Respiratory Flashcards
Definition of COPD
Persistent airflow limitation
FER = FEV1/FEC < 0.70 + symptomatic
Triggers of acute exacerbation of COPD
70% triggered by infection (viral and bacterial)
30% no clear aetiology i.e. “non-infective” –> environmental, PE, AMI
Symptom reduction pharmacotherapy of COPD
First line: monotherapy with LAMA > LABA
Second line: combination therapy with LAMA/LABA
Exacerbation prevention pharmacotherapy of COPD
First line: ICS/LABA or LAMA/LABA
Indications of ICS in COPD
- History of hospitalisations for exacerbations
- > / 2 moderate exacerbations of COPD per year
- Blood eosinophils >/ 300 cells/uL
- History of concurrent asthma
Triple therapy options for COPD
Fixed triple therapy treatment
- Fluticasone/Vilanterol/Umeclidinium (daily breath activated)
- Beclomethasone/Formoterol/Glycopyrronium (twice daily MDI)
Open triple therapy
- ICS + LABA + LAMA (generally 2 inhalers)
Non-pharmacological management of COPD
Pulmonary rehab
Smoking cessation
Pharmacotherapy for smoking cessation
Buproprion
Varenicline
NRT
Contraindications for bupropion
Should not be used in patients with history of bipolar disease
Contraindications for NRT
Should be avoided in unstable angina, recent MI, stroke or severe arrhythmias
Contraindications of varenicline
Should not be used in patients with unstable psychiatric symptoms or history of suicidal ideation
Definition of asthma
History of respiratory symptoms (i.e. wheeze, SOB, chest tightness and cough varying over time and intensity) with variable expiratory airflow limitation
Clinical features of asthma
Episodic symptoms
Atopy
Triggers
Work-related exposures
Asthma symptoms in childhood
Triggers of asthma
Smoking
Dust mite
Air pollutions
Moulds, pets, cockroaches
Viral illness
Workplace exposure
GORD
Role of FeNO in asthma
Measure of NO exhaled in breath
Low FeNO can be helpful when reviewing patients who take puffer therapies - proves compliance and response to treatment
Seen in non-eosinophilic asthma
Role of methacholine bronchoprovocation test
Negative test excludes asthma
Spirometry findings in asthma
Can be normal
Could show obstruction (FER < 0.70 or < LLN)
Assess reversibility –> significant finding when > 12% and > 200mL increase in FEV1
Role of bronchoprovocation in asthma
Used if strong clinical suspicion and normal spirometry
Direct challenge test with methacholine (>20% fall in FEV1) - good negative predictive valve for excluding active asthma
- false positive seen in allergic rhinitis, CF, heart failure, COPD, bronchitis
Indirect challenge with mannitol or hypertonic saline (>15% fall in FEV1)
- better PPV for asthma than methacholine
Categories in asthma
Intermittent asthma
- Normal FEV1, symptoms/SABA <2/week, no limitations
Persistent asthma
- Mild – normal FEV1, symptoms/SABA >2/week, minor limitation
- Moderate – mildly abnormal FEV1 (60-80%), daily symptoms, some limitations
- Severe – abnormal FEV1 < 60%, daily symptoms + nocturnal, limited function
Notes
- Two or more flares requiring OCS in 12M –> persistent
- Hospital admission or ED presentation –> moderate
- ICU admission –> severe
Formoterol preparations
- Symbicort (budesonide/formoterol)
- Fostair (beclomethasone/formoterol)
- Flutiform (fluticasone/formoterol)
Biologic therapies in asthma
Omalizumab - IgE
Mepolizumab - IL-5
Benralizumab - anti-IL5 receptor
Bupilimub - IL-4 and IL-13
Tezepelumab - TSLP
Typical HRCT features of UIP
Honeycombing
Traction bronchiectasis (least specific)
Reticular opacities (peripheral and lower lobe predominant)
No atypical features
Smoking related ILD
Idiopathic ILD
Respiratory bronchiolitis ILD
Desquamative interstitial pneumonia
Other disease labels of ILD
ILD of known cause
- Dust (asbestosis, silicosis)
- CTD associated
- Hypersensitivity pneumonitis
- Radiation induced
- Drug induced
Granulomatous ILD
- Sarcoidosis
Idiopathic ILD
- Chronic/fibrosing – idiopathic pulmonary fibrosis, idiopathic non-specific interstitial pneumonia
- Acute/subacute – cryptogenic organising pneumonia, acute interstitial pneumonia
- Smoking related – respiratory bronchiolitis ILD, desquamative interstitial pneumonia
Other
- Lymphangioleiomyomatosis (LAM)
- Pulmonary Langerhans histocytosis
Diagnosis of ILD
Clinical data (history and examination)
HRCT
PFTs – helpful to evaluate severity and monitor progress
Pathology (features of autoimmunity)
BAL/biopsy – not always required and not always possible
- If probable UIP pattern on HRCT can be diagnosed as IPF by MDM without biopsy
- Surgical lung biopsy (elective)
* ~1-2% mortality
* Consider if age < 50 yrs, atypical HRCT findings, rapidly progressive disease
- No role in transbronchial biopsy
Indications for lung transplant
Risk of death > 50% within 2 years
Likelihood of surviving > 90 days post TP > 80%
No life-limiting comorbidity (in 5 yrs post TP)
Satisfactory supports/psychosocial
Contraindications of lung transplant
Age > 65 yrs
Smoking/EtOH/drug dependence
Malignancy (5 yrs disease)
Chronic infection
Obesity or malnutrition
Osteoporosis in severe symptoms
Indications for lung transplant in idiopathic pulmonary fibrosis
DLCO < 40% predicted
FVC < 80% predicted
Dyspnoea or functional limitation attributable to lung disease
Decrease in SpO2 to 88%
Role of prednisone/AZA/NAC in ILD
PANTHER study
- Found to be harmful with increased death and hospitalisation
- no physiological or clinical benefit
Role of antifibrotic therapy for ILD
Nintedanib and pirfinedone have been shown to alter disease progression
- suitable for mild/moderate IPF
Nintedanib mechanism of action and side effects
Inhibits multiple tyrosine kinases
Side effects
- Diarrhoea (>60%)
- Nausea (up to 25%)
- LFT derangement
Pirfenidone mechanism of action and side effects
Inhibits TGF-beta and fibroblast proliferation
Side effects
- Rash (30%)
- Nausea (up to 35%)
- Diarrhoea (25%)
HRCT features of non-specific interstitial pneumonia
- Ground glass opacity (partial filling of air spaces but preserved bronchial and vascular markings)
- Reticular opacity
- Traction bronchiectasis
- Diffuse – can have subpleural sparing
- Fibrotic vs cellular
Management of NSIP
- Glucocorticoids
- Second agents – mycophenolate or azathioprine
- Those with more severe disease
- Failure to respond
- Worsens as steroids reduced
- Third line agents – IV cyclophosphamide (monthly), rituximab
- Lung transplantation
HRCT features of hypersensitivity pneumonitis
- Typical features
- Centrilobular nodules and/or ground glass opacities
- Mosaic attenuation (inspiratory), three density pattern, gas trapping (expiratory)
- Fibrosis – linear opacities, coarse reticulation and lung distortion, traction bronchiectasis, honey combing (relative sparing of lower zones, random involvement both axially and craniocaudally)
- Some HP have radiological pattern consistent with UIP reinforces diagnosis of idiopathic pulmonary fibrosis generally only reached if no features suggestive of alternative diagnosis
Clinical features of hypersensitivity pneumonitis
- Recurrent ‘atypical’ pneumonia
- Symptoms after moving to new job or home
- Exposure to pets
- Exposure to moulds
- Hot tub/sauna/swimming pool exposure
- Improvement when on holiday or over weekends
Bronchoscopy and lung biopsy features of hypersensitivity pneumonitis
- BAL – lymphocytic pattern suggestive (~30% lymphocytes)
- TBBx can demonstrate non-caseating granulomas
- Surgical lung biopsy or cryobiopsy where imaging, exposure or BAL are inconclusive
HRCT features of sarcoidosis
- Bilateral hilar and mediastinal LAD
- Nodular (upper zone) + hilar and mediastinal LAD
- Parenchymal – at least stage II disease
Features of Lofgren syndrome
Fever, polyarthritis, erythema nodosum, bilateral hilar lymphadenopathy
Bronchoscopy features of sarcoidosis
- BAL – elevated CD4:CD8 – supportive finding
- Endobronchial biopsy – positive in 40-70%
- Transbronchial biopsy – positive in 50-75%
- EBUS – positive in 80-90%
- Combined approach may have highest yield (>90%)
Extrapulmonary complications and features of sarcoidosis
- Ocular – ophthalmology review
- Calcium – urinary calcium excretion rate, serum Ca2+, vitamin D (1,25)
- Cardiac – ECG, TTE, MRI or PET
- Brain – MRI, LP
Indications and treatment for sarcoidosis
- Indications
- Progressive symptomatic pulmonary disease
- Asymptomatic pulmonary disease with persistent infiltrates or progressive loss of lung function
- Cardiac disease
- Neurological disease
- Eye disease not responding to topical therapy
- Symptomatic hypercalcaemia
- Other symptomatic/progressive extrapulmonary disease
- Treatment
- Inhaled corticosteroids +/- steroid sparing agents
Clinical classification of pulmonary hypertension
Group 1: pulmonary arterial hypertension
Group 2: PH associated with LHD
Group 3: PH associated with lung disease and/or hypoxia
Group 4: PH associated with obstruction
Group 5: PH associated with unclear and/or multifactorial mechanisms
Haemodynamic characteristics of pulmonary HTN
mPAP > 20mmHg
Haemodynamic characteristics of pre-capillary PH (group 1, 3, 4, 5)
mPAP > 20mmHg
PAWP </ 15mmHg
PBR > 2 WU
Haemodynamic characteristics of isolated post-capillary PH (group 2 and 5)
mPAP > 20mmHg
PAWP > 15mmHg
PVR </ 2WU
Haemodynamic characteristics of combined post-capillary PH
mPAP > 20mmHg
PAWP > 15mmHg
PVR > 2WU
Risk factors for PAH
CTD (systemic sclerosis, Raynaud’s disease, SLE, MCTD, RA)
HIV infection
Portal hypertension
Congenital heart disease
Schistosomiasis
Gene mutations associated with PAH
Bone morphogenetic proteins (BMPR) –> inhibits smooth muscle proliferation and induces apoptosis
Activin1 like kinase receptor (ALK1, ACVR1)
Serotonin transporter gene mutations (5HTT)
Endoglin (ENG)
Mothers against decapentaplegic homologue 9 (SMAD9)
Potassium channel subfamily K member 3 (KCNK3)
Caveolin (CAV1)
Vascular mediators of PAH
Increased endothelin levels (vasoconstrictor and mitogen)
Decreased nitric oxide levels (vasodilator and antiproliferative)
Decreased prostacycline levels (vasodilator, antiproliferative, inhibits platelet function)
Symptoms of pulmonary HTN
Dyspnoea on exertion
Fatigue
Bendopnoea
Palpitations
Haemoptysis
Exercise-induced abdominal distension and nausea
Weight gain due to fluid retention
Syncope
PAH treatment targets which pathways
Endothelial dysfunction pathways
- Endothelin pathway
- NO pathway (sGC stimulator and PDE5 inhibitors)
- Prostacyclin pathway
Endothelin receptor antagonists examples
Dual ERA
- Bosentan
- Macitentan
Selective ERA
- Ambrisentan
Drugs affecting nitrous oxide pathway in PAH
PDE5 inhibitors - sildenafil and taladalafil
- increases intracellular concentration of cAMP and cGMP
Riociguat - vasodilator by stimulating soluble guanylate cyclase (sGC)
- also worked for chronic thromboembolism pulmonary hypertension (CTEPH)
Drugs affecting prostacycline pathway
Prostacycline analogues
- Epoprostanol
- Treprostinil
- Iloprost
Non-prostanoid IP receptor agonists
- Selexipag
Initial treatment for low/intermediate risk patients with PAH
Combined therapy with ERA and PDE5 inhibitor unless cardiopulmonary comorbidities
Initial treatment for high risk patients with PAH
Combined ERA + PDE5 inhibitors and IV/SCA PCA
Consider referral for lung transplantation
If adding IV/SC PCA, add selexipag or switch PDE5i to riociguat
Further treatment intermediate-low risk patients despite receiving combined ERA/PDE5i therapy
Addition of selexipag (Non-prostanoid IP receptor agonists)
Can consider switch from PDE5 inhibitor to riociguat
Indication for lung transplant in PAH
PAH refractory to medical therapy (intermediate-high or high or REVEAL > 7)
Rapidly progressive disease
Use of IV prostanoid therapy
Known or suspected pulmonary veno-occlusive disease (PVOD) or pulmonary capillary hemangiomatosis
Renal or hepatic compromise secondary to PAH
Pathophysiology of OSA
Increased upper airway collapsibility
Poor muscle control and function
Low arousal threshold
High loop gain
Symptoms of OSA
Snoring
Witnessed apnoea
Noctural choking or gasping
Excessive daytime sleepiness
Symptoms that typically present in women with OSA
Insomina
Depression, irritability, mood changes
Anxiety
Non-restorative sleep
Lethargy
Fatigue
Sleep fragmentation
Frequent awakenings
Clinical phenotypes of OSA and how they respond to PAP
Sleepy
- best response to PAP with improvement in almost all symptoms
Minimally symptomatic
- some night time or daytime symptoms related to sleep
- some improvement in ED and physical fatigue
Disturbed sleep
- more insomnia type symptoms
- some improvement occurring with PAP but no difference in most symptoms than no PAP
Cardiovascular changes in OSA
Increase SNS activity
Increase inflammation
Increase endothelial dysfunction
Metabolic changes in OSA
Decrease insulin sensitivity
Increase leptin resistance
Increase lipolysis
Increase impairment of lipoprotein clearance dysfunction
Complications of OSA
- Systemic hypertension
- Hypoxia-induced cardiac arrhythmia (e.g., (atrial fibrillation, atrial flutter)
- Pulmonary hypertension and cor pulmonale
- Global respiratory insufficiency
- Cardiac infarction, stroke, and sudden cardiac death (the risk of sudden death is high in infants and the elderly)
- Polycythemia
- Risk of accidents (e.g., car crashes, occupational accidents) due to microsleep
- Increased risk of developing vascular dementia
- Poor sleep leads to increased appetite and obesity
- Metabolic - DM, NASH
- CKD
OSA severity classification
AHI (Apnoeas and hypopnoeas/hr of sleep)
- AHI < 5 normal
AHI 5-15 mild
AHI 15-30 moderate
AHI > 30 severe
Management for OSa
PAP therapy
Mandibular advancement splints
Sleep position modification devices
Surgery
Weight loss
Smoking cessation
Benefits of PAP in OSA
Improvement in symptoms
Improvement in HTN
CVD prevention
Improvement of glucose metabolism
Reduces AHI
Reduces MVA risk
Improves ED
Improves QOL
Surgical options for OSA
Uvulopalatopharyngoplasty (UPPP) and variants
- reduction in AHI ~33%
Maxillo-mandibular advancement
Bariatric surgery
Difference between eucapnic or hypocapnic CSA and hypercapnic CSA
Eucapnic or hypocapnic CSA
- High or irregular drive to breathe
- No daytime hypoventilation
(Heart failure, post stroke, CKD, dialysis, high altitude, idiopathic)
Hypercapnic CSA
- Low drive to breathe
- Nocturnal and daytime hypoventilation
(NM disorders, pulmonary disorder, opioids + baclofen, central congenital alveolar hypoventilation)
Diagnosis criteria for RLS
- Urge to move legs, accompanied by or thought o be caused by uncomfortable and unpleasant sensation in legs
- Not account for by another condition
- Causes concern, distress, sleep disturbance or impairment of mental/physical/social/occupational/educational/behaviour or other important areas of functioning
Non-pharm treatment of RLS
Lifestyle modifications
- EtOH consumption reduction
- reduce stress
- avoid shiftwork
- avoid vigorous physical activity before bedtime
Avoid medications that worsen RLS
- Antihistamines
- Neuroleptics
- Antidepressants
Non-pharm symptom relief
- Good sleep hygiene
- Concentrating activities
- Tactile, temperature, stimulation
- Massage, hot showers, weighted blankets
Pharmacotherapy for RLS and complications
Dopamine agonists
- risk for augmentation
- impulse control disorders are common
Pregabalin (or gabapentin)
- Depression and suicidality
Iron replacement
Benzodiazepines - consider for intermittent symptoms
Opiates - efficacy and risk of dependence, CSA and respiratory depression
Definition of bronchiectasis
Chronic respiratory disease characterised by clinical syndrome of
- cough
- sputum production
- bronchial infection
- abnormal and permanent dilatation of bronchi
CT features of bronchiectasis
Defined as bronchial dilatation suggested by one or more of the following
- Bronchoarterial ratio > 1
- Lack of airway tapering
- Airway visibility within 1cm of costal pleural surface or
- touching mediastinal pleura
Signet ring sign
Pathophysiology of bronchiectasis
Induction of bronchiectasis requires
- Infectious insult
- Impaired drainage, airway obstruction or defect in host defense
Leads to neutrophilic airway inflammation and bronchial destruction
Causes of bronchiectasis
Idiopathic ~40%
Post infectious ~30%
Immunodeficiency ~5%
COPD ~5%
CTD ~4%
ABPA ~3%
Primary ciliary dyskinesia ~2%
Asthma ~1%
Non-tuberculous mycobacteria
Infrequent causes < 1%
IBD
GORD/aspiration
A1-AT deficiency
Diffuse panbronchiolitis
Yellow nail syndrome
Obstruction or foreign body
Congenital or airway abnormality
Congenital or airway abnormality
Inhalation of toxic fumes
Obliterative bronchiolitis post transplant
Outcomes in bronchietasis overlap syndrome
Mortality is worse for overlap syndromes i.e. bronchiectasis rheumatoid overlap syndrome and bronchiectasis COPD overlap syndrome
Variables affecting severity of bronchiectasis
Age
BMI
FEV1 %
Hospital admissions
Number of exacerbations in previous 12 months
MRC breathlessness score
P. aeruginosa colonisation
Colonisation with other organisms
Radiological severity
Key management strategies of bronchiectasis
Airway clearance
Smoking cessation
Vaccination
Sputum cultures
Pulmonary rehab
If frequent or severe exacerbations –> macrolides and/or inhaled abx
Concomitant asthma/COPD –> ICS/LABD
High sputum burden/difficulty expectorating –> mucoactive agents
Pseudomonas aeruginosa –> abx
Risk factors for exacerbation
Prior history of exacerbation
Chronic bacterial infection especially pseudomonas aeruginosa
Respiratory viral infections
Environmental air pollution
IgG2 deficiency
Definition of bronchiectasis exacerbation
> 3 of following symptoms lasting at least 48 hours
- cough
- sputum volume and/or consistency
- sputum purulence
- breathlessness and/or exercise intolerance
- fatigue and/or malaise
- haemoptysis
Treatment of bronchiectasis exacerbations
Abx therapy for exacerbation treatment
- should be based off prior sputum culture results and prior response to abx
Duration of therapy: 10-14 days for first exacerbation, 14 days for patients with recurrent exacerbation
Role of long term macrolides for bronchiectasis
Consider for patients with frequent exacerbations
Found to
- Reduced frequency of exacerbations
- Improved time to first exacerbations
- Improved quality of life
- Had no significant impact on FEV1
Definition of cystic fibrosis
Autosomal recessive disease of regulator gene CFTR response for transmembrane transport of Na and Cl in ciliary epithelium resulting in variable clinical expression of disease
Organs affects cystic fibrosis
Respiratory system (85% of mortality causes)
Pancreas
Sweat glands
Male reproductive system
Diagnosis criteria of CF
At least one of the following:
Phenotypic features of CF
- chronic pulmonary disease
- chronic sinusitis
- characteristic GI and nutritional abnormalities
- salt loss syndrome
- obstructive azoospermia
History of CF in sibling
Positive newborn screening test
AND at least one of following:
- Elevated sweat chloride concentration
- Two CFTR gene variants known to cause CF on separate alleles
- Abnormality in nasal potential differential testing that are typical for CF
Threshold for sweat chloride testing confirming CF
> / 60mmol/L –> CF diagnosis
30-59mmol/L –> CF possible, further testing required i.e. genetic analysis, physiologic testing
Definition of CFTR related disorder
Clinical disease limited to only one organ system associated with some evidence of CFTR dysfunction (does not meet full genetic or functional criteria for CF diagnosis)
Clinical manifestations
- Isolated obstructive azoospermia, chronic sinusitis, chronic pancreatitis, or pulmonary disease
Clinical features of CF
Respiratory colonisation
Sinusitis
Pancreatic disease
Distal ileal obstruction
Anaemia
Aquagenic wrinkling
C. diff
Increased risk of malignancies
Biliary disease
Male or female infertility (M > F)
CF athropathy
Osteoporosis
Recurrent VTE
Nephrocalcinosis
Nephrolithiasis
Most frequent pathogens in CF
S aureus in younger ages
P aeruginosa in older ages i.e. > 35 yrs
Pillars of treatment in CF
Antimicrobials
- Acute exacerbations –> based on prior sputum cultures
Anti-inflammatory
- Macrolides
- Ibuprofen
Airway clearance
- Chest physio
- Mucolytics
- Physical activity
CFTR modulators
Indication and examples for CFTR modulators in CF
Targets specific defects in CFTR protein
Ivacaftor
- targets class III (channel gating defect), IV (channel conductance defect) and VI (defect of stability at membrane)
Tezacaftor, lumacaftor, elexacaftor
- targets class I (synthesis defect), II (processing defect), and V (reduced CFTR production)
Ivacaftor MOA
CFTR potentiator
Targets 6551D mutation
Tezacaftor and lumacaftor MOA
Targets △F508 mutation which interferes with protein folding and channel gating activity
Indications for lung transplant/consideration of pretransplant assessment for CF
FEV1 < 30% predicted
Rapid decline in FEV1 despite optimal treatment
Malnutrition and diabetes
Frequent exacerbations
Recurrent massive haemoptysis which cannot be controlled by bronchial artery embolisation
Relapsing or complicated PTX
ICU admission
Relative contraindications for lung transplant in CF
Age > 65 yrs
Critical/unstable clinical situation
Seriously limited functional status
Colonisation with Burkholderia cenocepacia, Burkholderia gladioli and Mycobacteria abscessus
Diseases not optimally treated
Importance of burkholderia cepacia complex in CF
Chronic infection resulting in accelerated decline in lung function and shortened survival
Usually multi-drug resistant
Worse outcomes with lung transplantation
Definition of ABPA
Complex hypersensitivity reaction to colonisation of airways by aspergillus fumigatus
Occurs almost exclusively in asthma and cystic fibrosis
Episodes of repeated bronchial obstruction, mucoid impaction and inflammation results in bronchiectasis and fibrosis
Risk factors of ABPA
Asthma
Cystic fibrosis
Pathophysiology of ABPA
Involves
- immediate hypersensitivity (type 1)
- antigen antibody complexes (type 3)
- eosinophil rich inflammatory response (type 4b)
Diagnosis of ABPA
Predisposing conditions (either one present) - asthma, cystic fibrosis
Obligatory criteria (both present)
- positive skin prick test or increase IgE levels to aspergillus fumagatus
- elevated IgE concentration
Other criteria (at least 2 must be present)
- positive aspergillus precipitants or increase IgG to A. fumigatus
- Radiology consistent with ABPA
- total eosinophil count > 0.5 x 10^6 in steroid naive patients
CT findings of ABPA
Proximal cylindrical bronchiectasis
Mucous plugging
Tree in bud opacity
Atelectasis
Peripheral consolidation
Ground glass opacity
Mosaic attenuation with gas trapping
Treatment of ABPA exacerbation
Prednisone is mainstay treatment
Diagnosis of ABPA exacerbations
Doubling of IgE above baseline
New radiographic infiltrates (especially in upepr and mid zones)
Treatment for acute or recurrent ABPA
Antifungal therapy - itraconazole (can also use voriconazole or posaconazole)
