Wk8 - Respiratory Flashcards
How can we measure lung function?
At home- Peak flow, (oximetry)
At the GP surgery- Spirometry, oximetry
In a specialist lab- Spirometry, transfer factor, lung volumes, blood gases, bronchial provocation testing, respiratory muscle function, exercise testing etc.
Spirometry
- Definition
Definition: Forced expiratory manoeuvre from total lung capacity followed by a full inspiration
“take a big breath in as far as you can and blow out as hard as you can for as long as possible- then take a big breath all the way in”
Best of 3 acceptable attempts (within 5%) - best effort is taken as their spirometry
Spirometry pitfalls
Appropriately trained technician
Effort and technuque dependent
What is the normal FEV1/FVC ratio?
> 70% = N
If <70% = airflow obstruction
Reference ranges for lung function
FEV1 of 85% predicted may be considered “normal”
FEV1 of 100% percent predicted may represent significant decline if values supra-normal at the start
Corrected for age, gender, race, height and atmospheric values
Obstructive lung disease
Generally asthma or COPD
FEV1/ FVC ratio <70% (0.7 ratio).
Severity of COPD stratified by %predicted FEV1 mild >80% mod 50-80%, severe 30-50%, very severe <30%
Reversibility testing
Nebulised or inhaled salbutamol given
Spirometry before and 15 min after salbutamol
15% AND 400ml reversibility in FEV1 suggestive of asthma
Other investigations ofr asthma
PEFR testing
Look for diurnal variation and variation over time
Response to inhaled corticosteroid
Occupational asthma
Bronchial provocation
Spirometry before and after trial of inhaled/ oral corticosteroid
Restrictive lung disease
FEV1 AND FVC reduced
FEV1/ FVC ratio >70%
Causes of restrictive spirometry
Interstitial lung disease (stiff lungs) Kyphoscoliosis/ chest wall abnormality Previous pneumonectomy Neuromuscular disease Obesity Poor effort/ technique
Interpreting spirometry
First look at FEV1/ FVC ratio
If <70%, obstruction
If obstructed, look at % predicted FEV1 (severity) and any reversibility (COPD vs asthma)
If FEV1/ FEV ratio normal, look at % predicted FVC (if low, suggests restrictive abnormality)
Can also get mixed picture, eg obesity and COPD
Transfer factor
Is a measure of gas exchange
Single breath of a very small concentration of carbon monoxide
CO has very high affinity to Hb
Measure concentration in expired gas to derive uptake in the lungs
Affected by: Alveolar surface area Pulmonary capillary blood volume Haemoglobin concentration Ventilation perfusion mismatch
Reduced in: Emphysema Interstitial lung disease Pulmonary vascular disease Anaemia (increased in polychthaemia)
2 methods of measuring lung volume
(unable to measure residual volume by spirometry) Helium dilution (inspire known quantity of inert gas) Body plethysmography (respiratory manoevures in a sealed box lead to changes in air pressure- can derive lung volumes. Archimedes principle!)
Lung volumes reduced in
restrictive lung disease
Increased RV and RV/TLC in
obstructive lung disease
Oximetry
Non-invasive measurement of saturation of haemoglobin by oxygen
Depends on oxyhaemoglobin and deoxyhaemoglobin absorbing infrared light differently
Depends on adequate perfusion (shock, cardiac failure)
Does NOT measure carbon dioxide, so no measurement of ventilation
False reassurance in a patient on oxygen with normal saturations (acute asthma, COPD, hypoventilation)
Causes of hypoxaemia
Hypoventilation (eg drugs, neuromuscular disease)
Ventilation/ perfusion mismatch (eg COPD, pneumonia)
Shunt (eg congenital heart disease)
Low inspired oxygen (altitude, flight)
Ventilation perfusion mismatch
Happens to a degree in normal lungs
Main cause of hypoxaemia in medical patients (e.e.g pneumonia)
Areas of lung that are perfused but not well ventilated (eg pneumonic consolidation)
Mixing of blood from poorly ventilated and well ventilated parts of the lung causes hypoxaemia
Does not fully correct with oxygen administration
Shunt an “extreme” form of V/Q mismatch where blood bypasses the lungs entirely. Does not correct with oxygen administration
Blood gas analysis - what you are looking at
Always look at the pO2 first
Is the patient in respiratory failure requiring additional oxygen?
Then look at the PCO2 (type 1 vs type 2 respiratory failure)
Then consider acid base balance
Acute respiratory acidosis- elevated pCO2, normal bicarbonate, acidosis
Compensated respiratory acidosis- elevated pCO2, elevated bicarbonate (renal compensation), not acidotic
Acute on chronic respiratory acidosis- elevated pCO2, elevated bicarbonate, acidotic
COPD definition
COPD is characterised by airflow obstruction.
The airflow obstruction is usually progressive, not fully reversible and does not change markedly over several months.
The disease is commonly caused by smoking.
Effects of cigarette smoking on the lungs
Cilial motility is reduced (cilia are damaged/destroyed by smoking) - (so sputum is not cleared - increased infections)
Airway inflammation (neutrophilic inflammation)
Mucus hypertrophy and hypertrophy of Goblet cells
Increased protease activity, anti-proteases inhibited
Oxidative stress (increased free radicals e.g. hydrogen peroxide)
Squamous metaplasia → higher risk of lung cancer
Genetics for COPD
Alpha 1 antitrypsin deficiency: genetic present in 1 – 3 % of COPD patients serine proteinase inhibitor M alleles normal variant SS and ZZ homozygotes have clinical disease Unable to “counterbalance” destructive enzymes in lung Non-smokers get emphysema in 30s – 40s Smokers get emphysema much earlier
Smokers have increased risk of COPD if it is in the family
Clinical syndrome of COPD
Chronic Bronchitis:
the production of sputum on most days for at least 3 months in at least 2 years
Emphysema:
abnormal, permanent enlargement of the airspaces distal to the terminal bronchioles
Features seen in airways in patient with cOPD
Infiltration with neutrophils and CD8+ lymphocytes Loss of interstitial support Increased epithelial mucous cells Mucus gland hyperplasia Squamous metaplasia
Features of chronic bronchitis
Chronic Bronchitis:
larger airways > 4mm in diameter
Inflammation leads to scarring and thickening of airways
Small airways disease:
“Bronchiolitis” in airways of 2 -3 mm
May be an early feature of COPD
narrowing of the bronchioles due to mucus plugging, inflammation and fibrosis
Cell type involvement in COPD inflammation
Cell types
Macrophages, CD8 and CD4 T lymphocytes, neutrophils
Inflammatory Mediators
TNF, IL-8 and other chemokines
Neutrophil elastase, proteinase 3, cathepsin G
(from activated neutrophils)
Elastase and MMPs (from macrophages)
Reactive oxygen species
Airway inflammation persists after smoking ceased
What are 2 most clinically signifiacnt types of emphysema
Types causing airflow obstruction:
Centri-acinar –
damage around respiratory bronchioles
more in upper lobes
Pan-acinar –
uniformly enlarged from the level of terminal bronchiole distally
can get large bullae
associated with α1 anti-trypsin deficiency
Consequent loss of surface area for gas exchange
Name the 3 types of emphysema
Centriacinar
Panacinar
Paraseptal
Mechanisms of airflow obstruction in COPD
Loss of elasticity and alveolar attachments due to emphysema - airways collapse on expiration
causes airtrapping and hyperinflaltion →increased work of breathing→breathlessness
Goblet cell metaplasia with mucus plugging of lumen
Inflammation of the airway wall
Thickening (and scarring) of the bronchiolar wall
- smooth muscle hypertrophy and peribronchial fibrosis
Clinical COPD on CxR
Hyperinflation with emphysema - also blacker as lost lung tissue and blood vessels
6 anterior ribs seen (?)
Diagnosing COPD
Consider the diagnosis of COPD for people who are over 35, and smokers or ex-smokers, with any of: exertional breathlessness chronic cough regular sputum production frequent winter ‘bronchitis’ wheeze
Spirometry - FEV1/FVC ratio <70%
Stage 1 (mild) - FEV1 % predicted - 80%
2 (moderate) - 50-79%
3 (severe) - 30-49%
4 (very severe) - <30%
Or FEV1 <50% with respiratory failure = very severe
Treatment of COPD
Inhaled bronchodilators
Short-acting beta-agonists: salbutamol
Long acting: salmeterol, tiotropium
Inhaled corticosteroids
Budesonide and fluticasone – combination inhalers
Oxygen therapy
Oral theophyllines
Mucolytics - carbocysteine
Nebulised therapy
The 2 phenotypes in respiratory failure with COPD
Blue bloater: Hypocapnic low respiratory drive Type 2 respiratory failure ↓PaO2, ↑PaCO2, cyanosis warm peripheries bounding pulse flapping tremor confusion, drowsiness, right heart failure Oedema, raised JVP
Pink puffer: Emphysemitis high respiratory drive Type 1 respiratory failure ↓PaO2, ↓PaCO2
desaturates on exercise pursed lip breathing use accessory muscles wheeze indrawing of intercostals tachypnoea
Recognition of different inflammatory processes in COPD and asthma
Asthmatic airway inflammation: CD4+ T lymphocytes Eosinophils - completely reversible
COPD airway inflammation: CD8+ T lymphocytes Macrophages Neutrophils - Irreversible
COPD vs asthma features
-
Causes of raised acnion gap (in metabolic acidosis)
renal failure Diabetic or other ketoacidosis lactic acidosis toxins e.g. salicylate, some IEM (Excess production of H+ or inability to excrete it
Causes of N anion gap in metabolic acidosis
renal tubular acidosis Diarrhoea carbonic anhydrase inhibitors ureteric diversion (Excess HCO3- loss)
What can be used to measure DKA
Serum Osmolal Gap
OG = measured osmolality - calculated osmolality
Normal OG <10mOsm/kg
N serum osmolality = 275-295mOsm/kg
Non-invasive ventilation in COPD
Provides positive pressure to the airways to support breathing
Recommended as the first line intervention in addition to usual medical care in COPD exacerbations with persistent hypercapniac respiratory failure
Considered if there is a respiratory acidosis (pH < 7.35, H+ > 45) present or if acidosis persists despite maximal medical therapy
Reduces respiratory rate
Improves dyspnoea and gas exchange
Lowers mortality
Reduces need for ventilation in ITU
Reduces length of hospital stay
Cor pulmonale is a syndrome of…
Right heart failure secondary to lung disease
Salt and water retention leading to peripheral oedema
Signs of cor pulmonale
Peripheral oedema
Raised jugular venous pressure
A systolic parasternal heave
Loud pulmonary second heart sound
Pulmonary hypertension and right ventricular hypertrophy may develop
Treatment - diuretics to control peripheral oedema
What is allergy?
Allergy is an immune system mediated intolerance
Clinical reaction
Acute - sudden or slow - progressive
Based on immune system intolerance
Requires exposure to a trigger
Memory,
characteristic clinical features
Dependent on which arm of the immune system
Chronic allergy leads to tissue remodelling
Acute inflammation - repair
Allergy in the airways
Affects airflow
Increases resistance
Causes wheeze/stridor - turbulence
Measured by spirometry
Imaging (CXR) not helpful
Gas transfer not helpful
Extra-thoracic disease
not susceptible to intra-thoracic pressure For example Laryngeal oedema (thyroid, scarring, epiglotitis) Stridor Flow-volume loops CXR not helpful Aspiration to Right middle/lower lobe
Bronchial disease - clinical consequences
Susceptible to intra-thoracic pressure
Clinical consequences: Medium - Small airways flaccid walls Not supported by cartilage Expiratory phase narrowing - wheeze Muco-ciliary clearance impairment – sputum Characteristic flow-volume loops CXR – unhelpful (hyperinflation)
Pathological, Physiological and clinical aspects of asthma
Pathological: Inflammation Scabby epithelium Thickened BM Thickened smooth muscle Mast cells in smooth muscle
Physiological: Yellow mucous Repair pathways Non elastic airways Increased responsiveness Increased sensitivity
Clinical: Cough Cough/wheeze Wheeze Hyper-reactivity
Hyper-sensitivity
Definition of asthma
Appropriate symptoms with signs:
- Wheeze, cough, yellow/clear sputum
- Breathlessness, exercise intolerance
Episodic, triggered, variable – paroxysmal
- Exercise,
- cats - Allergy
- Chemical/physical (salicylate/aspirin) - - Hyper-reactivity
- Diurnal – nocturnal awakening
Respond to asthma therapies
Asthmatic airways
Airway smooth muscle hypertrophy is seen (smooth muscle is is infiltrated by mast cells (contain histamine - whos main target is mooth muscle)
Diagnosis of asthma
Appropriate clinical story
Supportive physiological tests:
1. Patient is given a diary and a peak flow meter
2. Pharmacological hypersensitivity (more sensitive to histamine) - not done now (not diagnostic, is a supportive test)
What cytokines are increased in asthmatic ariways?
IL-5
TSLP
IL-13
TNFalpha
TGFbeta
VEGF
These drive inflammation as recruit –> mast cells, lymphocytes, macrophages, epithelial cells
Family of drugs used against asthms
Anti-IgE biological therapy
Corticosteroids
Anti-leukotriene receptor drugs
Bronchodilators
Triggers EAA
Bird dander – Pigeon fancier’s lung, budgie lung Mushroom worker’s lung Farmer’s lung (fungal spores) Aspergillus lung Cheese workers Wheat weevil Mollusc shell workers Malt worker’s lung Humidifier lung
Pneumothorax definition
‘Air within the pleural cavity’
Negative intrapleural pressure
Opposing forces of chest wall (outwards) and lung (inwards)
Any breach of the pleural space leads to collapse of the elastic lung
Can be traumatic, iatrogenic or spontaneous
Traumatic - stabbing, fractured rib
Iatrogenic - CT guided lung biopsy, TBLB, pleural aspiration
Spontaneous:
Primary - young patient, no underlying lung disease (often tall, thin young men)
Secondary - underlying lung disease (COPD (bullae rupturing), cystic fibrosis)
Pathophysiology of primary pneumothorax
Development of subpleural blebs/ bullae at lung apex
Possible additional diffuse, microscopic emphysema below the surface of the visceral pleura
Spontaneous rupture leads to tear in visceral pleura
Air flows from airways to pleural
space (pressure gradient)
Elastic lung then collapses
Pathophysiology of secondary pneumothorax
Inherent weakness in lung tissue (eg emphysema)
Increased airway pressure (eg asthma, ventilated patient)
Increased lung elasticity (eg pulmonary fibrosis)
Patient is generally much more symptomatic
(poor underlying lung function)
Management more complex, prognosis less good
More likely to require intervention
Symptoms and signs of pneumothorax
Pleuritic chest pain
Breathlessness (can be minimal if primary)
Respiratory distress (especially if secondary)
Reduced air entry on affected side
Hyper-resonance to percussion (?)
Reduced vocal resonance
Tracheal deviation if tension (+/- circulatory collapse)
Differential diagnosis: PTE, musculoskeletal pain, pleurisy/ pneumonia
Management of pneumothorax
Size less important than symptoms
Small pneumothorax very symptomatic if bad COPD
Can tolerate complete lung collapse very well if healthy
2cm rim of air at the axilla equates to 50% volume
<2cm defined as small, >2cm large
Options for management:
Observation (serial CXR) if small or not very symptomatic- can be as outpatient
Aspiration (small bore catheter 2nd intercostal space midclavicular line- aspirate air with syringe/ 3 way tap)
Intercostal drain with underwater seal
Good guideline developed by British Thoracic Society
What if a drain fails to work? (for Tx of pneumothorax)
VATS (Video Assisted Thoracic Surgery)
Considered if not resolved in 5 days
Can staple blebs
Talc pleurodesis (causes inflammatory reaction and pleural adhesion, highly effective)
Pleural abrasion/ stripping
Surgical pleurodesis considered if 2nd pneumothorax on same side, first contralateral event Professional considerations (eg airline pilots, scuba divers)
After a spontaneous pneumothorax has resolved on CXR, how long should the patient wait before flying
> = 7 days
After a spontenous pneumothorax has resolved on CXT, how long should they wait before diving?
Should not dive again
(as have at least 30% of having another pneumothorax) - the pressures on diving are far greater - can develop a tension pneumothorax)
Features of tension pneumothorax
A medical emergency
‘One way valve’ leads to increased intrapleural pressure
Venous return impaired, cardiac output and blood pressure fall
PEA arrest without intervention
Immediate management: insert venflon 2nd intercostal space midclavicular line to relieve pressure
Risk factors for spontanoeus pneumothorax
Smoking, male gender and height are risk factors
Underlying lung disease (secondary)
Recurrence rate 40-50% after first episode
Definitions of obstructive sleep apnoea and obstructive sleep apnoea syndrome
Obstructive Sleep Apnoea
Recurrent episodes of partial or complete upper (pharyngeal) airway obstruction during sleep, intermittent hypoxia and sleep fragmentation
Obstructive Sleep Apnoea Syndrome
Manifests as excessive daytime sleepiness
Mechanism of OSAS
Pharyngeal narrowing –>
Symptoms of OSAS
Snorer
Witnessed apnoeas (relative or partner has noticed)
Disruptive sleep – nocturia/choking/dry mouth/ sweating
Unrefreshed sleep
Daytime somnolence
Fatigue/ Low mood/ Poor concentration
Assessment of OSAS
History- history from partner is very important Clinical examination: Weight BMI BP - often hypertensive Neck circumference (>40cm) Craniofacial appearance (Retrognathia, Micrognathia - ENT issues) Tonsils Nasal patency
Questionairres:
The Epworth Sleepiness Score
The STOP-BANG Questionnaire
The Berlin Questionnaire
Investigations: Limited Polysomnography (Limited Sleep Study) 5 channel home study Oxygen Saturations Heart Rate Flow Thoracic and Abdominal effort Position
Investigation for more complex case:
Full polysomnography
ECG - sleep staging, position, flow, oxygen saturation, videoed, audio, limb leads, snore, eye movements (to tell what stage of sleep their at)
Transcutaenous Oxygen Saturations and Carbon Dioxide Assessment (TOSCA) - home or inpatient (looks at heart rate, saturations and CO2) - probe on your ear (gets to a high temperature)
Advantages of full polysomnography
Correct patient
Accurate assessment of sleep efficiency
Sleep staging via EEG
Parasomnic activity- acting out dreams, sleep talking
Sleep studies - looking at: Apnoea hypoapnoea Respiratory effort related arousals Apnoea - Hypopnoea Index (AHI) Oxygen desaturation index (ODI)
These are all looked at for diagnosis
Apnoea
the cessation, or near cessation, of airflow
4% oxygen desaturation, lasting ≥ 10 secs
Hypopnoea
Hypopnoea is a reduction of airflow to a degree insufficient to meet the criteria for an apnoea
Respiratory effort related arousals
arousals associated with a change in airflow that does not meet the criteria for apnoea or hypopnoea
Apnoea-Hypopnoea Index (AHI)
The apnoea-hypopnoea index (AHI) is calculated by adding the number of apnoeas and hypopnoeas and dividing by the total sleep time (in hours)
Oxygen desaturation index (ODI)
the number of times per hour of sleep that the SpO2 falls ≥ 4% from baseline
Diagnosis of OSA
AHI ≥15 is diagnostic of OSA
AHI 5-15 with compatible symptoms
AHI < 5 Normal
AHI 5-15 Mild
AHI 16-30 Moderate
AHI >30 Severe
Treatment of OSAS
Treat the symptomatic- OSAS (daytime sleepiness)
AIM: Improve daytime somnolence and QOL
Explain OSAS
Weight loss
Avoid triggering factors- alcohol
Treat underlying conditions- tonsils, hypothyroidism, nasal obstruction
Continuous Positive Airways Pressure (CPAP) - Splints airway open, stops snoring, stops sleep fragmentation, Improves daytime sleepiness + QOL
Compliance - >4 hours for >70% daysFixed vs Autoset CPAP
Nasal vs Full Face Mask (if breathe through mouth with need a full face mask)
For those who have mild-moderate OSAS and unable to tolerate CPAP –> Mandibular Advancement DEvicce –> pulls jaw forward to open airway
Sleep position trainers: Supine OSA Vibration when on back (wakes you up) Weeks to change sleeping position Appropriate in few patients with Supine OSA
Untreated OSAS
Hypertension Right heart strain Cardiovascular disease Increased risk of CVA Increased accidents at work/poor concentration
Increased road traffic acidents
4 times for likely to have a RTA
OSAS and driving
OSA WITHOUT DAYTIME SOMNOLENCE, DO NOT NEED TO STOP DRIVING
OSAS (DTS)- LIKELY IMPAIRMENT OF DRIVING, INFORM DVLA ON DIAGNOSIS
OSAS CAN HOLD LICENCE IF COMPLIANT WITH TREATMENT AND REDUCED DTS
CAT 2 LICENCE REQUIRE ONGOING MONITORING BY DVLA WITH REGARDS TO TREATMENT COMPLIANCE
Mainstay treatment for OSAS?
CPAP
Aetiology of lung cancer
90% of lung cancer is attributable to life style choices
Smoking is the main avoidable risk for lung cancer attributable to 86% of cases
Predisposes to lung cancer of all major histological types but link strongest for squamous and small cell
Smoking risks:
<5% are life long non-smokers
10-20 cig/day : 30x risk
60 cig/day : 60x risk
Stopping smoking reduces risk but depends on number of years of smoking and takes time
Risk factors for lung cancer
Smoking Environmental tobacco smoke Ionising radiation – radon, uranium Air pollution Asbestos Other e.g. fibrosing conditions of lung, human papilloma virus, hereditary (polymorphisms in cytochrome p450)
Signs and symptoms of lung cancer
Cough Haemoptysis Shortness of Breath Chest pain (Weight loss/Anorexia General malaise)
Central lung cancer - signs and symptoms
Haemoptysis
Bronchial obstruction – SOB, retention pneumonia
Cough
Peripheral lung cancer - signs and sympotms
May have few symptoms
Pain if pleura or chest wall involved
Local spread of lung tumour
Pleura
- Haemorrhagic effusion
Hilar lymph nodes
Adjacent lung tissue
- May involve large blood vessel leading to haemoptysis
Pericardium
- Pericardial effusion with subsequent involvement of pericardium
Mediastinum
- Superior vena caval obstruction
- Recurrent laryngeal nerve (hoarseness, vocal cord paralysis)
- Phrenic nerve (phrenic nerve paralysis - paralysis of the diaphragm)
Pancoast tumour
- Involvement of brachial plexus giving sensory and motor symptoms (pain and weakness)
- Horner’s syndrome/Oculosympathetic palsy(cervical sympathetic chain)
SVC obstruction with lung cancer
Oedema of face and arms
Raised JVP
Dilated veins on chest
Distant spread of lung cancer
Haematogenous Common due to invasion of pulmonary veins Liver, bone, brain, adrenal Lymphatic Cervical lymph nodes
Non-metastatic effects of lung cancer
ACTH secretion - adrenal hyperplasia - raised blood cortisol - Cushings syndrome (buffalo hump, fragile skin, central obesity)
ADH secretion of tumours - retention of water - dilutional hyponatraemia (SIADH)
Parathyroid horomone related hormone secretion - osteoclastic activity - hypercalcaemi
Encephalopathy
Cerebellar degeneration
Neuropathy
Myopathy
Eaton Lambert myasthenia-like syndrome
Cancer Associated Retinopathy
etc……………
Histological classification of lung cancer
SMALL CELL and NON-SMALL CELL lung cancer is the MOST important decision for treatment
SMALL CELL – usually advanced at diagnosis and responds to CHEMOTHERAPY
NON-SMALL CELL – may be localised at diagnosis and can be treated by SURGERY or RADIOTHERAPY
With advancement in therapies subdivision of NON-SMALL CELL cancers is increasingly important
Small cell carcinoma Non-small cell: Adenocarcinoma (most common) Squamous cell carcinoma (2nd most common) Large cell carcinoma Other (e.g. carcinoid tumour)
Site of central lung tumour vs peripheral
Central tumours arise in and around hilus of the lung and are usually squamous or small cell carcinomas
Peripheral tumours are predominantly adenocarcinomas
FEatures of small cell carcinomas
Most aggressive form of lung cancer Metastasizes early and widely Often initial good response to chemotherapy – but most patients relapse Appearance - Oval to spindle shaped cells - Inconspicuous nucleoli - Scant cytoplasm - Nuclear moulding (more prominent in cytology) - Apoptotic bodies
Features of squamous cell carcinoma
Tend to arise centrally from major bronchi
Often within dysplastic epithelium following squamous metaplasia
Slow growing and metastasize late therefore may be good candidate for surgery
May undergo cavitation
May block bronchi leading to retention pneumonia or collapse
Appearance
A malignant epithelial tumour showing keratinzation and/or intercellular bridges
In situ squamous cell carcinoma may seen in the adjacent airway mucosa
Features of adenocarcinoma
Common tumour in females
Also seen in non-smokers (but also associated with smoking)
Two thirds arise in the periphery sometimes in relation to scarring
Appearance
Glandular, solid, papillary or lepidic (grows along alveoli walls)
Mucin production
FEatures of large cell carcinoma
A diagnosis of exclusion
Usually arises centrally
An undifferentiated malignant epithelial tumour that lacks the cytological features of SCLC and glandular or squamous differentiation
Tend to be central
Carcinoid tumour
Tumour of neuroendocrine cells
Central or peripheral
Classified as Typical or Atypical
Can metastasize but MUCH better prognosis than other conventional lung cancers (5YS for typical 85-90%; Atypical 5YS 50-75%)
Molecular targets identified (targeted therapy) for non-small cell lung cancer
Epidermal Growth Factor Receptor (EGFR)
Echinoderm Microtubule-Associated Protein like 4-Anplastic lymphoma kinase fusion gene
Immunotherapy – PDL1
Testing for mutations in EGFR
Testing for ALK fusion
Performed on biopsy or cytology specimens
PCR or Sequencing used to look for mutations in EGFR
Deletions in Exon 19 commonly associated with good response to EGFR inhibitors
ALK fusion:
FISH
Immunohistochemistry for protein product
Almost any cancer can spread to the lung but common sites are
Breast Colorectal Kidney Head and neck Testicular Bone (osteosarcoma) Sarcomas Melanoma Thyroid
Signs and symptoms of metastases to lungs
Cough Shortness of breath Frequent chest infections Haemoptysis Pain Weight loss
(very similar to lung cancer)
What is mesothelioma/
Primary pleural tumour (also occurs in peritoneum, pericardium and tunica vaginalis testis)
Almost always due to asbestos exposure
Very long lag period before disease develops
Tumour had either an epithelial or sarcomatoid appearance or a mixture of both (biphasic)
What is dermatophytes?
Fungi that cause common infections of skin, nails and hair
Do not colonise ‘live’ tissues, instead keratinised areas such as nails and outer skin
- Specialised niche, use keratinases, elastase and other proteinases as virulence factors
Have a slow anaeorbic metabolism
Makes them slow to respond to drug treatment - need a prolonged treatment period
Healthy and immunocompromised infected
Also known as ‘ringworm’ or ‘tinea’
Treatment against dermatophytes
Many over the counter products Sprays, Creams, Tablets, Powders, Liquids Topical administration, usually Oral medication Severe infections, nail infections Topical medication has not worked Adults only Active ingredients Terbinafine (Lamisil®) Itraconazole Ketoconazole Miconazole
Examples of systemic fungal infections? 9through the airways)
Fungal meningitis - Cryptococcus neoformans Aspergillosis of the lungs - Aspergillus fumigatus Pneumocystis pneumonia - Pneumocystis jiroveci
Only in immunocompromised
Treatment: can be problematic
Features of crytococcus neoformans
Inhaled opportunistic pathogen Encapsulated yeast Contracted from environment, e.g. pigeon droppings Crytococcosis of lungs, and meningitis Often secondary infection with HIV Treatments 2 weeks of i.v. Amphotericin B for meningitis Fluconazole or flucytosine (non-CNS)
Features of Aspergillus fumigatus
Can give rise to 3 different conditions:
Allergic bronchopulmonary aspergillosis (ABPA)
- Allergic reaction to the fungal infection
- Association with cystic fibrosis, asthma
- Prednisone (anti-allergic agent)
Invasive pulmonary aspergillosis (IPA)
- Becomes systemic and spreads throughout the body
- Common in immunocompromised
- Treatment: voriconazole; Amphotericin B
Aspergilloma
- a fungal ball that develops in an area of past lung disease or lung scarring
- e.g. tuberculosis or lung abscess
- No treatment unless bleeding occurs: surgery
Features of Pneumocystitis jiroveci
Common environmental fungus No pathology on immunocompetent Pneumonia Fever Cough Shortness of breath, rapid breathing Treatment and prophylaxis Trimethoprim-sulfamethoxazole (Rapid treatment is needed) - combination treatment
Examples of Azoles
Imidazole, Triazole, and thiazole antifungals
Largest class of antifungal agents Many applications Examples Miconazole (Micatin® or Daktarin®) Ketoconazole (Nizoral, Fungoral and Sebizole®) Clotrimazole (Lotrimin, Lotrimin AF and Canesten) Econazole Isoconazole Fluconazole Itraconazole Abafungin
Mechanism of azole action
Azoles are inhibitors of 14-methylsterol α-demethylase which produces ergosterol (a lipid - essentially a cholesterol for fungi - it is essential) - by inhibiting it you are curing the fungal infection)
Ergosterol is an essential component of the fungal plasma membrane
Does not occur in animal or plants cells
Equivalent of cholesterol in yeast, fungi
On this one difference a pharmacopoeia is build!
Drawback of azoles = cross-resistance
Why are sterols important in fungals?
In eukaryotes sterols such as cholesterol insert themselves into the lipid bilayer and are essential for its proper functioning and viscosity
What is Amphotericin B?
Amphotericin B also exploits the ergosterol / cholesterol difference
It is not an enzyme inhibitor
Exploits the presence of ergosterol
Has a charged hydrophilic side & a hydrophobic side which interacts with ergosterol
Binds on its hydrophobic side
Hydrohilic side has to interact with water and therefore form a pore in the membrane
Needs to be given IV
What is contained within the mediastinum
Consists of blood vessels, trachea, oesophagus, T duct and phrenic nerves, thymus
When the mediastinum moves the heart may also move
Exacerbation of asthma management
High flow oxygen Nebulised bronchodilators (500mg salbutamol, 500mcg ipatropium bromide) Oral prednisolone 40mg Oral doxycycline 300mg IV magnesium 2g Discussion with ITU Consider IV aminophylline infusion
MOA of corticosteroids
Binds to activtaed glucocorticoid receptors to suppress multiple pro-inflammatory genes that are activated in asthmatic airways by reversing histone acetylation
Indications:
Asthma
COPD with reccurent exacerbations
Exacerbations of asthma/COPD
Side effects:
Diabetes, osteoporosis, hypertension, muscle wasting, peptic ulceration, cataracts, cushing’s syndrome, adrenal suppression, acute pancreatitis, hyperlipiaemia, increased appetite, salt and water retention, immune suppression
MOA of bronchodilators - B2 agonsists
MOA - higher specificity for pulmonary (B2) receptors vs cardiac (B1) receptors
Stimulates adenyl cyclase to increase intracellular cAMP –> relaxation fo bronchial smooth muscle
Indications - treatment of asthma + COPD
Side effects - tremor, hypokalaemia, hyperglycaemia, hypomagnesaemia, flushing, tachycardia, arrhythmias, headache, muscel cramps
Short acting - salbutamol, terbutaline (elimination half-life 3-5 hours)
Long-acting - sameterol, formoterol, vilanterol, indacaterol
Salbutamol can be given via inhaled, nebulised, oral, intravenous routes
Inhalational route preferable/nebulised if severe
Bronchodilators: Anti-muscarinics MOA
Inhibition of cholinergic M1 and M3 receptors in lung –> reduction in cGMP and inhibition or parasympathetic-mediated bronchoconstriction
Indications:
treatment of asthma + COPD
Side effects - blurred vision, dry mouth, urinary retention, nausea, constipation, nebulised ipatropium may precipitate acute angle closure glaucoma - use a mouthpiece not a mask
Short-acting - ipatropium bromide
Long-acting - tiotropium, glycopyronium, umeclidinium.
Renally excreted
Bronchodilators: Methylxanthines (aminophylline/theophylline) MOA
Non-selective inhibition of phosphodiesterase –> increased intracellular cAMP –> bronchial smooth muscle relaxation
Indications:
Adjunct to inhaled therapy in asthma/intravenous infusion in severe exacerbations of asthma
Side effects - GI upset, palpitations, tachycardia/arrhythmias, headache, insomnia, hypokalaemia
Time to steady onset - 2-3 days - plasma theophylline levels at 5 days/3 days after dose adjustment
narrow therapeutic window: 10-20mg/L
Toxicity: severe vomiting, hypokalaemia, seizures, arrhythmias, hypotension
Metabolised in the liver - caution in liver disease and with concomitant use of enzyme inducers (rifampicin) and inhibitors (clarithromycin, ciprofloxacin)
SMoking increases theophylline clearance - dose may need adjustment following smoking cessation
What can azithromycin be used for (a resp disease)
Reduction in exacerbations of COPD
What are the 4 causes for bilateral hilar adenopathy
Sarcoidosis
Lymphoma
TB
Malignancy
What is seen on an CXR with a right upper lobe collapse
Opacification of right upper zone
Displacement of the horizontal fissure superiorly
Bulging of fissure medially: Golden’s reverse’s sign
Trachea displaced to right
Always suspect tumour but other causes possible
Investigations:
History, examination, bloods, CT & bronchoscopy
Features of left UL collapse
Opacification left upper zone
Displacement of the oblique fissure superiorly
Bulging of fissure medially: Coldern’s reverse’s sign
Trachea displaced to left
Always suspect tumour but other causes possible
Left LL collapse
Wedge triangular opacification behind the left heart border ‘sail boat sign’
Displacement of the left hilum inferiorly
Obliteration of the left hemidiaphragm
Hyperlucent remaining left lung.
Always suspect tumour but other causes possible
Ivestigations: history, examination, bloods, CT and bronchoscopy
Does lobar collapse normally cause mediastinal shift?
No
Causes of pneumothorax
Trauma - stab, iatrogenic, rib fracture Spontaneous Ventilation Pulmonary disease - all fibrosis, CF Asthma Infections - TB, sepsis, septic infarct Malignancy - metastatic sarcoma Pneumomediastinum - ruptured oesophagus, trachea, tracheostomy Obscure - endometriosis
Radiological signs on the CXR of pneumothorax
Depression of the left hemidiaphragm Tracheal displacement Hyperlucency of the left hemithorax Small left basal pleural effusion Displacement of the heart to the right Pleural line or completely collapsed lung
Complications of pneumothorax
Haemothorax
Tension - mild to marked mediastinal displacement +/- depression of diaphragm
Adhesions; slow re expansion or bleed if tear
Delayed expansion adhesions, airways obstruction
Re expansion oedema
Pleural effusion =
fluid in the pleural space
Normally fluid generated by parietal, absorbed by visceral
Types of fluid: Transudate Exudate Blood - haemothorax Chyle - chylothorax Mixed
Causes of pleural effusion
Hypoproteinanaemia - cirrhosis, nephrotic syndrome
Cardivascular - CCF, constrictive pericarditis
Neoplasm - bronchial mets, lymphoma, mesothelioma
Infection - bacterial, fungal, viral etc
Trauma
Thromboembolism
Inhalation - asbestos exposure
Collagen vascular disease - SLE, RA
Sub-diaphragmatic - ascites-Meigs, pancreatitis, subphrenic abscess, CAPD
Massive diffusion ost likely malignant disease, heart failure, cirrhosis, TB, empyema, trauma
Causes of opacification (white lung) of hemithoraxx
Pleural effusion Consolidation Collapse Massive tumour Pneumonectomy Fibrothorax Combination fo above Lung agenesis
Pleural effusion: CXR signs
Blunting cost phrenic angle and meniscus sign
Supine film - opacification adn visualised vascular markings
Massive effusion with contralateral shift
Sub-pulmonary effusion
Free fluid collects initially under the lung
CXR: high hemidiaphragm, lateral peak to contour, confirmed on lateral decubitas film
Hemidiaphragm appears more opaque
Mechanisms of pleural effusion
Pleural effusions arise when balance between pleural fluid production and aborption has been disturbed.
Increased hydrostatic pressure (CCF)
Decrease osmotic pressure (hypoalbuminaemia)
Inc vascular permeability (pneumonia)
Dec lymphatic drainage (mediastinal carcinomatosis)
Inc intra-pleural negative pressure (atelectasis)
Pleural fluid sampling
As a minimum:
100ml to cytology
Biochemistry for LDH/glucose/protein (Light’s criteria)
Ideally paired serum samples
Microbiology - including TB culture, send in blood culture bottles if empyema suspected.
Do not drain to dryness:
Remove 1 L if symptomatic then stop
Transudate vs exudate
Transudate: Protein <30 g/l LDH <2/3 upper limit of normal value for serum LDH Often bilateral Usually clear
Exudate: Protein >30g LDH >2/3 upper limit of normal value for serum LDH Pleural/serum protein ratio >0.5 Pleural LDH/serum LDH ratio > 0.6 Usually unilateral Clear, cloudy or blood-stained
Common causes of transudates
Cardiac failure
Hepatic cirrhosis
Nephrotic syndrome
Hypoalbuminaemia
Common causes of exudate
Bacterial pneumonia
Malignancy
Mesothelioma
TB
Summary of investigation of pleural effusion
History, exam, CXR
If likely transudate then treat, if not do pleural aspirate (with US) - check protein, LDH, pH, cytology, gram stain, culture, sensitivity
If get diagnosis from fluid then treat, if not do CT chest
Do thorascopy (medical/VATS)
Do pleural biopsy +/- chest drain
Cause found then treat, if not reconsider treatable options/wait
Features of medical thoracoscopy
Procedure of examining the parietal pleura, visceral pleura and diaphragm with a thoracoscope
Rigid or semi-rigid flexible thorascope
Indicated in undiagnosed cytology negative pleural effusions.
Performed under local anaesthesia and mild sedation:
- direct visualisation of the pleural surface
- biopsy of areas which appear abnormal
- therapeutic manoeuvres e.g. complete fluid drainage and pleurodesis during the same procedure
The procedure: Oramorph/atropine premed Patient in lateral decubitus position Spot marked with US Local anaesthetic (20ml 1% lidocaine) Creation of pneumothorax Blunt dissection, port inserted Drainage of fluid with suction catheter Inspection of pleural surface - Biopsies (x 10); Talc pleurodesis if clearly malignant
Chest drain removed once lung re-expanded
Pleural malignancy
Primary pleural malignancy - mesothelioma (still common) - poor prognosis, treatment supportive
Lung cancer
Pleura is common site for metastatic spread - especially breast, ovarian (and also bowel, renal, lymphoma)
Diagnostic yield of aspiration - often need tissue for genetics
Traditionally insert drain followed by medical (talc) pleurodesis on ward
Management options for malignancy in pleural effusions
Drain to dryness once and discharge (if diagnosis secure and already have tissue) - give patient contact number of ward
Medical pleurodesis
Thoracscopic pleurdodesis
Indwelling plerual catheter (IPC)
Pleural infection
Up to 50% of pneumonias will have an associated effusion (parapneumonic)
Effusion with signs of sepsis
Management of empyema
Small bore chest drain
FRequent sterile salin flushes
Iv antibiotics
DVT prophylaxis
Fibrinolytics - streptokinase, DNA ase and TPA (alteplase)
Pathological changes associated with COPD
Inflammatory changes initiated by exposure to noxious particles or gases underlies most of the pathological lesions
- larger airways > 4mm in diameter
- hypersecretion of mucus
- hyperplasia of mucus glands in larger airways
- chronic inflammatory infiltrate - T lymphocytes (CD8), macrophages, neutrophils
- scarring and thickening of airways
Small airways disease
• early process in the development of COPD
• airways 2 - 3 mm in diameter, “ bronchiolitis”
• goblet cell hyperplasia
• narrowing of the bronchioles due to mucus plugging, inflammation and fibrosis
Define an exacerbation of COPD
An exacerbation is a sustained worsening of the patient’s symptoms from their usual stable state which is beyond normal day-to-day variations, and is acute in onset. Commonly reported symptoms are worsening breathlessness, cough, increased sputum production and change in sputum colour. The change in these symptoms often necessitates a change in medication.
Management of exacerbation of COPD in hospital
Assess severity: Symptoms, ABG, CXR
Controlled oxygen therapy: 24 -28 % oxygen, aim to maintain SpO2 88 – 92 %; repeat ABGs at 1 hour
Bronchodilators: nebulised salbutamol 2.5 – 5 mg and ipratropium bromide 0.5 mg qds (and PRN)
consider IV aminophylline if not improving
Corticosteroids: prednisolone 30 – 40 mg od
Antibiotics: if signs of bacterial infection (purulent sputum, increased sputum volume, WCC, CRP
Non-invasive ventilation (NIV): for acidotic type II respiratory failure
Other: consider DVT prophylaxis (LMWH), monitor fluid balance and nutrition, manage co-morbidities
Name the clinical signs and CXR changes associated with pleural effusion (cbl)
Clinical signs :
• decreased breath sounds, stony dull to percussion, decreased tactile or vocal fremitus
CXR appearance:
• need > 300 ml of fluid to be present to see on CXR
• uniformly white appearance
• blunting of the costophrenic and cardiophrenic angles.
• A meniscus at the upper edge
What are the 2 main categories of pleural effusion? (cbl)
Exudate – fluid protein usually > 30 g/l – e.g. in pneumonia, maliganancy, TB
Transudate – fluid protein < 30 g/l (usually < 20 g/l) – heart failure, liver failure, nephrotic syndrome
What scale is used to assess the severity (level of breathlessness) of COPD
MRC Dyspnoea Scale
Define respiratory failure
Define respiratory failure as PaO2< 8 kPa on room air (21% inspired oxygen)
How would you assess if long-term oxygen therapy is appropriate for him at present? - a man with COPD exacerbation
In (COPD) patients who have:
PaO2< 7.3 kPa when stable (Patients ABGs on Powerpoint – too good for LTOT)
OR PaO2 7.3 – 8 kPa
AND any of secondary polycythaemia , nocturnal hypoxaemia ,
peripheral oedema, pulmonary hypertension
and NON-SMOKERS FOR > 3 MONTHS
Define asthma
A chronic inflammatory condition of the airways that causes recurrent episodes of wheezing, breathlessness, chest tightness and cough, particularly at night and/or early morning.
These symptoms are usually associated with widespread but variable bronchoconstriction and airflow limitation that is at least partly reversible, either spontaneously or with treatment.
Key features of asthma
- increased airways hyper-responsiveness to a variety of stimuli resulting in episodic bronchoconstricton
- inflammation of the bronchial walls
- increased mucus secretion
Causes and triggers of asthma
Atopic Asthma (Extrinsic asthma) – usually starts in childhood
Atopic individuals - raised total serum IgE and the presence of specific IgE against common aeroallergens, or positive skin tests to common aeroallergens.
Non-atopic (intrinsic asthma) – often starts in middle age – possible triggers include respiratory viruses, air pollutants
Environmental factors - “hygiene hypothesis” in early childhood – growing up in a relatively “cleaner” environment predisposes to the development of allergy / Th2 responses. Bacterial components direct the immune system to Th1 responses.
Viral infections - rhinovirus, RSV
Drugs - NSAIDs, beta blockers
Genetic factors - IL-4/IL-13 pathways, ADAM 33, others
Allergen induced asthma
Immediate Asthma (early reaction) • starts within minutes, maximal at 15 - 20minutes, subsides by 1 hour • bronchoconstriction triggered by direct stimulation of subepithelial vagal receptors, increased mucus production, vasodilatation and increased vascular permeability
Late-Phase Reactions
• follows immediate reaction, more sustained attack of airflow limitation that may respond less well to bronchodilators
• inflammation with recruitment of, eosinophils, neutrophils and lymphocytes
Name three cell types and three inflammatory mediators involved in airway inflammation in asthma.
Inflammatory Cells Seen
o Activated T helper (Th2) lymphocytes produce IL-3, IL-4, IL-5 and IL-13 which maintain the allergic phenotype
(IL-4 stimulates IgE production, IL-5 - activates eosinophils, IL-13 stimulates mucus secretion and promotes IgE production)
o Eosinophils - in bronchial walls and secretions of asthmatics, attracted to airways by IL-3, IL-5, GMCSF and chemokines (eotaxin, RANTES), release mediators such as LTC4 when activated
o Mast cells - increased in mucous glands, smooth muscle and epithelium, produce histamine, PGD2, cysteinyl leukotrienes, tryptase
o Dendritic cells – present allergens to T lymphocytes
Mediators in the (late) acute asthma response:
Leukotrienes: LT C4, D4, E4 - bronchoconstriciton, increase vascular permeability, increase mucus secretion
Acetylcholine: - released from intrapulmonary nerves - directly stimulates muscarinic receptors on airway smooth muscle
Histamine: - bronchoconstrictor
Prostaglandin PGD2 - bronchoconstriction and vasodilation
Others - Platelet-activating factor, IL-1, TNF, IL-6, chemokines, neuropeptdides (eotaxin), nitric oxide
Pathological features in asthma
- Increased Airway Inflammatory cells
- Plasma exudation
- Oedema
- Smooth Muscle hypertrophy
- Mucus plugging
- Shedding of epithelium
Immediate Tx for exacerbation of asthma
¥ Oxygen 40-60% (maintain SpO2 94 - 98%)
¥ Salbutamol 5mg or terbutaline 10mg via an oxygen-driven nebuliser
¥ Ipraptropium bromide 0.5mg via an oxygen-driven nebuliser
¥ Prednisolone tablets 40-50mg or IV hydrocortisone 100mg or both if very ill
¥ No sedatives of any kind
¥ Chest radiograph only if pneumothorax or consolidation are suspected
IF NOT IMPROVING AFTER 15 - 30 MINUTES (OR IF LIFE THREATENING FEATURES ARE PRESENT):
¥ Discuss with senior clinician and ICU team
¥ Consider giving infusion of IV magnesium sulphate 1.2-2g infusion over 20 minutes and then either IV aminophylline or IV salbutamol (or terbutaline)
¥ Consider transfer to ITU for mechanical ventilation if does not improve
SUBSEQUENT MANAGEMENT
¥ IF PATIENT IS IMPROVING continue:
¥ 40-60% oxygen
¥ Prednisolone 40-50mg daily (should continue for at least 5 days or until recovery)
¥ Nebulised ß2 agonist and ipratropium 4-6 hourly
Investigations for asthma
- Serial Peak Expiratory Flow measurements - look for diurnal variation
- Spirometry – have airflow obstruction, > 400 ml improvement in FEV1 following bronchodilator
- Metacholine or histamine bronchial provocation test - look for a drop of 20 % in FEV1 from baseline
- Exhaled nitric oxide - a marker of airway inflammation (raised level > 25 ppb)
- CXR - usually normal - ? pneumothorax in acute asthma, or infiltrates in ABPA
- Skin prick tests or specific IgE levels - should be done - common allergens
- Blood and sputum tests - may have raised blood eosinophils, often have raise sputum eosinophils but not routinely done
Stepwise approach to asthma management (cbl)
Step 1: occasional relief bronchodilator: Inhaled short-acting beta2 agonist as required (up to once daily)
Step 2: regular inhaled preventer therapy - inhaled corticosteroid
Step 3: inhaled corticosteroid + long-acting inhaled beta2 agonist
If long-acting beta2 agonist stopped (not working, not tolerated), add one of
Leukotriene receptor antagonist
Modified-release oral theophylline
Modified-release oral beta2 agonist; child under 12 years not recommended
Step 4: high-dose inhaled corticosteroid + regular bronchodilators e.g. nebulised therapy, anti-muscarinics
Step 5: regular corticosteroid tablets
If still not controlled, then other possible therapies Anti-IgE therapy (Omalizumab), anti-IL-5 (Mepolizumab), anti-TNF treatments (Etanercept) (and rarely methotrexate, ciclosporin) – considered at specialist asthma clinics
Definition of idiopathic pulmonary fibrosis (cbl)
• a specific form of chronic fibrosing interstitial pneumonia of unknown aetiology
• limited to the lung
• histopathological appearance of usual interstitial pneumonia (UIP) on surgical lung biopsy
• known causes of ILD such as drugs, environmental exposure and connective tissue disease have been excluded
• abnormal lung function tests with evidence of restriction and/or impaired gas exchange
characteristics abnormalities on CXR or HRCT chest (bibasal reticular abnormalities with minimal or no ground glass opacities on HRCT)
Key clinical features of idiopathic pulmonary fibrosis (cbl)
- Age of onset > 50,
- male > female
- Progressive breathlessness, productive cough, cyanosis
- Respiratory failure, cor pulmonale, pulmonary hypertension
- Fine bilateral end-inspiratory crackles
- Finger clubbing (2/3)
- usually a h/o cigarette smoking
Drug induced ILD - what drugs cause it
Antibiotics - Nitrofurantoin
Disease-modifying antirheumatic drugs - Methotrexate, Sulphasalazine, gold, penicillamine, lefluonamide, etanercept
Cardiovascular agents - Amiodarone, ACE-inhibitors, statins
Chemotherapeutic agents - Bleomycin, cyclophosphamide
Illicit drugs - Heroin, methadone, talc
Miscellaneous - Oxygen, radiation, aspirin, interferons
IDF - you request a Ct chest. What blood tests and further investigations would you ask for?
Investigations: (Patients results in brackets)
Routine Blood Tests
FBC (normal) ESR (30 mm in first hour, raised)
U+E, LFTs, Calcium (normal) CRP (normal)
Immunology Discuss predisposing conditions
- Rheumatoid factor 25 kU/l (normal < 15) – likely non-specific inflammatory response
- ANA screen (negative)
- ANCA screen ( (negative)
- Avian precipitans and Aspergillus precipitians (negative)
- Serum Angiotensin converting enzyme (ACE) level (sarcoid)
- Serum immunogobulins (raised in active sarcoid)
As condition progresses or if felt to have evidence of respiratory failure or cor pulmonale at presentation. (ABGs and walk test on Powerpoint)
Arterial blood gases
Six minute walk test/ambulatory oxygen assessment - to assess if desaturation on exertion.
Echocardiogram - to look for the development of pulmonary hypertension
Radiological features that support a diagnosis of IPF (cbl)
Radiology - changes predominantly at lung bases CXR and HRCT on Powerpoint, patient + other example
CXR - ground glass changes*→ irregular reticulonodular shadowing → honeycombing
High resolution CT Chest
- subpleural reticular abnormalities
- honeycombing - thick-walled cysts 0.5 - 2 cm in diameter in respiratory and terminal bronchioles
- traction bronchiectasis
Key histological features of UIP (usual interstitial pneumonia)
- Dense interstitial fibrosis predominantly in the subpleural region
- Destruction of the normal lung architecture and with cystically dilated air spaces and intervening fibrous tissue
- Inflammatory infiltrate, mainly of lymphocytes, plasma cells and prominent intra-alveolar macrophages
- a few fibroblastic foci
- Overall appearances in keeping with usual interstitial pneumonia
Macroscopical features of UIP (IPF?)
- pleural surfaces of the lung are “cobblestoned”
- fibrotic areas of lung - firm rubbery and white
- disease mainly basal and subpleural, with thickening of the interlobular septae
Histology of IPF
- patchy interstitial fibrosis, varies in intensity and age (temporal heterogeneity)
- fibroblastic foci in early fibrosis - areas of fibroblastic/myofibrobalastic proliferation - become less cellular as disease progresses and collagen deposited
Pathogenesi of IPF (cbl)
• “repeated cycles” of epithelial activation/injury by some unidentified agent
- abnormal activation of epithelial cells lead to a dysregulated repair process
- Abnormal epithelial repair at site of injury/inflammation leads to the formation of the fibroblastic foci
- inflammatory pathways also promote fibrosis
Cell types involved in pulmonary fibrosis
• damaged epithelial cells
- activated to release growth factors - TGFβ1 one of most important
• fibroblasts/myofibroblasts
- myofibroblasts secrete excessive amounts of extracellular matrix proteins, mainly collagens
• type 1 pneumocytes are reduced
- injured cells produce TGFβ1 which promotes the transformation of fibroblasts to myofibroblasts
- fail to develop from type 2 pneumocytes add to the deveopment of dysfunctional alveolar epithelium
- reduced levels of calveolin 1, an anti-fibrotic molecule produced by these cells
• eosinophils, mast cells, macrophages and lymphocytes
- release cytokines such as IL-4, IL-1, TNFα and IFNγ
- No genetic factors consistently associated with sporadic cases of IPF
- MUC5B gene polymorphisms is associated with familial cases of IPF
Treatment for IPF (UIP)
Pirfenidone
• approved for use in IPF (patients with FVC 50 - 80 % predicted)
• antifibrotic and anti-inflammatory effects; slows lung function decline
• mechanism of action unclear but likely to suppress fibroblast proliferation, so reducing the production of fibrosis-associated proteins and cytokines
Nintedanib
• intracellular inhibitor of multiple tyrosine kinases
• slows lung function decline in recent trial.
Steroids and immunosuppressants are not routinely recommended for treatment of IPF
• Steroids not effective in most cases
• Azathioprine may worsen prognosis when used with prednisolone
No longer advised to give the “triple therapy”of steroids+azathioprine+N-acetylcysteine
Trial of steroids may be considered if there is felt to be a possibility of an inflammatory component in some cases e.g. younger women with a possible underlying connective tissue disease.
N-acetyl cysteine
• does not improve survival or slow lung function decline (King TE Jr et al, NEJM 2014; 370:2093)
• is a mucolytic, so might be tried if a patient has cough or sputum, as has little toxicity
For many patients, espcially if over 80 years oldtherapy for IPF is essentially aimed at symptom control
Long term oxygen therapy
Diuretics for fluid retention if develop cor-pulmonale
Antibiotics to treat infection
Lung transplantation in younger patients (age < 65)
Prognosis of IPF
Outcome - Median survival 3 -5 years from time of diagnosis
Rate of progression varies - generally have a steady, progressive decline but may also have sudden steps of decline after exacerbations/infections Most patients (around 75%) will die of respiratory illness. Approximately 1in 10 patients will develop lung cancer.
Which symptoms and signs should alert you to a possible diagnosis of lung cancer (cbl)
Symptoms Suspicious of Lung Cancer
¥ Cough - that doesn’t go away or a long standing cough gets worse
¥ Recurrent infections
¥ Breathlessness – lobar/lung collapse (co-existing COPD)
¥ Haemoptysis
¥ Unexplained weight loss
• Chest and/or shoulder pains
• Hoarse voice
Clinical Signs which may be associated with Lung Cancer
Finger clubbing
Signs of lobar collapse or a pleural effusion
From metastases - hepatomegaly, cervical lymphadenopathy, bony tenderness
Cahexia
Horner’s syndrome (Pancoast tumour)
Evidence of superior vena cava obstruction (SVCO) or spinal cord compression (SCC)
Cushingoid
Main RxF for developing lung cancer
Smoking in 85%
Passive smoking, occupational asbestos, silica and nickel exposure, pulmonary fibrosis
Most common investigations for suspected lung cancer
CXR
• Routine bloods – FBC, U+E, LFTs, serum calcium, CRP
• CT chest and upper abdomen – look for lymph nodes, evidence of liver or adrenal metastases
• Bronchoscopy – will detect more central lesions
CXR Changes in Lung Cancer
• Mass lesion
• Pleural effusion
• Lobar or lung collapse
• Slowly resolving consolidation
• Mediastinal widening or hilar lymph nodes
• Normal
Other techniques
• CT / Positron emission tomography (CT-PET) - combined imaging to look for metastases
• Endobronchial ultrasound – to visualize and guide needle biopsy of mediastinal lymph nodes
• Ultra-sound guided aspiration of supraclavicular lymph nodes
• VATS (video-assisted thoracoscopic surgery) – to diagnose and treat pleural effusions
Lung function tests – need full PFTs if considering surgery (for surgery generally need an FEV1 > 1.5 litres) Patient has normal lung function
ECG
Classify lung cancer into either small cell or non-small cell
Non Small Cell Carcinoma (NSCLC) Subtypes
- Squamous cell (40-60%) - closely linked to smoking history, keratinization and/or intercellular bridges on histology, central airways, high frequency of p53 mutations
- Adenocarcinoma (10 -20%) - glandular differentiation or mucin production, most common form in women and non-smokers, more peripherally located, TTF-1 positive, if EGFR mutations present may benefit from treatment with EGFR inhibitors
- Large cell (5-15%) - undifferentiated epithelial tumour
Small cell
Staging of non-small cell carcinoma
Non Small Cell Carcinoma (NSCLC) Subtypes
- Squamous cell (40-60%) - closely linked to smoking history, keratinization and/or intercellular bridges on histology, central airways, high frequency of p53 mutations
- Adenocarcinoma (10 -20%) - glandular differentiation or mucin production, most common form in women and non-smokers, more peripherally located, TTF-1 positive, if EGFR mutations present may benefit from treatment with EGFR inhibitors
- Large cell (5-15%) - undifferentiated epithelial tumour
Non-small cell carcinoma Tx
Surgery - early stages (usually Stage I or II)
Radiotherapy –
• Curative intent (radical radiotherapy) in some with early stages if not thought to be fit for surgery
o Side effects – radiation pneumonitis in 10 – 15 % (acute infiltrate < 3 months after treatment), radiation fibrosis around one year after
• For symptom control (palliative radiotherapy) – good for bone and chest wall pain, haemoptysis, occluded bronchi, SVCO
Chemotherapy –
• Platinum-based chemotherapy (cisplatin/carbplatin) in combination with paclitaxel or gemcitibine
• Can be used to down-stage tumours for surgery or to palliate symptom
Genetic testing in Adenocarcinoma of Lung
Adenocarcinomas are now tested for genetic mutations, and if positive, specific treatments may be offered:
EGFR mutations – erlotinib
ALK mutations – crizotinib
PD-L1 mutations – immunotherapy e.g. Nivolumab
Histology of small cell carcinoma - + Tx
• small epithelial cells, scanty cytoplasm, ill-defined cell borders, finely granular nuclear chromatin (salt and pepper pattern), high mitotic count
Staged as Limited or Extensive disease
Limited disease – confined to one hemithorax and the ipsilateral supraclavicular fossa (30%)
Extensive disease – all other patients (70%)
Without treatment: survival 2-3 months in limited disease, 4 weeks in extensive disease
With treatment:
Limited disease survival 15 – 20 months, 10 -13 % 5 year survival
Extensive disease – 8 -13 months median survival, 1-2% survive 5 years
Other Treatments for both types of lung cancer
• Endobronchial treatments – laser, stents to deal with tumour obstructing large airways
Palliative care – opiates to treat pain and breathlessness
Common sites of metastatic lung cancer
- Lymph nodes – mediastinal (causing superior vena caval obstruction),cervical, axillary
- Pleural effusion
- Liver
- Bone - bone pain, may cause spinal cord compression
- Brain
- Adrenals
Which emergency condition associated with lung cancer should be excluded?
Superior vena cava obstruction – due mediastinal nodes compressing SVC
• Symptoms - breathless, dysphagia, stridor, swollen oedematous face and right arm
• Signs – venous congestion in the neck, dilated veins in the arm
• Treatment – high dose steroids, vascular stents, anti-coagulation, radiotherapy or chemotherapy
Spinal cord compression
• Symptoms – leg weakness and numbness, reduce bladder and bowel control
• Signs – upper motor neurone signs in legs, sensory level
• Treatment – high dose steroids, urgent oncology input (radiotherapy) and/or neurosurgical input
