Cystic Fibrosis (CF)
Bronchiectasis (BE)
ldiopathic Bronchiectasis (IB)
Allergic Bronchopulmonary Aspergillosis (ABPA)
Hyper igE syndrome
Rheumatoid Arthritis (RA) lmmunodeficiency associated bronchiectasis
Sarcoidosis (SARC)
Mesothelioma (MSTO)
Pulmonary Hypertension (PH)
Chronic thromboembolic pulmonary hypertension (CTEPH)
Pulmonary arterial hypertension (PAH)
PH owing to lung disease and/or hypoxia PH with unclear multifactorial mechanism Pulmonary venoocclusive disease
lnterstitial Lung Disease (ILD)
ldiopathic Pulmonary fibroses (IPF) Lymphangioleiomyomatosis (LAM) Connective tissue diseases Pulmonary alveolar proteinosis Eosinophilic pneumonia Langerhans Hystiocitosis X
Other Rare Lung Diseases (ORLD)
Lung malformations
Disorders of respiratory drive (Ondine curse)
Acute Respiratory Distress Syndrome lnfa ntile Apnea
Chronic Lung Allograft Dysfunction (CLAD)
Bronchiolitis obliterans syndrome (BOS) Neutrophilic reversible allograft dysfunction Restrictive allograft syndrome (RAS)
Primary Ciliary Dyskinesia (PCD)
PCD including Reduced Generation of multiple Motile Cilia (RGMC), Kartagener Syndrome
Cystic Fibrosis (CF)
Cystic fibrosis (CF) is a progressive, inherited genetic disease that causes persistent lung infections and limits the ability to breathe over time. With improvements in diagnosis and care, life expectancy is increasing progressively and CF has become a disease of adults.
Causes
CF is a genetic condition, caused by defects in a gene called cystic fibrosis transmembrane regulator (CFTR) that is responsible for regulating the transport of salt and water across cells lining the airway and gut. This, along with recurrent infections, can result in a build-up of thick, sticky mucus in the body’s airways – particularly the lungs and digestive system. There are no known environmental causes of the disease, although exposure to tobacco smoke, air pollution and allergens, may all contribute to the long-term progression of the condition.
Symptoms
CF used to be thought of as a disease of the lungs and digestive system, but it is now known to affect several organs in the body including the liver, bones, ear, nose and sinuses. Symptoms of CF include:
- A cough producing phlegm or mucus, frequent respiratory infections and progressive breathlessness
- Sinusitis
- Difficulty absorbing food, leading to poor nutrition
- Diabetes
- Cirrhosis, or scarring, of the liver
- Reduced fertility
Chronic, or persistent, infection cause progressive damage to the airways and lungs, including bronchiectasis and eventually lead to failure of the lungs due to their inability to maintain normal levels of oxygen and carbon dioxide in the body.
Diagnosis and Treatment
Diagnosis of CF can be achieved by screening new-born babies as part of the newborn blood spot test (heel prick test). A sweat test should also be performed to check for abnormally high salt content in the sweat, indicative of CF. Genetic testing can confirm the presence of the faulty gene, or the “carrier” status of someone with a family history of CF.
The multi-organ involvement in CF makes it a complex disease to treat. Therefore, pwCF should always receive care in a specialized CF center where care is provided by a multi-disciplinary team consisting of at least a specialist physician, nurse specialist, physiotherapist, dietician, psychologist, and a social worker. Until a decade ago, all therapies were solely based on the treatment of symptoms due to loss of CFTR function. There are airway clearance techniques and nebulized drugs for mucus obstruction, oral and inhaled antibiotics for infections, and pancreas enzymes for malabsorption. They have all led to substantial improvement in life expectancy and quality of life.
New targeted therapies have caused a tremendous shift in the care for pwCF in many countries. CFTR modulating drugs (CFTR modulators) are the first drugs that succeed to treat the underlying genetic defect of cystic fibrosis and thereby to change the lives of pwCF. They have the unique potential to prevent disease expression and limit disease progression. Ivacaftor, a so-called potentiator, was the first modulator that got market approval by the EMA in 2012, specifically for patients with gating mutations (class III), which covers ~ 4% of pwCF worldwide. In 2021, EMA approved the triple combination elexacaftor/tezacaftor/ivacaftor for pwCF that carry at least one F508del mutation. Overall, the advent of these CFTR modulators are life-changing for up to 90% of pwCF, but there is still a wide range in individual responses. Unfortunately, not all pwCF can benefit from these highly effective modulator drugs because of high pricing, or because their (rare) mutation is not listed for reimbursement. Currently, there are multiple pharmaceutical companies that have modulator therapies or alternatives like mRNA and gene-therapy in their pipeline.
ERN-LUNG Actions
The ERN-LUNG Cystic Fibrosis Core Network works closely with the European Cystic Fibrosis Society (ECFS) to develop high quality standards of care and best practice guidelines, and to accelerate research and orphan drug development through it’s well-established Clinical Trials Network (ECFS-CTN). The ECFS has been qualified by the European Medicines Agency (EMA) as an appropriate platform for the collection of CF data for Post Authorization Safety Studies and Post Authorization Efficacy Studies. Besides further elaboration of our CTN, our research priorities include the further development of Standards of Care and European SOPs for several frequently used diagnostic tools, the setup of Quality Control measures using a Delphi-procedure within the network, collaboration on set-up of eLearning on CF focusing on both patients and caregivers, and collaboration with EMA to pave the way for further treatment possibilities for patients with ultra-rare variants.
Inez Bronsveld
Lead: Cystic Fibrosis (CF)
Primary Ciliary Dyskinesia (PCD)
Primary Ciliary Dyskinesia (PCD) is a clinically and genetically heterogeneous group of congenital diseases based on the malfunction of motile cilia. Approximately half of those affected with PCD present a mirror-image arrangement of the internal organs (situs inversus), which is referred as Kartagener syndrome. More specifically, Kartagener syndrome is a rare congenital malformation consisting of the triad of situs inversus, bronchiectasis and sinusitis. An estimated 500,000 – 800,000 people worldwide are affected by PCD, but unfortunately the diagnosis is made in only a small proportion of patients, so the definite number is likely to be higher. This is because the disease is unknown even to many doctors. Moreover, the tools necessary for the diagnosis of PCD requires expertise and is time consuming and expensive; thus it is currently available only in a few specialized centers.
Causes
Pulmonary disease in PCD is related to defects in lung defence and clearance mechanisms due to abnormal ciliary structure and function with impaired mucociliary clearance. This corresponds to an impairment in the coordinated movement of the cilia, thin hair-like constituents of virtually every cell in the human body, that serves an important transport function and thus contributes to the cleaning of the airways of the upper respiratory tract (nose, paranasal sinuses) including the smallest bronchi of the lungs. As a result, mucus progressively accumulates in the airways, which cannot be removed. PCD patients thus suffer frequent infections of the lungs, middle ear and sinuses. Over time, these infections become chronic and can lead to permanent damage, especially in the lungs.
Symptoms
The symptoms of PCD can be already seen at birth: breathing is hard, the nose is obstructed by secretions, coughing is present, and part of the lung may even be collapsed. In addition, PCD patients develop a chronic cough and frequently have clinically severe respiratory infections. Since airway cleaning is disturbed, not only the respiratory tract in the lung but also the nasal passages have chronic obstruction. Already in early infancy, there is an enlargement of the tonsils (adenoids) and there are frequent middle ear infections. Chronic middle ear effusions are a frequent cause of hearing loss, which is often spontaneous in adolescence. School age children suffer from frequent sinus infections. The course of the disease is usually determined by the extent of pulmonary involvement. Infections of the lung may lead to collapse of a portion of the lung; if it is not possible to reopen this section of the lung, a chronic infection may develop there. Additionally, thick mucus can completely obstruct the bronchi and lead to destruction of not only the bronchi (bronchiectasis) but also the entire lung section. Since these damaged sections of the lung are very susceptible to pathogens, infections are relatively unhindered and can spread to other parts of the lung.
Since cilia occur in almost all cells of the body, other organ systems can be affected. Male PCD patients are often infertile due to a lack of sperm motility and potentially affected women have a slightly increased risk for ectopic pregnancies. Rarely, other diseases such as hydrocephalus (enlargement of the cerebrospinal fluid spaces), retinitis pigmentosa (a rare retinal disease), cystic kidney disease, certain heart defects or hearing loss also occur in PCD patients.
Diagnosis and Treatment
Early diagnosis of PCD is important in order to provide prophylactic treatment to prevent or decrease damage to the respiratory system from recurrent infections. Diagnosis is based on the characteristic clinical features features: persistent wet cough, situs anomalies, congenital cardiac defects, persistent rhinitis, chronic middle ear disease with or without hearing loss, a history in term infants of neonatal upper and lower respiratory symptoms or neonatal intensive care admittance. Diagnostic methods include transmission electron microscopy (TEM) identifying specific ciliary ultrastructural defects in biopsy samples and high-speed video microscopy to assess cilia waveform and beat frequency. For further clarification, a novel diagnostic immunofluorescence microscopy (IF) method and electron microscopy can be used to help identify individual defects of ciliary structure. Molecular genetic testing of the causative genes can confirm diagnosis; currently, mutations in more than 40 genesare associated with PCD.If disease-causing mutations are known in a family, prenatal diagnosis can be performed. PCD is inherited in an autosomal recessive manner. Genetic counselling should be provided to affected families. Rare reports mention X-linked or autosomal dominant inheritance.
Although recurrent respiratory infections cannot be avoided completely by a consistent treatment, the frequency and severity of exacerbations can be reduced significantly. Aggressive treatment to improve mucus clearance (physiotherapy and inhalation therapy) is recommended. Bacterial infections are immediately treated with antibiotics and routine immunization is recommended. Sinus disease can be treated with nasal steroids and nasal lavage. Polyps may require surgical treatment. If a section of the lung should collapse, it is necessary to determine whether the lung section can be preserved by bronchoscopy. Patients with end-stage lung disease are candidates for lung transplantation. Audiological assessment, hearing aids, and communication assistance should be offered where necessary.
ERN-LUNG Actions
Within ERN-LUNG, we optimize current efforts to improve PCD patient care and quality of life. We will improve and formalize cross border patient care, with exchange of biological material for diagnostic purposes as the current main means in PCD. We will continuously update diagnostic and clinical PCD guidelines with support by the European Respiratory Society (CRC BEAT-PCD). Ongoing teaching and training activities will be updated according to regular training gap analyses. All centres participate in the International PCD Registry to facilitate evaluation of clinical outcomes and to enable large clinical studies. The recently established ERN-LUNG PCD Clinical Trial Network (CTN) chaired by Prof. Kim G Nielsen (Kim.G.Nielsen@regionh.dk) and co-chaired by Dr. Johanna Raidt (Johanna.Raidt@ukmuenster.de) and Bernard Maitre (bernard.maitre@aphp.fr) will foster clinical research and enable us to provide evidence based therapy of PCD in the future.
Heymut Omran
Lead: Primary Ciliary Dyskinesia (PCD)
Interstitial Lung Disease (ILD)
Interstitial lung diseases (often abbreviated as ILD) include a heterogeneous, i.e. inconsistent group of various lung diseases affecting the interstitial tissue of the lung (the so-called interstitium) and/or the pulmonary alveoli. Unfortunately, ILDs are orphan, i.e. sometimes unknown and rare lung diseases, which often leads to uncertainty. Common to all ILDs is that they usually have typical clinical, imaging and pathological changes. ILDs are separated in several groups:
– There are so-called granulomatous ILDs, e.g. Sarcoidosis or hypersensitivity pneumonitis (also known as exogenous allergic alveolitis). The latter is an allergic overreaction of the lung by inhaled dusts – an often-known subspecies is e.g. the so-called bird-fancier’s lung.
– Another group of ILDs includes rare interstitial lung diseases such as lymphangioleiomyomatosis (LAM), pulmonary alveolar proteinosis or eosinophilic pneumonia.
– Separated from these diseases, is another disease group – the idiopathic interstitial “pneumonia” which also includes Idiopathic Pulmonary Fibrosis (IPF), a constantly progressive disease with a significant burden of disease.
– The fourth group contains diseases which are associated with known diseases, mainly systemic / autoimmune diseases such as scleroderma – or rheumatoid arthritis associated ILDs. ILDs caused by drugs also fall into this group.
Causes
The causes of ILDs are manifold and are differentiated into known and unknown causes. Increased scarring of the lungs causes pulmonary fibrosis in some cases. Known causes include, for example, effects of drugs on the lung (e.g., amiodarone or MTX) or the involvement of the lung in a connective tissue disease.
Symptoms
ILDs usually have a gradual onset and the symptoms are often completely unspecific at the beginning. Cough and shortness of breath during exercise are the first symptoms. As a rule, many months pass before the diagnosis of ILD can be made. In advanced disease there may be blue or purple discolouration especially of lips, hands and feet (due to very low oxygen in the blood) and clubbing, or swelling, of the fingers.
Treatment
Most patients who are affected by this disease are confused by the large number of technical terms and the many different causes of these diseases. Since these are very complex clinical manifestations, the diagnosis and treatment are difficult and require a comprehensive and cross-disciplinary expert knowledge and assessments by several specialist disciplines – in particular internal medicine / pulmonology, radiology and pathology. The diagnosis usually includes examining the detailed history and conducting various lung function and blood tests, radiological and bronchoscopic examinations.
The therapy varies according to the type of lung disease and must be in consultation with the patient. The treatment options vary greatly depending on the type of disease and its prognosis. Only in detailed discussion with the patient can the decision on the necessity and type of therapy be made jointly. Other important therapy components are the treatment of certain comorbidities, regular vaccinations, e.g. against flu (influenza), if necessary a long-term oxygen therapy or the participation in lung sport and a rehabilitation.
ERN-LUNG Actions
The ERN-LUNG ILD Core Network works closely with the patient organization European Idiopathic Pulmonary Fibrosis and Related Disorder Federation (EU-IPFF) on joint activities to disseminate information on patient access and quality of care in Europe. In collaboration with the ERS, we are also involved in the ARIANE-IPF project, which is one of the Clinical Research Collaboration (CRC) initiatives of the ERS to create a European IPF meta-registry. With the aim of encouraging initiatives to improve and verify the diagnostic accuracy of ILD, we have also contributed to a study developing a novel “virtual” diagnosis software called “IPFdatabase”. You may find more information and useful infographics on the ELF webpage.
Vincent Cottin
Lead: Interstitial Lung Disease (ILD)
Bronchiectasis (BE)
Bronchiectasis (BE) is a common, progressive respiratory disease characterised by permanent dilatation of the bronchi and presenting with a clinical syndrome of cough, sputum production and recurrent respiratory infections. Once considered an “orphan” disease, there is growing evidence of benefit for various aspects of treatment now in bronchiectasis. The most common reason for initial referral is a chronic productive cough or recurrent respiratory tract infections.
Causes
BE can be caused by severe infections such as pneumonia or non-tuberculous mycobacterial infection, autoimmune conditions such as rheumatoid arthritis, inflammatory disorders such as allergic bronchopulmonary aspergillosis and inherited conditions including primary ciliary dyskinesia. There are more than 100 conditions recognised to be associated with BE. Despite testing in 30-60% of patients the cause is not identified and patients are classified as idiopathic.
Symptoms
Patients report cough, sputum production, recurrent respiratory tract infections and frequently other symptoms such as fatigue, chest pain and haemoptysis (coughing up of blood).
Diagnosis and Treatment
The above symptoms can overlap with the symptoms of other chest conditions like Chronic Obstructive Pulmonary Disease (COPD) or asthma, so it is common for people to have the tests for these conditions first, before BE is suspected. Common diagnostic tests include a chest x-ray, spirometry test, sputum microbiology analysis, followed by more specialist immunological tests, screening for adult cystic fibrosis and a computerised tomography (CT) scan needed to diagnosis BE.
Treatment is targeted towards reducing exacerbations, improving symptoms and improving quality of life through treating bacterial infection, promoting mucociliary clearance, reducing inflammation and promoting healthy lifestyles. Unfortunately the evidence for most treatments recommended in the 2017 European Respiratory Society guidelines is poor due to an absence of high quality research studies.
ERN-LUNG Actions
The ERN-LUNG Bronchiectasis Core Network is working to improve the quality of care for patients with BE in Europe and the evidence base for evaluation and treatment of the disease. For this purpose it is also closely aligned to the European Respiratory Society Clinical Research Collaboration EMBARC. We are also very active in research – one of our highlights is the EMBARC-BRIDGE study, whose objectives are to define and validate endotypes of stable BE, to develop biomarkers that can be used to classify BE patient phenotypes and endotypes, among others. Our patient representatives and medical experts have contributed to the development of content and resources curated on the Bronchiectasis Patient Priorities website, an initiative of the European Lung Foundation.
Eva Polverino
Lead: Bronchiectasis (BE)
Pulmonary Hypertension (PH)
There are two main types of pulmonary vascular diseases: pulmonary embolism and pulmonary hypertension.
Pulmonary embolism (PE) is a blocked blood vessel or artery in the lungs due to blood clots, often following thrombosis in the veins of the leg or elsewhere.
Pulmonary hypertension (PH) is a pathophysiological disorder that may involve multiple clinical conditions and can complicate the majority of cardiovascular and respiratory diseases. PH refers to high blood pressure in the pulmonary arteries, which carry blood from the heart to the lungs. It can damage the right side of the heart, impairing its functioning and making it unable to efficiently circulate blood around the body. This in turn can lead to heart failure and can be fatal.
Causes
Pulmonary embolism is usually caused by a blood clot originating in the legs or pelvis which can then break off and travel along the venous system to the pulmonary arteries. Certain groups of people are more susceptible to developing blood clots, including the elderly, people who have undergone medical or surgical events that have resulted in long periods of bed rest, people with a previous history of blood clots and those under hormone replacement therapy and oral contraceptive therapy.
Pulmonary hypertension’s causative factors are more varied, ranging from genetic to pre-existing conditions to idiopathic. There are 5 groups of PH and each is treated very differently :
– Pulmonary arterial hypertension (PAH) due to different causes
– Pulmonary hypertension due to left heart diseases
– Pulmonary hypertension due to lung diseases or lack of oxygen (hypoxia)
– Chronic thromboembolic pulmonary hypertension (CTEPH), where the blood vessels are blocked or narrowed by blood clots
– Pulmonary hypertension with an unclear cause or several different triggers
Symptoms
People with pulmonary embolism may have no symptoms, or they may experience any of the following: Breathlessness, chest pain, cough, haemoptysis (coughing up blood), fever, rapid heart rate, rapid breathing, fainting.
Pulmonary hypertension is characterized by breathlessness, extreme tiredness (fatigue), reduced ability to exercise, chest pain, haemoptysis (coughing up blood), hoarseness.
Diagnosis & Treatment
Pulmonary embolism (PE) is often difficult to diagnose. It usually involves identifying symptoms and looking at a person’s medical history, along with routine tests such as a chest x-ray or an electrocardiogram. Tests to check for the condition also include a blood test, called a D-dimer, to rule out pulmonary embolism and computed tomography (CT) angiography. In an emergency situation, a test called a bedside echocardiography, which uses ultrasound to create images of the heart, can help to diagnose PE. Additionally, ultrasounds can help check if there’s a blood clot in the leg of pelvic veins, which could lead to PE.
PE can be treated by anticoagulant drugs to reduce the blood’s ability to thicken or thrombolytic drugs which can dissolve the clots in the pulmonary arteries (recommended for people who have persistent heart failure and a high risk of PE). If these treatments don’t work, surgery to remove the clot is another option.
Pulmonary arterial hypertension (PAH) is difficult to diagnose early on as many patients have no or few symptoms or just appear tired and unfit. Later in the course of the disease, signs of right heart failure are indicative of PAH. PAH can develop at any age but the average age of a person diagnosed with PAH is 50 years. An initial assessment involves analysis of a person’s symptoms and other factors such as age and existing conditions. The two main procedures used to confirm the diagnosis are an echocardiogram that is used to estimate the pressure in the pulmonary arteries, and right heart catheterisation, an invasive procedure that measures the blood pressure in the right side of the heart and pulmonary arteries.
There is no known cure for PH but basic drugs such as anticoagulants or oxygen supplementation can help. Patients with PAH can be treated with specific therapies, known as prostacyclins, endothelin receptor antagonists or type 5 phosphodiesterase inhibitors. If pulmonary hypertension is due to chronic thrombo-embolic disease, a surgical operation known as pulmonary endarterectomy can cure the disease by clearing the clot and scar material in the arteries of the lungs. Lung transplantation may be an option in severe conditions.
ERN-LUNG Actions
The ERN-LUNG PH Core Network, composed of both pulmonologists and cardiologists, is one of three partners of a Task force on CTEPH, along with ERS and the International CTEPH Association. CTEPH is an important treatable form of PH and we are interested to produce a clinical statement. We are working on updating the current ESC / ERS guidelines on PH, to have 3 types of guidelines for experts, non-experts and patients, with the aim to have a new publication in 2022. An ERS Clinical Research Collaboration (CRC) on PH/PAH has been approved, acronymed PHAROS, with the objective of setting up a platform for clinical research in PH in close collaboration with ERN LUNG, to coordinate research on topics not of immediate interest to the industry. Some of the initial projects will focus on establishing an inventory of existing and local PH registries and look at interoperability, on evaluating patient access to care across Europe, on characterising PH patients with failing right ventricle, and on phenotyping and treatment of patients with PH due to lung diseases. Our research priorities in general include the improvement of screening and early diagnosis of heritable pulmonary hypertension, the development of risk stratification instrument in pulmonary hypertension, defining the best treatment strategies of PAH and CTEPH.
Marc Humbert
Lead: Pulmonary Hypertension (PH)
Mesothelioma (MSTO)
Mesothelioma (MSTO) is a rare malignant form of cancer that develops in the lining of the lungs, abdomen or heart and is caused due to asbestos exposure. It is most frequently located in the thoracic (pleural MSTO) or abdominal cavity (peritoneal MSTO). The average life expectancy of MSTO patients is 12-21 months after diagnosis.
Causes
MSTO is almost always caused by exposure to asbestos, a group of minerals made of microscopic fibres that can easily get stuck in the lungs thereby damaging them over time. Although in most countries there is restrictive legislation on the use of asbestos for many years, the number of patients diagnosed with MSTO is still rising. This can be ascribed to the fact that asbestos is still widely present in the western world, for instance on roofs of houses, so still people get exposed to asbestos. Aging also increases the risk of getting an asbestos related disease.
Symptoms
The symptoms of MSTO tend to develop gradually over time. They typically don’t appear until several decades after exposure to asbestos. Common signs and symptoms include chest or abdominal pain, shortness of breath, fatigue, loss of appetite and unexplained weight loss, coughing, difficulty breathing and swallowing, fever and night sweats.
Diagnosis and Treatment
After recognizing symptoms, the key specialist diagnostic tests include a chest or abdominal X-ray, a computerised tomography (CT) scan, a thoracoscopy or laparoscopy. Mesothelioma biopsies remove cancerous fluid or tissue for analysis that will then be used for histopathology to confirm the diagnosis and histologic type of mesothelioma, as well as determine treatment options.
Overall treatment options are limited. The only registered treatment at present is chemotherapy. This chemotherapy increases general survival but the increase in time is unfortunately very limited. Surgery in mesothelioma may be an option in a limited number of patients.Fortunately there are improvements in the knowledge on how the disease develops, and improvements in treatment options.
ERN-LUNG Actions
The ERN-LUNG MSTO Core is a member of the national Network Genomic Medicine (nNGM), a network aiming for nationwide accessibility of molecular diagnostics and improvement of availability of clinical trials for patients with lung cancer in Germany. We are collaborating with the European Respiratory Society on developing a new guideline on the management of malignant pleural MSTO. We are also collaborating with EuraCAN (ERN on rare adult solid cancers, subgroup on thoracic tumours) with whom we have clear cross-over aspects.
Joachim Aerts
Lead: Mesothelioma (MSTO)
Alpha-1 AntiTrypsin Deficiency (AATD)
Alpha 1-antitrypsin deficiency (AATD) is a genetic disease. People with AAT deficiency have low levels of AAT protein in their blood and are more likely to get lung disease earlier in their life than someone with higher levels of AAT. The most common lung disease that people with AAT deficiency are likely to get is chronic obstructive pulmonary disease (often called COPD).
Causes
Mutations in the SERPINA1 gene cause AAT deficiency. In normal state, AAT protects the body from a powerful enzyme called neutrophil elastase that is secreted by white blood cells to fight infection. Hence without enough functional alpha-1 antitrypsin, neutrophil elastase attacks normal tissues especially in the lungs and destroys alveoli, causing lung disease. Abnormal AAT can also accumulate in the liver and damage this organ.
Symptoms
AAT deficiency can cause similar lung symptoms to those seen in COPD or asthma. Early symptoms include cough, excess sputum and wheezing. Symptoms may not appear all the time at first, which means that some patients who just have wheezing may be diagnosed with asthma by mistake.Affected individuals often develop emphysema, which is a lung disease caused by damage to the small air sacs in the lungs (alveoli). There may also be symptoms such as jaundice, caused by the disease’s effect on the liver, or panniculitis, an inflammation of the fatty layer under the skin, in rare cases.
Diagnosis and Treatment
AATD is diagnosed through measuring AAT serum levels through a blood test, and targeted genotyping or genetic testing to look at the SERPINA1 gene sequence. Computer tomography (CT) lung densitometry is also used to detect the progression of emphysema.
AATD can be controlled but not cured. However, early diagnosis is very important so that treatment can begin as soon as possible. General treatments for lung damage might be prescribed such as inhaled bronchodilators, supplemental oxygen or pulmonary rehabilitation. Intravenous alpha-1 antitrypsin augmentation therapy is available in some European countries as a limited “cure” option.
ERN-LUNG Actions
The AATD Core has a Clinical Trials Network (CTN) existing since 1997. Besides continuing with drug trials in our CTN, our priority is to study the natural course of AATD for lung disease and for liver disease in collaboration with ERN RARE-LIVER (ERN on hepatological diseases). The main focus is currently on the EARCO initiative which stands for European Alpha-1 Research Collaboration. It is a pan-European network committed to promoting clinical research and education in AATD. The core project is the European AATD registry.
Jan Stolk
Lead: Alpha-1 AntiTrypsin Deficiency (AATD)
Chronic Lung Allograft Dysfunction (CLAD)
Chronic lung allograft dysfunction (CLAD) encompasses a range of pathologies that cause a transplanted lung to not achieve or maintain normal function. CLAD manifests as a chronic airflow restriction and/or obstruction and is predominantly a result of chronic rejection.
CLAD Phenotypes
Three distinct phenotypes of chronic rejection, distinguished by their diagnostic criteria, are now recognized:
- Bronchiolitis obliterans (BOS), an inflammatory obstruction of the lung’s tiniest airways called bronchioles, which presents clinically in a non-specific manner with shortness of breath or dyspnea on exertion, dry coughing and/or wheezing, usually 3 months post-transplant. The underlying pathology of BOS may be early, with an excess of sub-epithelial fibrous tissue, or late, with obliteration of the lumen by fibrosis.
- Restrictive allograft syndrome (RAS), demonstrating restrictive pulmonary function decline and characteristics of peripheral lung fibrosis, and worse survival compared to the more common The pathology of RAS is commonly late–onset, diffuse alveolar damage progressing to end-stage pulmonary fibrosis with or without pleural involvement.
- Mixed phenotype which includes all cases that transition from a BOS phenotype to an RAS phenotype and vice-versa.
Causes
The exact physiopathology of CLAD remains partially understood, but numerous factors contribute to the dysfunctional process: immunological risk factors (acute cellular rejection, lymphocytic bronchiolitis, self-antigen exposure, and donor-specific antibodies) and non-immune mechanisms (primary graft dysfunction (PGD), gastroesophageal reflux, bacterial or viral infections and pollutant exposure) lead to the activation of the innate and adaptive immune systems and chronic lung inflammation. Impaired wound healing and fibrosis of the lung will then end in small airway obstruction for the BOS phenotype or in parenchymal and pleural fibrosis for the restrictive CLAD phenotype.
Diagnosis and Treatment
Transbronchial biopsy and bronchoalveolar lavage (BAL) have a major role in the detection of treatable causes prior to the diagnosis of definite CLAD and should be performed at the start of the diagnostic process to investigate the decline in lung function not explained by obvious, non-CLAD causes. Diagnosis is based on a combination of forced expiratory volume (FEV1) decline (≥20%), spirometry tests, total lung capacity (TLC) decline (≥10%), and analysis of computerized tomography (CT) scans after transplantation for the appearance and evolution of lung abnormalities.
There are few treatment options for CLAD including immunosuppressive therapy, total lymphoid irradiation and antibiotic therapy. Effective pharmacologic therapy of CLAD remains an unmet medical need. Retransplantation may be the only therapeutic option for advanced CLAD in well-selected patients.
ERN-LUNG Actions
We are developing international guidelines on CLAD and have recently published two consensus reports, one standardising the nomenclature of CLAD and its clinical phenotypes, and another on RAS after lung transplantation. We are also in the process of setting up our Clinical Trials Network EuroCLAD, which will serve as a platform for studies in CLAD after lung transplantation.
Jens Gottlieb
Lead: Lung Allograft Dysfunction (CLAD)
Other Rare Lung Diseases (ORLD)
All other rare lung diseases not specifically grouped within one of the other disease-specific or group-specific core networks are invited to gather in this core network to cluster expertise and learn from the best. The main goals of this Core Network have been summarized by the leadership group as the provision of highly specialized patient-centered care, improvement of cross-border collaborations for continuity of care, and reinforcing epidemiological information as well as sustaining research and training. Three disease groups have been selected as putative focal area of this Core Network, i.e. Congenital Lung Malformations, Disorders of the Respiratory Drive, and Cystic Lung Diseases. The sub-group formation is work in progress.
Helge Hebestreit
Lead: Other Rare Lung Diseases (ORLD)
Sarcoidosis (SARC)
Sarcoidosis is a systemic disorder mostly affecting young adults, which can lead to irreversible organ damage. It most commonly affects the lungs, skin, eyes, and lymph nodes. About one third of patients with sarcoidosis have multiple organ involvement. There is a geographical variation of sarcoidosis epidemiology, with the highest incidence and prevalence in Nord European countries. The severity of disease seems to be associated with Ethnicity or genetic background.
Etiology and pathogenesis:
The exact cause of sarcoidosis is still unknown, but it is believed to be triggered by exposure to certain environmental irritants, infections with genetic predisposing factors underlying the disease. Familiar cases are also known. The pathogenesis of sarcoidosis is complex and not completely understood. It is believed to be caused by the abnormal immune response of the body to an unknown trigger. The immune system mistakenly attacks healthy tissues and organs, leading to the formation of small clusters of inflammatory cells called granulomas. These granulomas can accumulate in different parts of the body and cause inflammation and tissue damage.
Symptoms:
The symptoms of sarcoidosis can vary depending on the affected organs. In some cases, sarcoidosis may not cause any symptoms, while in others, it can cause significant discomfort and even life-threatening complications. Common symptoms of sarcoidosis include fatigue cough, shortness of breath, fever, skin rashes, joint pain, enlarged lymph nodes, and eye inflammation.
Diagnosis:
The diagnostic flow typically encompasses clinical evaluation, imaging, and laboratory tests. Chest X-rays or CT scans belong to first-line diagnostics, in the majority of cases a biopsy of affected tissue is necessary to confirm the diagnosis. The diagnostic process can be complex, and may involve consultation with specialists such as pulmonologists, rheumatologists, cardiologists and dermatologists to help determine the extent and severity of the disease.
Management and Treatment:
There is no cure for sarcoidosis, but the condition can be managed effectively with proper medical care. The management of sarcoidosis involves regular monitoring of the affected organs, including imaging studies, pulmonary function tests, and blood tests (biomarkers). In some cases, when the risk of irreversible organ damage or mortality is high, when functional impairment is present, or patients ‘quality of life is affected, the use of corticosteroids in first line or other immunosuppressive drugs may be necessary to control the inflammation and prevent disease progression. However, the treatment of sarcoidosis depends on the severity of the symptoms and the extent of the organ involvement. In mild cases, no treatment may be necessary, and the condition may resolve on its own. In more severe cases, combination of corticosteroids and other immunosuppressive drugs may be prescribed. Lung transplantation is an option for patients with progressive pulmonary fibrotic disease. While there is no cure or approved medication for this condition, the symptoms can be effectively managed with proper medical care including oxygen therapy, pulmonary rehabilitation, and drugs for symptoms relief. Early diagnosis and treatment are essential to prevent further organ damage and improve the quality of life of patients with sarcoidosis. Several drugs are in clinical development and results from Phase II and III trials are expected in the next few years.
Sarcoidosis in children
Sarcoidosis can also occur in children, although it accounts for less than 5% of all cases. The symptoms and treatment of sarcoidosis in children are similar to those in adults, but there are peculiar aspects that parents and caregivers should be aware of.
Common symptoms of sarcoidosis in children include general signs at the forefront with fever, fatigue, weight loss. Oher signs such as cough, shortness of breath, skin rashes, joint pain, and enlarged lymph nodes are also frequent. Diagnosing sarcoidosis in children can be challenging, as the symptoms are nonspecific and overlap with those of other diseases. Thus, the diagnostic workup includes a combination of medical history, physical examination, imaging studies, and laboratory tests. In some cases, a biopsy of the affected organ may be necessary to confirm the diagnosis.
The treatment of sarcoidosis in children depends on the severity of the disease and the organs involved. Therapeutic abstention is rare and corticosteroids are largely used, sometimes with – or followed by – immunosuppressive drugs to control the inflammation and prevent further damage to the organs.
In around half of the cases, sarcoidosis in children is a self-limiting disease that responds well to treatment and resolves in childhood. However, some children may present sarcoidosis relapses over time, including in adulthood or develop chronic sarcoidosis, which can lead to permanent organ damage and disability. Parents and caregivers should be aware of the symptoms and seek medical attention if they suspect their child has sarcoidosis.
ERN-LUNG Actions
We are developing international surveys to identify sarcoidosis specific registries and biobanks. We are also in the process of setting up our Clinical Trials Platform to provide an overview of ongoing clinical trials in Europe and performing centers. Moreover, we are starting initiatives to produce consensus statements and guidelines on sarcoidosis.
Core Network participating centers and structure of the Board
The list of Healthcare Providers/Centers belonging to the Core Network Sarcoidosis can be found here. The structure of the CN Sarcoidosis can be found under this link.
Francesco Bonella
Lead: Sarcoidosis