Educational aspects of rare and orphan lung diseases.

People with rare lung diseases often suffer the burden of delayed diagnosis, limited treatment options, and difficulties in finding expert physicians. One of the reasons for the delay in diagnosis is the limited training for healthcare practitioners on rare diseases. This review explores the main concerns and needs for education on rare lung diseases from the perspectives of both patients and professionals. Despite the increasing interest in rare lung disorders and some recent breakthrough developments on the management of several diseases, healthcare professionals, including general practitioners and hospital workers, receive little education on this topic. Nonetheless, many healthcare professionals show much interest in receiving further training, especially on diagnosis. Patients and families want easier access to high-quality education materials to help them manage their own disease. Well-educated patients are better equipped to deal with chronic diseases, but patient education can be challenging as patients' individual health issues, and diverse backgrounds can create significant barriers. Raising more awareness for rare lung diseases and further development of patient-centred international expert networks like the European Reference Network on Rare Lung Diseases (ERN-LUNG), which includes both experts and patient representatives, are essential for improving care and education on rare lung diseases. Initiatives such as the Rare Disease Day, have been successful in increasing awareness for rare conditions. The development of online tools for accessing information has had positive effects and should be further supported and extended in the future.

Adenosine A2A receptors are up-regulated and control the activation of human alveolar macrophages.

Chronic inflammatory lung diseases remain a health concern and new anti-inflammatory treatments are needed. Targeting adenosine A2A receptors (A2AR) affords robust anti-inflammatory effects in animal models, but the translation of this promising strategy to humans has been challenging, possibly due to interspecies differences in receptor distribution and effects. Thus, we now assessed the efficiency of a selective A2AR agonist to control the activation of fresh human alveolar inflammatory cells. We collected bronchoalveolar lavage fluid from patients with interstitial lung disease and loaded alveolar cells with the intracellular free calcium probe FURA-2/AM. Calcium transients were then recorded in response to superfusion with a proinflammatory peptide (N-formylmethionyl-leucyl-phenylalanine - FMLP), in the absence or presence of the selective A2AR agonist CGS21680. In a second experiment, cells were continuously exposed to FMLP and A2AR density was assessed by immunocytochemistry. Sixteen patients were included, nine for analysis of calcium transients, and seven for immunocytochemistry. When alveolar macrophages were exposed to 100 nM FMLP for 120 s, a peak elevation of intracellular free calcium levels (97.0% over baseline) was recorded; CGS21680 (100 and 300 mM) significantly reduced this peak to 89.5% and 81.5%, respectively. The immunofluorescence analysis revealed a time-dependent increase of A2AR density in alveolar macrophage upon exposure to 1 µM FMLP, up to 148% of control at 6 h. These results show that pro-inflammatory stimuli up-regulate A2AR and their activation dampens the impact of pro-inflammatory stimuli. This supports that targeting A2AR is a promising therapy for human lung inflammatory diseases, especially for diseases with a strong inflammatory component.

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.

Epidemiology of interstitial lung diseases and their progressive-fibrosing behaviour in six European countries.

The PERSEIDS study aimed to estimate incidence/prevalence of interstitial lung diseases (ILDs), fibrosing interstitial lung diseases (F-ILDs), idiopathic pulmonary fibrosis (IPF), systemic sclerosis-associated ILD (SSc-ILD), other non-IPF F-ILDs and their progressive-fibrosing (PF) forms in six European countries, as current data are scarce. This retrospective, two-phase study used aggregate data (2014-2018). In Phase 1, incident/prevalent cases of ILDs above were identified from clinical databases through an algorithm based on codes/keywords, and incidence/prevalence was estimated. For non-IPF F-ILDs, the relative percentage of subtypes was also determined. In Phase 2, a subset of non-IPF F-ILD cases was manually reviewed to determine the percentage of PF behaviour and usual interstitial pneumonia-like (UIP-like) pattern. A weighted mean percentage of progression was calculated for each country and used to extrapolate incidence/prevalence of progressive-fibrosing ILDs (PF-ILDs). In 2018, incidence/105 person-years ranged between 9.4 and 83.6 (ILDs), 7.7 and 76.2 (F-ILDs), 0.4 and 10.3 (IPF), 6.6 and 71.7 (non-IPF F-ILDs), and 0.3 and 1.5 (SSc-ILD); and prevalence/105 persons ranged between 33.6 and 247.4 (ILDs), 26.7 and 236.8 (F-ILDs), 2.8 and 31.0 (IPF), 22.3 and 205.8 (non-IPF F-ILDs), and 1.4 and 10.1 (SSc-ILD). Among non-IPF F-ILDs, sarcoidosis was the most frequent subtype. PF behaviour and UIP-like pattern were present in a third of non-IPF F-ILD cases each and hypersensitivity pneumonitis showed the highest percentage of progressive behaviour. Incidence of PF-ILDs ranged between 2.1 and 14.5/105 person-years, and prevalence between 6.9 and 78.0/105 persons. To our knowledge, PERSEIDS is the first study assessing incidence, prevalence and rate of progression of ILDs across several European countries. Still below the threshold for orphan diseases, the estimates obtained were higher and more variable than reported in previous studies, but differences in study design/population must be considered.

Granulomatous-lymphocytic interstitial lung disease: an international research prioritisation.

The first ever research prioritisation exercise in GLILD: this survey identified areas of interest in the diagnosis, treatment and management of GLILD, which can be used as a roadmap for future research https://bit.ly/3nVuzti.

Comorbidity in idiopathic pulmonary fibrosis - what can biomarkers tell us?

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive parenchymal scarring, leading to dyspnoea, respiratory failure and premature death. Although IPF is confined to the lungs, the importance of IPF comorbidities such as pulmonary hypertension and ischaemic heart disease, lung cancer, emphysema/chronic obstructive pulmonary disease, gastroesophageal reflux, sleep apnoea and depression has been increasingly recognized. These comorbidities may be associated with increased mortality and significant loss of quality of life, so their identification and management are vital. The development of good-quality biomarkers could lead to numerous gains in the management of these patients. Biomarkers can be used for the identification of predisposed individuals, early diagnosis, assessment of prognosis, selection of best treatment and assessment of response to treatment. However, the role of biomarkers for IPF comorbidities is still quite limited, and mostly based on evidence coming from populations without IPF. The future development of new biomarker studies could be informed by those that have been studied independently for each of these conditions. For now, clinicians should be mostly attentive to clinical manifestations of IPF comorbidities, and use validated diagnostic methods for diagnosis. As research on biomarkers of most common diseases continues, it is expected that useful biomarkers are developed for these diseases and then validated for IPF populations. The reviews of this paper are available via the supplemental material section.

ERS International Congress, Madrid, 2019: highlights from the Interstitial Lung Diseases Assembly.

This article discusses a selection of the scientific presentations in the field of interstitial lung diseases (ILDs) that took place at the 2019 European Respiratory Society International Congress in Madrid, Spain. There were sessions from all four groups within Assembly 12: group 12.01 "Idiopathic interstitial pneumonias", group 12.02 "ILDs/diffuse parenchymal lung diseases (DPLDs) of known origin", group 12.03 "Sarcoidosis and other granulomatous ILDs/DPLDs" and group 12.04 "Rare ILDs/DPLDs". The presented studies brought cutting-edge developments on several aspects of these conditions, including pathogenesis, diagnosis and treatment. As many of the ILDs are individually rare, the sharing of experiences and new data that occur during the Congress are very important for physicians interested in ILDs and ILD patients alike.

Managing Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency Disorders: e-GLILDnet International Clinicians Survey.

Background: Granulomatous-lymphocytic interstitial lung disease (GLILD) is a rare, potentially severe pulmonary complication of common variable immunodeficiency disorders (CVID). Informative clinical trials and consensus on management are lacking. Aims: The European GLILD network (e-GLILDnet) aims to describe how GLILD is currently managed in clinical practice and to determine the main uncertainties and unmet needs regarding diagnosis, treatment and follow-up. Methods: The e-GLILDnet collaborators developed and conducted an online survey facilitated by the European Society for Immunodeficiencies (ESID) and the European Respiratory Society (ERS) between February-April 2020. Results were analyzed using SPSS. Results: One hundred and sixty-one responses from adult and pediatric pulmonologists and immunologists from 47 countries were analyzed. Respondents treated a median of 27 (interquartile range, IQR 82-maximum 500) CVID patients, of which a median of 5 (IQR 8-max 200) had GLILD. Most respondents experienced difficulties in establishing the diagnosis of GLILD and only 31 (19%) had access to a standardized protocol. There was little uniformity in diagnostic or therapeutic interventions. Fewer than 40% of respondents saw a definite need for biopsy in all cases or performed bronchoalveolar lavage for diagnostics. Sixty-six percent used glucocorticosteroids for remission-induction and 47% for maintenance therapy; azathioprine, rituximab and mycophenolate mofetil were the most frequently prescribed steroid-sparing agents. Pulmonary function tests were the preferred modality for monitoring patients during follow-up. Conclusions: These data demonstrate an urgent need for clinical studies to provide more evidence for an international consensus regarding management of GLILD. These studies will need to address optimal procedures for definite diagnosis and a better understanding of the pathogenesis of GLILD in order to provide individualized treatment options. Non-availability of well-established standardized protocols risks endangering patients.

Research highlights from the 2018 ERS International Congress: interstitial lung diseases.

This article reviews a selection of the scientific presentations on interstitial lung disease (ILD)/diffuse parenchymal lung disease (DPLD) that were made at the 2018 European Respiratory Society (ERS) International Congress in Paris. A number of advances in the epidemiology, pathogenesis, diagnosis and treatment of these disorders were presented and discussed by clinicians and researchers. The research topics span over all four groups of ERS Assembly 12: Interstitial Lung Diseases (Group 12.01: Idiopathic interstitial pneumonias; Group 12.02: ILD/DPLD of known origin; Group 12.03: Sarcoidosis and other granulomatous ILD/DPLD; Group 12.04: Rare ILD/DPLD).

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.

New members of the ECMC and lessons from the ATS Conference.

Meet the new members of the @EarlyCareerERS committee http://ow.ly/DfHA30kE7sk.

Neuronal Adenosine A2A Receptors Are Critical Mediators of Neurodegeneration Triggered by Convulsions.

Neurodegeneration is a process transversal to neuropsychiatric diseases and the understanding of its mechanisms should allow devising strategies to prevent this irreversible step in brain diseases. Neurodegeneration caused by seizures is a critical step in the aggravation of temporal lobe epilepsy, but its mechanisms remain undetermined. Convulsions trigger an elevation of extracellular adenosine and upregulate adenosine A2A receptors (A2AR), which have been associated with the control of neurodegenerative diseases. Using the rat and mouse kainate model of temporal lobe epilepsy, we now tested whether A2AR control convulsions-induced hippocampal neurodegeneration. The pharmacological or genetic blockade of A2AR did not affect kainate-induced convulsions but dampened the subsequent neurotoxicity. This neurotoxicity began with a rapid A2AR upregulation within glutamatergic synapses (within 2 h), through local translation of synaptic A2AR mRNA. This bolstered A2AR-mediated facilitation of glutamate release and of long-term potentiation (LTP) in CA1 synapses (4 h), triggered a subsequent synaptotoxicity, heralded by decreased synaptic plasticity and loss of synaptic markers coupled to calpain activation (12 h), that predated overt neuronal loss (24 h). All modifications were prevented by the deletion of A2AR selectively in forebrain neurons. This shows that synaptic A2AR critically control synaptic excitotoxicity, which underlies the development of convulsions-induced neurodegeneration.

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.

[Pulmonary Amyloidosis: A Diagnostic Challenge]. / Amiloidose Pulmonar: Um Desafio Diagnóstico.

Amyloidosis is characterized by amyloid extracellular deposition in organs and tissues. Pulmonary involvement is a rare manifestation of the disease and it can be focal or as part of systemic amyloidosis. We report two cases. Case 1: 71 year-old female with bronchiectasis and Sjogrenâ syndrome, who complained of anorexia, weight loss and a productive cough. The diagnostic study included a surgical lung biopsy and histological examination demonstrated pulmonary amyloidosis. Case 2: 83 year-old male patient, ex-smoker, asymptomatic, whose routine chest x-ray showed a nodular opacity in the right lung field. A transthoracic biopsy revealed an amyloid lung tumor. These cases illustrate a rare disease which in Case 1 also coexisted with Sjögrenâs syndrome and bronchiectasis. The most important differential diagnosis is cancer and so a definitive diagnosis is essential, as amyloidosis is usually benign and indolent.

A amiloidose caracteriza-se pela deposição extracelular de substâcia amilóide em diferentes órgãos e tecidos. O atingimento pulmonar é raro e pode acontecer de forma isolada ou associado a doença sistémica. Descrevem-se dois casos clínicos. Caso 1: Mulher de 71 anos, com antecedentes de bronquiectasias e síndrome de Sjögren, que referia anorexia, emagrecimento e tosse produtiva. O estudo incluiu uma biópsia pulmonar cirúrgica que demonstrou amiloidose localizada ao aparelho respiratório. Caso 2: Homem de 83anos, ex-fumador, assintomático. Enviado por opacidade nodular em radiografia de tórax de rotina. A biópsia pulmonar transtorácica revelou um tumor amilóide do pulmão (amiloidoma). Estes casos ilustram uma doença rara que no Caso 1 está associada a bronquiectasias e síndrome de Sjögren. O diagnóstico diferencial mais importante é a patologia neoplásica, sendo o diagnóstico definitivo importante, já que a amiloidose pulmonar é geralmente benigna e indolente.

Effect of free radicals on adenosine A(2A) and dopamine D2 receptors in the striatum of young adult and aged rats.

Parkinson's disease (PD) is a prevalent age-related motor dysfunction resulting from the hyperactivity of the indirect striatal pathway, which is controlled in an antagonistic manner by inhibitory dopamine D2 and facilitatory adenosine A(2A) receptors. Thus, dopamine precursors like l-DOPA are the standard therapy and A(2A) antagonists are now tested as anti-parkinsonians. Increased free radicals levels occur on aging and are proposed to be a contributing factor for PD. We now tested if free radicals affected A(2A) and D2 receptors in striatal membranes of young adult (2 months) and old (24 months) rats. The A(2A) receptor antagonist [3H]SCH 58261 bound to striatal membranes with a KD of 0.9 nM and a Bmax of 953 fmol/mg protein in young rats and with a KD of 0.8 nM and a Bmax of 725 fmol/mg protein in aged rats (24% decrease). The D2 receptor antagonist [3H]raclopride bound to striatal membranes with a KD of 4.0 nM and a Bmax of 598 fmol/mg protein in young rats and with a KD of 4.3 nM and a Bmax of 368 fmol/mg protein in aged rats (38% decrease). Exposure of striatal membranes to a free radical generation system (2 mM FeSO4 and 4 mM ascorbate) caused a similar decrease of [3H]SCH 58261 (35%) and [3H]raclopride (37%) binding in young adult rats but caused a greater decrease of [3H]SCH 58261 (49%) than of [3H]raclopride (20%) binding in aged rats. Thus, in aged rats, there is an unbalance of A(2A)/D2 receptor density favouring A(2A) receptors, which is restored on exposure to free radicals. This supports the hypothesis that the effectiveness of A(2A) receptor antagonists as anti-parkinsonians, demonstrated in young adult animals, may not be affected by a modified A(2A)/D2 receptor density in aged individuals suffering from exposure to increased free radical levels, as occurs in PD.

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.

[Lung abscess and thoracic empyema: retrospective analysis in an internal medicine department]. / Abcesso pulmonar e empiema torácico: análise retrospectiva num serviço de medicina interna.

INTRODUCTION: Lung abscess is a collection of necrotic and suppurated tissue located at the pulmonary parenchyma. Empyema is defined as the presence of pus in the pleural space. OBJECTIVES: To study the clinical and microbiological characteristics, treatment and prognosis of patients with lung abscess and/or empyema admitted to an Internal Medicine ward. METHODS: A retrospective analysis of medical records was performed, including all patients admitted to an Internal Medicine ward for lung abscess or empyema, between 2000 and 2008. RESULTS: Thirty patients were included (22 males/ eight females), accounting for 0.18% of all patients admitted in this ward in the same period. Three patients had pulmonary abscess, 18 empyema, and nine both diseases. The average age was 68.5 years (31 to 90). The most frequent complaints were dyspnoea (90%), fever (73.3%), cough (66.7%), weight loss (60%) and chest pain (53.3%). The most frequent associated disorders were stroke associated disability (46.7%), heart failure (43.3%) and arterial hypertension (33.3%). Thoracentesis was performed in all patients with empyema. In one patient with lung abscess an anaerobic microorganism was identified. In patients with empyema, cultures were positive in 61.1% of cases, with a slight predominance of methicillin-resistant Staphylococcus aureus (27.3%) and Prevotella intermedia (18.2%). In patients with both abscess and empyema, cultures of the abscess were positive in 44.4% and of the pleural fluid in 33.3%, with no predominant microorganism. Empiric antimicrobial therapy was started in all patients and later adapted to the antibiotic sensitivity test results. Surgery was performed in three patients. Seven patients (23.3%) died during admission. The average age of the patients who died was 81.3 years and of those who survived was 64.5 years. CONCLUSION: Lung abscess and empyema are infrequent diseases in an Internal Medicine ward, affect mostly males and have unspecific clinical manifestations. The chest X-ray, computed tomography (CT) and thoracentesis were the main diagnostic tests. Most cultures were negative. Medical treatment was the most frequent choice, with surgery being used in 10% of cases. Older age and multiple associated conditions were associated with a worse prognosis.

[Mediastinal masses: case series]. / Massas mediastínicas: análise de uma casuística.

INTRODUCTION: Mediastinal masses are tumoral lesions arising from intra-thoracic organs. They are an infrequent diagnostic challenge, requiring a structured clinical and radiological approach. OBJECTIVES: The study of the clinical, radiological and pathological characteristics, treatment and prognosis of patients, with mediastinal masses, admitted to an Internal Medicine ward in an University Hospital. METHODS: A retrospective analysis of the medical records of patients with this diagnosis made between years 2000 and 2008. RESULTS: Twenty-eight patients were included (15F/13M), with a mean age of 55.5 years (17-88). Twenty-six patients presented with symptoms, most frequently, dyspnoea, fatigue, dry cough, chest pain and anorexia. At examination, six exhibited superior vena cava syndrome. Chest X-ray showed pathological changes in 26. Chest CT scan added relevant information in all cases whenever it was performed. Histology was most frequently obtained by mediastinoscopy, open surgical biopsy, percutaneous thoracic biopsy and at necropsy. Histological diagnosis was not possible in ten patients. Final diagnoses included: lymphoma in four patients; sarcoidosis, thymic hyperplasia and undifferentiated squamous carcinoma of unknown origin in two patients each; other diagnosis in single cases were: thyroid teratoma, thymoma, atrial myxoid malignant fibrous histiocytoma, ganglioneuroblastoma, neuroendocrine thymic carcinoma, squamous cell lung cancer and germinative cell tumour. Thirteen patients were submitted to surgery, chemo and/or radiotherapy. Fifteen patients died during admission or when in follow-up. CONCLUSIONS: At our center, mediastinal masses are frequently of a malignant origin, affecting relatively young people; a late diagnosis and an associated poor prognosis was the rule, prompting for early intervention to improve outcome.