and is associated with poor adherence to treatment, impairing clinical results such as asthma control and increasing disease-related costs. We herein review key research and development (R&D) innovation in inhaler devices, highlighting major real-world critical errors in the handling and inhalation technique with current devices and considering potential solutions. Furthermore, we discuss current evidence regarding breath-triggered inhalers (BTI). MAIN BODY: The two most common significant problems with inhalers are coordinating actuation and inhalation with pressurized metered-dose inhalers (pMDIs), and the need to inhale forcibly with a dry powder inhaler. BTI R&D plans were designed to overcome these problems. Its newest device k-haler® has several other important features, generating a less forceful aerosol plume than previous pMDIs, with efficient drug delivery and lung deposition, even in patients with low inspiratory flow. The local and systemic bioavailability of fluticasone propionate and formoterol (FP/FORM) administered via k-haler® has been shown to be therapeutically equivalent when administered via the previous FP/FORM pMDI. This device requires very few steps and has been considered easy to use (even at first attempt) and preferred by the patients in a randomized crossover study. In our country, FP/FORM k-haler is available without additional costs compared to FP/FORM pMDI. All devices continue to require education and regular checking of the correct inhalation technique. CONCLUSION: BTI R&D can bring advantage over current available inhalers, avoiding the two most common identified critical errors in inhalation technique. K-haler® BTI is currently available, without an increased cost, and approved for adolescents and adults with asthma in whom treatment with inhaled combined therapy with long-acting beta2-agonists and corticosteroids is indicated. Its attractive and practical design to facilitate its use has been awarded. K-haler® represents added value through innovation to fulfill actual asthma patient needs, thus with potential relevant impact in asthma management and effective control.

Alpha-1 Antitrypsin Deficiency: Principles of Care.

Alpha-1 antitrypsin deficiency is an autosomal co-dominant inherited disorder that results in decreased circulating levels of alpha-1 antitrypsin (also known as alpha-1 proteinase inhibitor) and predisposes affected individuals to early onset lung and liver disease. There is currently no cure for alpha-1 antitrypsin deficiency. However, appropriate treatment and a high standard of clinical care can prevent patients from being seriously affected and having to undergo major medical interventions, such as organ transplantation. Beyond managing the symptoms associated with alpha-1 antitrypsin deficiency, alpha-1 proteinase inhibitor therapy is the only treatment for the condition's underlying cause. Early diagnosis is important to ensure efficient therapeutic strategies and to minimize further deterioration of lung function. alpha-1 antitrypsin deficiency is under diagnosed globally, partly because the disease has no unique presenting symptoms. This document was prepared by a Portuguese multidisciplinary group and it aims to set out comprehensive principles of care for Alpha-1 antitrypsin deficiency. These include the importance of registries, the need for clinical research, the need for consistent recommendations (regarding diagnosis, treatment and monitoring), the role of reference centres, the requirement for sustained access to treatment, diagnostic and support services, and the role of patient organizations.

A deficiência de alfa-1 antitripsina é uma doença hereditária autossómica co-dominante que resulta numa diminuição dos níveis plasmáticos de alfa-1 antitripsina (também conhecida por inibidor da alfa-1 proteinase) e predispõe os indivíduos afetados ao desenvolvimento de doença pulmonar e hepática precoce. Atualmente não existe cura para a deficiência de alfa-1 antitripsina. No entanto, o tratamento adequado e um elevado padrão de cuidados clínicos podem prevenir que os doentes sejam gravemente afetados e terem que se submeter a intervenções médicas major, como o transplante de órgão. Para além de atuar nos sintomas associados à deficiência de alfa-1 antitripsina, a terapêutica com o inibidor da alfa-1 proteinase é o único tratamento disponível que atua na causa subjacente desta patologia. O diagnostico precoce é importante para assegurar a implementação de estratégias terapêuticas eficientes e para minimizar a destruição adicional da função pulmonar. A deficiência de alfa-1 antitripsina está globalmente sub diagnosticada, em parte devido ao fato desta doença não apresentar sintomas únicos. Este documento foi preparado por um grupo multidisciplinar e visa estabelecer princípios de cuidados abrangentes para a deficiência de alfa-1 antitripsina. Estes incluem a importância dos registros, a necessidade de investigação clinica, a necessidade de recomendações consistentes (no que diz respeito ao diagnostico, tratamento e monitorização), o papel dos centros de referência, a necessidade de acesso sustentado ao tratamento, diagnostico e serviços de suporte, e o papel das associações de doentes.

The impact of weight loss beyond lung function: benefit with respect to asthma outcomes.

OBJECTIVE: We evaluated the effect of weight loss (WL) on lung function (LF) in obese individuals who underwent bariatric surgery, and on asthma control, quality of life, LF, and controller medication in a sub-group of obese asthma (OA) patients. MATERIALS AND METHODS: Obese individuals who underwent bariatric surgery between July 2015 and July 2017 were included in this prospective longitudinal study. They were classified as OA or obese non-asthmatics (O-NA). LF was assessed preoperatively and 6-9 months postoperatively. In OA patients, asthma control, quality of life, and treatment step were evaluated. P < 0.05 was considered significant. RESULTS: Twenty-six patients (OA: n = 8; O-NA: n = 18), 84.6% with class III obesity were enrolled. Preoperatively, OA patients showed worse values of LF parameters, with upper and lower airway CARAT scores of 6.1 ±â€¯3.1 and 13.4 ±â€¯4.1, respectively, and 75% were in step 4 of treatment. After WL, improvements in dynamic volumes, lung capacities, and total resistance were observed in both groups. Despite greater increases in OA patients, no significant differences were observed between groups. In OA patients, improvements in CARAT score of upper (3.9 ±â€¯1.9, p = 0.017) and lower (4.2 ±â€¯4.4, p = 0.027) airways, and in Asthma Life Quality scores (8.1 ±â€¯5.6, p = 0.017) were observed along with a decrease (-1.8 ±â€¯1.0, p = 0.017) in treatment step. CONCLUSIONS: All LF parameters improved after WL. Although the improvement was greater in OA patients, the difference between groups was not significant. Significant improvement from baseline in uncontrolled symptoms of OA patients and quality of life was observed after WL, along with a significant decrease in treatment step.

Chronic coffee consumption and respiratory disease: A systematic review.

PURPOSE: The widespread consumption of coffee means that any biological effects from its use can lead to significant public health consequences. Chronic pulmonary diseases are extremely prevalent and responsible for one of every six deaths on a global level. METHODS: Major medical databases for studies reporting on the effects of coffee or caffeine consumption on a wide range of non-malignant respiratory outcomes, including incidence, prevalence, evolution or severity of respiratory disease in adults were searched. Studies on lung function and respiratory mortality were also considered. RESULTS: Fifteen studies, including seven cohort, six cross-sectional, one case control and one randomized control trial were found. Coffee consumption was generally associated with a reduction in prevalence of asthma. The association of coffee with natural honey was an effective treatment for persistent post-infectious cough. One case-control study found higher risk of chronic obstructive pulmonary disease (COPD) with coffee consumption. No association was found with the evolution of COPD or sarcoidosis. Coffee was associated with a reduction in respiratory mortality, and one study found improved lung function in coffee consumers. Smoking was a significant confounder in most studies. CONCLUSIONS: Coffee consumption was associated with some positive effects on the respiratory system. There was however limited available evidence, mostly from cross sectional and retrospective studies. The only prospective cohort studies were those reporting on respiratory mortality. These results suggest that coffee consumption may be a part of a healthy lifestyle leading to reduced respiratory morbidity.

Severe ketorolac-induced asthma diagnosed by chest computed tomography.

Aspirin-exacerbated respiratory disease (AERD) affects 15% of severe asthmatics and drug reactions cause 200,000 annual deaths in Europe. A 65-year-old lady presented to emergency for progressive abdominal pain. Her medical history included gallstones, asthma, rhinosinusitis and hypertension. She was regularly medicated with inhaled fluticasone, vilanterol and tiotropium, nasal budesonide, pantoprazole, oxazepam and perindopril. She reported partial asthma control and an exacerbation requiring admission to a respiratory ward 6 weeks before. On examination, there was right upper quadrant tenderness and no other changes. Blood tests were normal, and an ultrasound showed gallbladder stones with normal wall. Intravenous ketorolac led to prompt pain resolution. After 30 minutes she became severely dyspnoeic, with an O2 saturation of 85% on high flow O2. She had no breath sounds on the left lung, and there was no wheezing or prolonged expiration. A chest X-ray showed no pneumothorax and a computed tomography (CT) angiography was performed showing bilateral mucoid impaction and sub-segmental atelectasis. Continuous bronchodilation and systemic steroids led to gradual improving in the following 6 hours. After 9 days of admission on a respiratory ward she was discharged home with no symptoms and normal oxygenation. Importantly, she denied previous allergies to nonsteroidal anti-inflammatory drugs (NSAIDs) and had actually taken diclofenac and nimesulid before with no reactions. This report illustrates both an intravenous NSAID causing severe AERD, and how a chest CT may be instrumental for the diagnosis of life-threatening asthma.

Post thyroidectomy gossypiboma.

Gossypiboma is an unfrequent surgical complication wich consists in the presence of a mass of textile origin surrounded by a foreign body reaction. The authors present a clinical case of a left paratracheal gossypiboma, diagnosed during the follow-up of a patient submitted to a total thyroidectomy two years before for a papilary carcinoma.

An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.

BACKGROUND: In 2002 the American Thoracic Society/European Respiratory Society (ATS/ERS) classification of idiopathic interstitial pneumonias (IIPs) defined seven specific entities, and provided standardized terminology and diagnostic criteria. In addition, the historical "gold standard" of histologic diagnosis was replaced by a multidisciplinary approach. Since 2002 many publications have provided new information about IIPs. PURPOSE: The objective of this statement is to update the 2002 ATS/ERS classification of IIPs. METHODS: An international multidisciplinary panel was formed and developed key questions that were addressed through a review of the literature published between 2000 and 2011. RESULTS: Substantial progress has been made in IIPs since the previous classification. Nonspecific interstitial pneumonia is now better defined. Respiratory bronchiolitis-interstitial lung disease is now commonly diagnosed without surgical biopsy. The clinical course of idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia is recognized to be heterogeneous. Acute exacerbation of IIPs is now well defined. A substantial percentage of patients with IIP are difficult to classify, often due to mixed patterns of lung injury. A classification based on observed disease behavior is proposed for patients who are difficult to classify or for entities with heterogeneity in clinical course. A group of rare entities, including pleuroparenchymal fibroelastosis and rare histologic patterns, is introduced. The rapidly evolving field of molecular markers is reviewed with the intent of promoting additional investigations that may help in determining diagnosis, and potentially prognosis and treatment. CONCLUSIONS: This update is a supplement to the previous 2002 IIP classification document. It outlines advances in the past decade and potential areas for future investigation.

Clinical case: Differential diagnosis of idiopathic pulmonary fibrosis.

BACKGROUND: The diagnosis of idiopathic pulmonary fibrosis can be quite challenging, even after careful clinical evaluation, imaging and pathological tests. This case report intends to demonstrate and discuss these difficulties, especially those concerning the differential diagnosis with chronic hypersensitivity pneumonitis. CASE PRESENTATION: A 58-year-old white male presented with shortness of breath, dry cough, fatigue and weight loss for two months. He was a former smoker and had regular exposure to a parakeet and poultry. Physical examination revealed bilateral basal crackles and chest imaging showed subpleural cystic lesions and traction bronchiectasis with a right side and upper level predominance. Auto-antibodies and IgG immunoglobulins to parakeet and fungal proteins were negative. Lung function tests displayed moderate restriction, low diffusion capacity and resting hypoxaemia. Bronchoalveolar lavage showed increased lymphocytes (28%) and neutrophils (12%) and surgical lung biopsy was compatible with a pattern of usual interstitial pneumonia. According to the possibility of either idiopathic pulmonary fibrosis or chronic hypersensitivity pneumonitis, treatment included prednisolone, azathioprine, acetylcysteine and avoidance of contact with the parakeet, but there was an unfavorable response and the patient was subsequently referred for lung transplant. CONCLUSION: Chronic hypersensitivity pneumonitis and idiopathic pulmonary fibrosis can present with the same clinical and radiological manifestations In this case, despite careful evaluation, no definite diagnosis could be achieved.