Lecture 17 - immunosuppression and lung diseases

Question 1

what are different types of lung infections?

Answer 1

• Upper respiratory tract infections affect approximately above the bronchi, common colds etc.
• Acute bronchitis - a persistent (2-3 weeks but can be longer) infection (usually viral) in the lower respiratory tract.
• Chronic Bronchitis - prolonged inflammation of the bronchial airways which leads to cough and mucus production.
• Pneumonia - infection in the lung parenchyma (basically alveolar structures). Also consolidation
• Pleuritis - Inflammation of the pleural membranes. It can have many causes, including Pulmonary Embolism and viral or bacterial infections.

Question 2

what is bronchiectasis, its pathology and clinical features?

Answer 2

Permanent dilation of the bronchi, often a cause of insufficiently treated lung disease that develops into dilated bronchi and has heightened susceptibility for future infections.

Pathology
Permanent enlargement of the airways. Weakening of the elastic and muscular component of the bronchial walls.
Excessive inflammatory response.

Clinical Features
Symptoms include a chronic cough with significant mucus production
Shortness of breath, coughing up blood and chest pains and wheezing.
Frequent lung infections.

Question 3

what are causes of bronchiectasis?

Answer 3

• Cystic Fibrosis- up to 50% of cases
• Lung infections- bacterial infections, TB, severe viral infections in childhood.
• Impaired host defences- immune problem.
• Immunosuppressive drugs.
• Aspergillosis – hypersensitivity to the fungus Aspergillus fumigatus-increased inflammation
• Lung injury/lung obstruction

Question 4

what is used to diagnose bronchiectasis?

Answer 4

high resolution computed tomography (HRCT) scan must be performed, evidencing persistent dilation of the airways.

Question 5

hat are CT diagnostic features?

Answer 5

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

Question 6

what are treatment principles of bronchiectasis?

Answer 6

management - avoid smoking, exercise to clear airways, good nutrition, vaccinations, pulmonary rehabilitation

mild - airway clearance techniques

moderate/ persistent symptoms - antiinflmammtories therapy ie corticosteroids or antibiotics such as amcrolides.

severe - long term oxygen therapy, inhaled corticosteroids, salbutamol for acute exacerbations, macrocodes or inhaled antibiotics, airway clearance techniques. may eventually require lung transplantation.

Question 7

what is the pathology in cause of in section in bronchiectasis?

Answer 7

It is thought that elevated levels of neutrophil elastase, reduction in neutrophil recruitment, proteinase 3, and cathepsin G overwhelm natural inhibitors, such as alpha1 -antitrypsin and secretory leukocyte protease inhibitor,6,7 which alters the microenvironment and increases the risk of infection

Question 8

what can the drug treatment used for bronchiectasis?

Answer 8

brensocatib

Question 9

what is brensocatib?

Answer 9

Brensocatib (INS1007) is an 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.

Question 10

what is pneumonia, what are the causes and symptoms?

Answer 10

Infections reach the alveoli and cause an inflammatory response. Alveoli fill with fluid, white blood cells, proteins and red blood cells. Micro abscesses filled with pus.

Inflammation-compromised gaseous exchange and the presence of viscous fluid causes the lung tissue to become firm (consolidated- no space for air).

Causes: bacteria, viruses, fungi and mycoplasma- rapid onset 24-48hr

Symptoms of dyspnoea, cough, fever and chest pains occur.

Question 11

when does consolidation occur in pneumonia?

Answer 11

“Consolidation” occurs when the air spaces of the lungs are filled with something other than air.

Question 12

what is used for the treatment mangement of pneumonia?

Answer 12

Mild to moderate -Treat the infectious agents- e.g. anti-bacterials
Rest- drink fluids (loosen mucus) steam baths
More severe- Oxygen therapy.

Question 13

what do patients with pneumonia have high revels of?

Answer 13

cardiolipin

Question 14

what is acute respiratory distress syndrome and what is is triggered by?

Answer 14

it is a form of severe hypoexemic respiratory failure where there is inflammatory injury to the alveolar/ capillary barrier and extravasation of protein-rich oedema fluid in the airspace

triggers are septic shock and pneumonia

Question 15

what is cystic fibrosis causes by?

Answer 15

mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR).

CFTR protein is a chloride/thiocyanate channel found in cells lining the lungs, and others organs

Question 16

what is the problem with the chloride channel in CF patients and what does this lead to?

Answer 16

In normal lung Cl- ions to pass out of the cell with sodium ions and water.
In CF lungs, when the CFTR is blocked, the chloride ions can’t leave the cellular compartment.
Mucus retention and chronic infection.
Associated inflammation leads to destruction of lung tissue.
Affects pancreas and digestive system
Lung disease is the most common cause of morbidity and mortality in CF

Question 17

what is used for the management of CF? BATCH

Answer 17

Oral antibiotics, or if a severe exacerbation of infection, intravenous antibiotics,
Inhaled mucolytics such as Dornase alpha or hypertonic saline
Chest physiotherapy to keep airways clear and encourage drainage
Short acting bronchodilators, e.g. salbutamol
Inhaled tobramycin is good for dealing with P. Aeruginosa infections

Question 18

what is used for the treatment of Cystic fibrosis? CAAP

Answer 18

Anti-inflammatory Treatment of Cystic Fibrosis
(for children over 6 years of age)
Prednisolone, Ibuprofen- reduce inflammation
Azithromycin- particularly useful if there are bacterial infections (off label?). Some evidence for benefit.

CFTR Modulators – new class of medicine
enhancers/potentiators keep the channel open longer (Ivacaftor)
Correctors – correct the protein misfolding (Lumacaftor)
Now use double and triple therapy (potentiator plus 1 or more correctors). Might not be in the guidelines (too expensive?).

Question 19

what is interstitial lung disease caused by, what disease contribute to it and what are the symptoms ?

Answer 19

Interstitium- Fluid filled space between cells containing collagen/elastin etc to make a latticework structure. Fibroblasts and macrophages also present

Many systemic connective tissue diseases affect the lung- inflammation and fibrosis.
Rheumatoid arthritis, scleroderma, systemic lupus erythematosus, polymyositis or dermatomyositis, and Sjögren’s syndrome.
Patients usually present with cough, dyspnoea and hypoxia, and show a diffuse ‘ground glass’ appearance of their lungs in CT scans.
Patients can also develop pulmonary hypertension

Question 20

what is sued for the treatment of interstitial lung disease? c2r2nm

Answer 20

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

Question 21

what happens in idiopathic pulmonary fibrosis , what are the triggers?

Answer 21

unknown cause
Aberrant wound healing- fibroblastic/inflammation
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.

Triggers: smoke, pollution, viruses- progressive and irreversible.

For this disease, corticosteroid and other anti-inflammatory therapies are ineffective.

Question 22

describe pifenidone as a treatment for Idiopathic pulmonary fibrosis

Answer 22

Pirfenidone is an 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.
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

Question 23

describe nintedanib and imatinib as treatments for IPF

Answer 23

Nintedanib- is an intracellular inhibitor of several tyrosine kinases that targets multiple growth factor receptors: vascular endothelial growth factor, fibroblast growth factor, and PDGF.

Imatinib, a 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.
Complex pathogenesis of IPF