Lecture 17: Immunosuppression and Lung Diseases Flashcards
Name five lung infections
- Upper respiratory tract infections
- Acute bronchitis
- Chronic bronchitis
- Pneumonia
- Pleuritis
Describe Upper respiratory tract infections
affect approximately above the bronchi, common colds etc.
What is acute bronchitis?
a persistent (2-3 weeks but can be longer) infection (usually viral) in the lower respiratory tract.
What is chronic bronchitis?
Prolonged inflammation of the bronchial airways which leads to cough and mucus production.
What is pneumonia?
infection in the lung parenchyma (basically alveolar structures). Also consolidation
What is pleurtisis?
Inflammation of the pleural membranes. It can have many causes, including Pulmonary Embolism and viral or bacterial infections.
What is bronchiectasis?
Permanent dilation of the bronchi, often a sequel of insufficiently treated lung disease that develops into a pathological pattern of dilated bronchi, heightens susceptibility to further lung infections.
What are the effects of bronchiectasis?
- Permanent enlargement of the airways. Weakening of the elastic and muscular component of the bronchial walls.
- Excessive inflammatory response.
What are the clinical features of bronchiectasis?
- Chronic cough with significant mucus production
- Shortness of breath, coughing up blood and chest pains and wheezing
- Frequent lung infection
What causes bronchiectasis?
- Cystic fibtosis
- Lung infections: bacterial infections, TB, severe viral infections in childhood.
- Impaired host defences
- Immunosuppressive drugs
- Aspergillosis: hypersensitivity to the fungus Aspergillus fumigatus-increased inflammation
- Lung injury/lung obstruction
What is the vicious cycle theory?
The destructive effect of chronic airway infections
Describe the bronchiectasis vicious cycle
- Inflammation
- Bronchial drainage
- Mucociliary clearance
- Mucous hypersecretion
- Infection / microbial colonization
How is bronchiectasis diagnosed?
High resolution computed tomography (HRCT) scan must be performed, evidencing persistent dilation of the airways.
What are the feautures of a CT that show bronchiectasis?
- The internal diameter of a bronchus is >1.5 times (>150%) the diameter of the pulmonary artery (also known as the ‘signet ring’ pattern)
- Bronchial wall thickening (parallel tram lines)
- “Tree-in-bud” appearance
- Failure of bronchial tapering
What are the general management treatments for bronchiectasis?
- Vaccination
- Pulmonary rehabilitation
- Sputum surveillance
How do you treat mild bronchiectasis?
Airway clearamce techniques - daily physiotherapy
What is pulmonary rehabilitation?
- exercise training to improve lung function
- breathing techniques to reduce shortness of breath
- education on medication management
How do you treat moderate/ persistant symptoms for bronchiectasis?
- Antiinflammatory therapy: inhaled corticosteroids
- Antibiotic therapy - macrolides
- Airway clearance techniques - regular physiotherapy with adjuctive devices/ hypersmolar agents
How do you treat severe symptoms for bronchiectasis?
- Therapy in advanced disease: long term oxygen therapy, surgery
- Antiniotic therapy: Macrolides/ inhlaed antibiotics
- Antiinflammatory therapy: inhaled corticosteroids
- Airway clearance techniques: regular physiotherapy with adjuctive devices/ hupersmolar agents
What is inflammation in bronchiectasis dominated by?
By neutrophils that, when activated, release neutrophil serine proteases, including neutrophil elastase
How are neutrophil serine proteases activated?
Activated during neutrophil maturation in the bone marrow by dipeptidyl peptidase 1 (DPP-1; also known as cathepsin C) by removing the N-terminal dipeptide; this allows active enzymes to be packaged into granules before the release of neutrophils into the circulation.
What is Brensocatib (INS1007)?
Oral, selective, competitive, and reversible inhibitor of DPP-1 that has been shown to inhibit neutrophil serine protease activity in the blood of healthy volunteers.
What increases the risk of infection?
Reduction in neutrophil recruitment
What causes pneumonia?
- Bacteria
- Viruses
- Fungi
- Mycoplasma
What happens during pneumonia?
- Inflammation of the alveoli
- Infections reach the alveoli and cause an inflammatory response
- Alveoli fill with fluid, white blood cells, proteins and red blood cells
- Micro absesses fill with pus
- Compromised gaseous exchange
- presence of viscous fluid causes the lung tissue to become firm - no space for air
what are the symptoms of pneumonia?
- Dyspnoea
- Cough
- Fever
- Chest pain
What is consolidation in pneumonia?
Occurs when the air spaces of the lungs are filled with something other than air
How do you treat mild to moderate pneumonia?
- Treat the infectious agents eg antibacterials
- Rest
- Drink fluids
- Steam baths
How do you treat severe pneumonia?
Oxygen therapy
What is found in tracheal aspirates of critically ill patients with pneumonia?
High levels of cardiolipin
What is cardiolipin?
Principal lipid component of the inner mitochondrial membrane
What happens to cardiolipin during cell death?
It undergoes oxidation and is released into the extracellular milieu.
What are raised cadiolipin levels assosiated with?
Impaired surfactant function resulting in high surface tension pulmonary oedema.
How does cardiolipin inhibit resolution of inflammation?
By suppressing production of anti-inflammatory IL-10
What is acute respiratory distress syndrome?
Form of severe hypoxemic respiratory failure. It is inflammatory injury to the alveolar/ capillary barrier. Extravasion of protein rich oedema fluid into the airspace
What is acute respiratory distress syndrome triggered by?
Septic shock and pneumonia
What is cyctic fibrosis caused by?
Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR).
What is cystic fibrosis transmembrane conductance regulator?
chloride/thiocyanate channel found in cells lining the lungs, and others organs.
How do chloride channels work in a normal lung?
Chloride ions pass out the cell with sodium ions and water
How do chloride channels work in cystic fibrosis lungs?
The CFTR is blocked, the chloride ions can’t leave the cellular compartment. This causes mucus retention and chronic infection. The inflammation leads to destriuction of lung tissue. It affects the pancrease and digesting system
What is the most common cause of morbidity and mortality in cyctic fibrosis
Lung disease
What is the treatment of cystic fibrosis?
- Oral antibiotics
- IV antibiotics for severe exacerbation
- Inhaled mucolytics eg dornase alpha or hypertonic saline
- Chest physiotherapy to keep airways clear and encourage drainage
- Short acting bronchodilators eg salbutamol
- Inhaled tobramycin: to deal with P. Aeruginosa infections
- CFTR modulators
What is the anti-inflammatory treatment for cystic fibrosis?
This is for children over 6
- Prednisolone, ibuprofen - to reduce inflammation
- Azithromycin
How do CFTR modulators work?
- Enhancers/ potentiators keep the channel open for longer
- Correctors - correct the protein misfolding
Name the CFTR modulators
- Ivacaftor
- Lumacaftor
What is interstitial lung disease?
Lung disorders affecting the interstitium. Include Rheumatoid arthritis, scleroderma, systemic lupus erythematosus, polymyositis or dermatomyositis, and Sjögren’s syndrome.
What is the interstitium?
Fluid filled space between cells containing collagen/elastin etc to make a latticework structure. Fibroblasts and macrophages also present.
What are the symptoms of interstitial lung disease?
- Cough
- Dyspnoea
- Hypoxia
- Show a diffuse ground glass appearance of lungs in CT scan
- Can develop pulmonary hypertension
What is the treatment for interstitial lung disease?
- Corticosteroids: Intravenous methyl prednisolone for exacerbations, oral prednisolone for maintenance.
- Re-purposed anti-cancer/RA drugs-Purines, cycloheximide
- Methotrexate: Inhibits folic acid and purine metabolism and T-cell proliferation. Controversial usage due to effects on lung tissue
- N-acetylcysteine in addition to being a mucolytic, it is thought to modulate inflammation and slow fibrosis
- Calcineurin inhibitors: (e.g. tacrolimus & ciclosporin). Inhibit T-cell activation (release of IL-2).
- Rituximab: mAb against CD20 on B-cells
What are the triggers for idiopathic pulmonary fibrosis?
- Smoke
- Pollution
- Viruses
Describe idiopathic pulmonary fibrosis
- Influx of fibroblasts, macrophages and myofibroblasts, deposition of proteins and subsequent fibrosis.
- The architecture of the parenchymal space is changed and the alveoli are infiltrated.
- Aberrant wound healing- fibroblastic/inflammation
Describe lungs with idiopathic pulmonary fibrosis
- Fibrosis
- Damaged broncioles and alveoli
- Fibrosis between alveoli
- Greatly decreased gas excahnge
What is the treatment for idiopathic pulmonary fibrosis?
- Pirfenidone
- Nintendanib
- Imatinib
What is pirfenidone?
Oral antifibrotic drug with pleiotropic effects. It has been shown to regulate important profibrotic and proinflammatory cytokine cascades in vitro while reducing fibroblast proliferation and collagen synthesis in animal models of lung fibrosis.
What does pirfenidone do?
Pirfenidone improved mortality (moderate confidence) reduced the rate of FVC decline (high confidence). Pirfenidone treatment increased 6-minute-walk distance and progression-free survival when compared with placebo.
Increased rates of photosensitivity, fatigue, stomach discomfort, and anorexia
What is nintedanib?
An intracellular inhibitor of several tyrosine kinases that targets multiple growth factor receptors: vascular endothelial growth factor, fibroblast growth factor, and PDGF.
What is imatinib?
Potent and more selective inhibitor of lung fibroblast–myofibroblast differentiation and proliferation, as well as an inhibitor of extracellular matrix production through inhibition of PDGF and transforming growth factor-b signaling showed no benefit.
