Respiratory Flashcards
Alpha-1-antitripsin deficiency is caused by a mutation in which gene?
SERPINA1 - AAT is part of a group of protein’s known as serine protease inhibitors. Mutations is genes for other proteins in this group, known collectively as serpinopathies, have been implicated in diseases in other organ systems.
Alpha-1 antitrypsin inhibits 4 enzymes. Deficiency of AAT is thought to lead to emphysema due to reduced inhibition of which enzyme produced by neutrophils in the lungs?
Elastase. Released by neutrophils, in the absence of AAT, damages the elastin in alveoli leading to emphysema.
AAT also inhibits trypsin, chymotrypsin and thrombin.
Alpha-1 antitrypsin deficiency has what inheritance pattern?
Autosomal codominant. Both alleles produce active protein and play a role in disease severity.
What SERPINA1 genotype is most likely to be present in a patient with phenotypic Alpha-1 antitrypsin deficiency?
PI*ZZ homozygotes. PI = protease inhibitor. Z = most common disease associated allele. M = normal allele. S is another abnormal allele, but not always associated with disease phenotype. SZ allele develop emphysema if they smoke. MZ allele heterozygotes may have an increased risk of COPD if they smoke but this is controversial.
What is the mechanism of liver disease in people with Alpha-1 antitrypsin deficiency?
Accumulation of pathological varieties of Alpha-1 antitrypsin in hepatocytes leading to cell death and hepatic inflammation.
What are the three classical features of Birt-Hogg-Dubé syndrome? And what is responsible for mortality in these pts most commonly?
Skin hamartomas (usually on head and neck), pulmonary cysts, and spontaneous pneumothorax usually before aged 40. It’s and autosomal dominant disease caused by mutations in the folliculin gene. Renal cancer affects 1/3 pts before 50 and is the leading cause of mortality in BHD pts. Regular surveillance is required.
What is lymphangioleiomyomatosis, what gene is it associated with, and how does it typically present? What is its plasma marker?
Multi system neoplastic disease. Most commonly associated with tuberous sclerosis (germline mutation in TSC gene), but also occurs spontaneously in women aged 30-40 most commonly. Pathogenesis is incompletely understood, but sees abnormal proliferation of smooth muscle like cells systemically a partially oestrogen dependent process. Classical clinical features are chylous pleural effusion, spontaneous pneumothorax and dyspnoea. Chest imaging sees pulmonary cysts. VEGF-D is a plasma marker that delineates it from other cystic lung disease.
What is catamenial pneumothorax?
Pneumothorax secondary to thoracic endometriosis.
What is the most common type of amiodarone induced lung toxicity?
Interstitial pneumonitis.
How long after commencing amiodarone does amiodarone induced interstitial pneumonitis usually have its onset? How does it present?
Almost exclusively >2 months on the medication, and usually 6-12 months after commencement. Usual presentation is insidious non-productive cough, fever, pleuritc chest pain, weight loss. Sometimes have raised crp, esr, WCC. Imaging can look like atypical pneumonia. Restrictive PFTS with impaired DLCO. Foam cells on BAL.
How does amiodarone induced organising pneumonia (formerly bronchiolitis obliterans organising pneumonia - BOOP) present?
Presents over weeks to months - more acutely than interstitial pneumonitis - with
non-productive cough, fever, dyspnoea, almost always raised inflammatory markers, CXR consistent with pneumonia. However, biopsy demonstrates excessive granulation tissue comprised of fibroblasts and myofubroblasts +/- lymphoid tissue.
Draw the lung capacities.
See diagram
Which zone of the lungs has the highest V/Q ratio?
Upper zone
Which zone of the lungs has the smallest alveoli?
Lower zone
Which zone of the lungs has the greatest ventilation?
Lower zone
Which zone of the lungs has the highest perfusion?
Lower zone
Which zone of the lungs has the lowest V/Q ratio?
The lower zone.
What are the components of functional residual capacity?
Experiratory reserve volume (ERV) and residual volume (RV).
What are the four components of lung volume?
Inspiratory reserve volume, tidal volume, expiratory reserve volume and residual volume.
What is vital capacity?
Inspiratory reserves volume, tidal volume and expiratory reserve volume.
What anatomical component of airways contributes most to resistance?
Bronchioles. Not alveoli.
What are the three defining features of asthma?
Variable airway obstruction, bronchial hypersensitivity, airway inflammation
What is the definition reversible airway obstruction on PFT?
Traditionally, FEV1 or FVC improvement of 12% AND 200mls 10-15mins post bronchodilation. However the latest European guidelines use a flat FEV1 or FVC increase of 10%.
How can you demonstrate for airway inflammation when trying to diagnose allergic asthma?
Measuring exhaled nitric oxide or measuring peripheral oesinophils are both valid ways of detecting inflammation in allergic asthma.
What are radiologists talking about when they say “tree in bud appearance”?
In conditions causing infective or inflammatory changes within the small bronchioles, the peripheral lung parenchymas takes on the appearance of a tree that is ‘in bud’ - that is a tree that has not yet flowered, but is covered in flower buds at its peripheries. Any number of infections can cause this appearance, but important non-infective causes include Sjogren’s disease and rheumatoid arthritis.
How can you tell if someone has bronchiectasis on CT scan?
Best recognised method is to compare the diameter of the peripheral airways to their paired vascultare. If the airwas wider than its accomanying vasculature, this indicates radiological bronchiectasis.
What is theophylline? How does it work? Why might you use it? What are its issues?
Theophylline is a phosphodiesterase inhibitor which leads to smooth muscle bronchodilation. It also inhibits the binding of adenosine to adenosine receptors on mast cells which reduces their probability of degranulating.
It is usually used when asthma patients on maximal inhaled corticosteroids are still symptomatic. It has a very narrow therapeutic window and its adverse effects are: cardiac dysrhythmia, seizures, and GI upset. It’s metabolised by liver P450 enzymes and its plasma levels are volatile during viral infections, liver impairment, or with drugs metabolised by the same enzymes - e.g. anticonvulsants.
How do Mepolizumab and Benralizumab is used to treat asthma. How does it work?
IL-5 and IL-5 receptor alpha antagonists respectivley. IL-5 is prodcued by Th2 cells and functions to recruit eosinophils as a chemoattractant. It also activates eosinophils in higher concentrations at sites that is produced. In eosinophilic asthma, eosinophils directly cause harm to the airways, so mepolizumab (anti-IL-5), and also benralizumab (anti-IL-5 receptor alpha ab) impair eosinophil function to treat moderate to severe asthma. Benralizumab leads to antibody-mediated cytotoxic cell death as it is an IgG1 based ab that binds to eosinophil IL-5 receptors. Patients included in the trials had peripheral plasma eosinophil counts of 150-300 cells/ml.
Dupilumab is used to treat atopic dermatits and asthma in Australia. How does it work?
Dupilumab is an anti-IL-4 receptor alpha monoclonal antibodiy. The IL-4 receptor alpha domain is a commone to the IL-4 receptor and the IL-13 receptor, and so Dupilumab blocks the effects of both. IL-4 is necessary for the differentiation of naive T cells into Th2 cells that drive the innappropriate allergic response seen in asthma. IL-13 stimulates the production of more goblet cells in epithelial layers, increases mucosal layer turnover, and recruits mast cells and M2 macrophages (those specialised to attack helminths). As with mepolizumab and benralizumab, asthma treatment relies on evidence that the disease is driven by eosinophils.
What are the urinary antigen tests that can be done for patients with suspected pneumonia?
Urinary legionella antigen and urinary streptococcus pneumoniae. More sensitive than blood and sputum cultures but remain highly specific.
How is cystic fibrosis inherited?
Autosomal recessive
What’s the name of the newborn test that screens for CF called?
Immunoreactive trypsinogen level. If increased, this is suggestive of CF. Trypsinogen is usually produced by the pancrease and excreted by pancreativ exocrine cells, however in patients with cystic fibrosis, pancreatic exocrine secretion is imparied leading raised trypinsogen levels in the blood.
How does the sweat test work for cystic fibrosis diagnosis?
Sweat with low chloride levels is considered diagnosistic for cystic fibrosis due to CFTR mutation impairing chloride secretion.
Which condition at birth is most commonly asscoaited with cystic fibrosis?
Meconium ileus
What ethnicity is most commonly associated with cystic fibrosis?
Caucasian. Approximately 1 in 28 white people carry a CFTR pathogenic variant. 1 in 3000 are born with cystic fibrosis.
What is class I CFTR mutation?
no functional CFTR mutations is made.
What is a class II CFTR mutation?
CFTR protein is made but it is mis-folded and is not trafficed to the cell surface correctly. This is the most common cause for cystic fibrosis, and the F508del mutation is the most common single mutation cause of cysitic firbosis impactin 80-90% of CF patients.
What is a class III CFTR mutation?
CFTR protein is formed into a channel but it does not open (e.g. G551D). Note that this is a significant mutation as the medication Ivacaftor (Kalydeco) opens the channel in G551D mutations.
What is a class IV CFTR mutation?
CFTR protein is formed into a channel but chloride ions doe not cross the channel properly.
What is a class V CFTR mutation?
CFTR is made properly, but not in sufficient quantities for it to perform its role.
What is a class VI CFTR mutation?
CFTR protein is made and is functional, but is not stable on the cell surface.
How does ivacaftor work in the treatment of cystic fibrosis?
Ivacaftor is a ‘potentiator’ that stabilises the CFTR protein and enables it to open properly. It is used in Class II (in combination with drug to transport the CFTR to the cell membrane), III, and IV disease. There are at least 95 genetic subtypes of that ivacaftor has been shown to be effective for treating. It is as part of dual of triple therapy in the treatmnet of class II mutations (where the CFTR protein is misfolded and doesn’t traffic to the cell surface).
How do lumacaftor and tezacaftor, and elexacaftor work for cystic fibrosis patients?
Tezacaftor/ivacaftor, tezacaftro/elexacaftor/ivacaftor and lumacaftor/ivacaftor combinations are used to treat F508del patients in combination. Lumacaftor, elexacaftor and texacaftor all work to transport the CFTR protein to the cell membrane. The ivacaftor then stabilises the CFTR protein and allows it to open and function correctly.
What is dornase?
Dornase is recombinant human DNAse that breaks down DNA left over from inflammatory cells in the airways. It’s inhaled alongside hypertonic saline to assist with clearance of airway secretions.
What treatments in CF, apart from the -caftor medications, have been shown to improve lung function?
Inhaled dornase daily, inhaled hypertonic saline daily, inhaled antibiotics (aztreonam or tobramycin) if the pt is colonised with pseudomonas, alternate daily pred dose in pts >18yo, daily macrolide use, ibuprofen (between age 6-18), lung transplantation (advanced CF). Notably, staphylococcal infection prophylaxis has not demonstrated lung function improvement.
What are the criteria for lung tranplantation in patients with CF?
FEV1 less than 35%. Increased IV abx use for exacerbations. PO2 less than 60mmHg. PCO2 greater than 50mmHg. Clinical organism resistance. Impaired quality of life.
What anatomical variant leads to infertility in men with cystic fibrosis?
Absent vas deferens
What is the aetiology of disease in patients with group 1 pulmonary hypertension?
These patients are said to have pulmonary arterial hypertension (pre-capillary pressure is raised). This can occur secondary to medications, connective tissue disease, or inherited causes. It can also be idiopathic.
What is the aetiology of group 2 pulmonary hypertension? What pattern of hypertension is seen?
This is caused by left heart failure. Increased pressures will be seen in the post-capillary vessels.
What is group 3 pulmonary hypertension?
This group is the result of chronic lung diseases and hypoxaemia.
What is group 4 pulmonary hypertension the result of?
Group 4 pulmonary hypertension is the result of chronic pulmonary artery obstrcuction aka CTEPH.
What is group 5 pulmonary hypertesnion?
This is hypertension secondary to unclear causes.
