ILD Flashcards
What will you find in BAL for Sarcoid?
CD4+/CD8+ ratio of more than 4
What is stage 2 sarcoid ?
LN and lung involvement
What is the median survival for people with IPF in the UK?
3 years from diagnosis (though is variable as 20% survives more than 5 years)
What are the clinical features of IPF?
Gradual onset exertional breathlessness and cough (often 9/12 prior to presentation)
What is estimated prevalence in the UK of IPF?
30,000 in UK
What is the purported cause of IPF?
Repeated alveolar epithelial injury leading to aberrant wound healing. Triggers include inhalation of metal/wood/GORD
What are the criteria for lung transplant in IPF?
TLCO <40%
FVC fall 10% over 6 months
TLCO fall 15% over 6 months
O2 desat to <88% on 6MWT
Should we ventilate patients with IPF?
Poor outcomes , do not routinely offer mechanical ventilation to patients with IPF who develop life threatening resp failure
What are the treatment guidelines for Pirfenidone in IPF?
FVC 50-80%
dose is 267mgTDS
What are the treatment guidelines for Nintedanib in IPF?
FVC > 50%
(Due to Inbuild trial can now give you FVC >80%, lower cut off still in place)
What are the main side effects of Pirfenidone?
Nausea
Photosensitive rash
(NB can cause Liver Function derangement)
What are the main side effects of Nintedanib
Diarrhoea
Weight loss
Incr bleeding risk
(NB can cause liver function derrangement)
How is IPF histologically characterised?
Temporal and special heterogeneity with areas of active fibroblastic foci (reflecting acute injury) and architectural distortion / honeycombing (reflecting chronic inflammation) interspersed with areas of normal lung. Reflecting different stages of evolution of disease process across the lung
IPF is seen as the archetypal ILD
What lung diseases associated with a UIP pattern
IPF
CTD-ILD
Chronic HP
Sarcoid
Nitrofurantoin ILD
Asbestosis
Who gets IPF?
Men
60-70 classically
Ex smokers often
What tests to do in IPF?
Bloods : ANA, ANCA, RhF, Anti CCP, Immunoglobulins, HIV, ?Avian precipitans ?Polymositis scleroderma panel (ie ruling out other causes). ESR and CRP often mildly raised , mild anaemia
NB can get positive RhF and / or ANA at low titres
Lung function
HRCT
?BAL
?Biopsy (rarely done)
TTE
What is Nintedanib
Tyrosine Kinase Inhibitor (TKI) which inhibits platelet derived growth factor (PDGFR) , fibroblast growth factor (FGFR) and vascular endothelial growth factor receptor (VEGFR)
Combined analysis of three nitedanib trials has shown that it improves all cause mortality by 30% and respiratory related mortality by 38%
What is Pirfenidone
Unclear exact mechanism but inhibits collagen synthesis and reduces fibroblast proliferation
What signifies a failure of treatment with anti fibrotic?
FVC decline >10% in 6 months / 1 year or TLCO decline >15% in 6 months/1 year
What are poor prognostic factors in IPF?
Low BMI
TLCO <40% at presentation
FVC fall > 10% in 6 months
TLCO fall > 15% in 6 months
Pulmonary hypertension
Fibroblastic foci on biopsy
What do patients either IPF usually die of ?
Respiratory failure and infection
NB increased risk of lung cancer
What is inpatient mortality for IPF exacerbation ?
60%
What is a UIP picture on scan?
Basal/subpleural preponderance of reticulation
Traction bronchiectasis
Honeycombing
Propellar blade
With ABSENCE of :
- XS ground glass
- Bronchocentricity
- Lots of interlobular septal thickening
What is honeycombing
Multilevel, walled , 3-10 mm size
Beware
Emphysema with any sort of infiltration surrounding it can look like honeycombing , traction bronchiectasis can etc
What are the ATS/ERS Classifications of UIP?
UIP Pattern
Probable UIP pattern
Indeterminate for UIP
CT findings suggestive of alternate diagnosis
CT findings demonstrate peribronchovascular predominant with subpleural sparing what should you consider ?
NSIP
CT findings demonstrate perilymphatic distribution what should you consider ?
Sarcoidosis
CT findings demonstrate upper or mid lung what should you consider ?
Fibrotic HP
CTD-ILD
Sarcoidosis
CT findings demonstrate subpleural sparing what should you consider ?
NSIP
Smoking related IP
CT findings demonstrate cysts what should you consider ?
LAN
PLCH
LIP
DIP
CT findings demonstrate mosaic attenuation or three density sign what should you consider ?
HP
CT findings demonstrate predominant GGO what should you consider ?
HP
Smoking related disease
Drug toxicity
Acute exacerbation of fibrosis
CT findings demonstrate profuse centrilobular micronodules what should you consider ?
HP
Smoking related disease
CT findings demonstrate nodules what should you consider ?
Sarcoidosis
CT findings demonstrate consolidation what should you consider ?
Organising pneumonia
CT findings demonstrate pleural plaques what should you consider ?
Asbestosis
CT findings demonstrate dilated oesophagus what should you consider ?
CTD-ILD
What is NSIP
Non Specific Interstitial Pneumonia is a histological pattern rather than a clinical entity.
Poorly understood probably encompasses several distinct clinical/radiological conditions , patients with NSIP on biopsy gave generally better prognosis and response to steroids compared with IPF
Who typically has NSIP
40-50yos
Idiopathic
CTD (NSIP may be first manifestation)
Drug related
Infection
Immunodeficiency (HIV, BMT, Chemo)
Describe HRCT features of NSIP
Groundglass change, often in a basal distribution with or without reticulation and traction bronchiectasis. Appearances usually more confluent and homogenous c/w patchy heterogenous distribution seen in IPF
Honeycombing usually absent but can occ see with fibrotic NSIP
What are the three types of NSIP on histology?
NSIP 1: Primarily inflammation , termed “cellular”
NSIP 2: Inflammation and fibrosis
NSIP 3 : Primarily fibrosis
Fx of NSIP and UIP sometimes seen on biopsies from the same individual - in such cases the diagnosis is considered to be IPF
How do you diagnose NSIP pattern ?
HRCT non specific and thus surgical biopsy often required for diagnosis - an exception is NSIP in the setting of CTD when histological confirmation is not required
Need to interpret Biopsy of NSIP along with context of clinical and radiological findings
How do you treat NSIP?
Steroids 0.5mg/kg/day
(Azathioprine / MMF useful if not responding to steroids alone)
(Cover with PPI, Bone Protection and Co-Trimoxazole prophylaxis against PCP)
Monitor with LFT
What is the prognosis in NSIP pattern
Variable, often stable on tx
Cellular pattern is associated with good prognosis , fibrotic NSIP is associated with markedly better prognosis than IPF (5year survival > 50% in fibrotic NSIP compared with 10-15% in IPF)
What are squeaks on auscultation?
Signs of active alveolitis
What is HSP?
Hypersensitivity pneumonitis is a group of lung diseases caused by inhalation of an organic antigens to which an individual has been previously sensitized
What do you see on histological samples for HSP?
Loose granulomas
What are the most common causes of HSP?
MOULD
Farmers lung — Thermophilic Actinomycete - mouldy hay, sugar cane, contaminated water
Pigeon fanciers lung —protein in the droppings
Mycobacterium avium —- hot tub lung
Is there a questionnaire for HSP?
None standardised , can use UCSF
How do we classify HSP?
Non fibrosing inflammatory HP
Fibrotic (Mixed inflammatory plus fibrotic or pure fibrotic)
What is required to classify as non fibrotic inflammatory HSP?
One HRCT fx of parenchymal infiltration:
- Ground glass
- Mosaic attenuation
One HRCT fx of small airways disease:
- Ill defined centrilobular nodules all lobes
- Air trapping
Distribution:
- Axial
- Craniocaudal
20% will have a normal CXR
What is required to classify a fibrotic (mixed inflammatory plus fibrotic or pure fibrotic) HSP?
One HRCT pattern of fibrosis:
- Reticulation
- Traction Bronchiectasis
- Honeycombing
One HRCT finding of small airways disease
- Ill defined centrilobular nodules
- Mosaic attenuation
- 3 density (nodules, GG, air trapping in same lobe)
Distribution:
- Axial
- Craniocaudal
- Mid lung
- Sparing bases
What would you expect to see on BAL to support HSP dx ?
Lymphocytes > 30%; > 50% is strongly suggestive
NB in smokers probably above 20% is significant
If fibrotic HSP will likely be a normal BAL
What conditions give you a lympocytosis on BAL?
HSP
CTD- ILD
Sarcoid
Infection
Drug Induced ILD
COP
NSIP
Chronic beryllium
In a normal adult what should the cell make up of their BAL be?
Macrophages > 85%
Lymphocytes 10-15%
Neutrophils <3%
Epithelial <1%.
NB if epithelial cells > 5% then you have not sampled the alveolar space
What gives you >1% eosinophils on BAL?
Eosinophillic Pneumonia
Drug induced pneumonia
BMT
Asthma, Bronchiolitis
Churg Strauss
ABPA
Bacterial, fungal, Helminth , Pneumocystis infection
Hodgkins
What gives you >3% neutrophils on BAL?
Collagen /vascular disorders
IPF
Aspiration Pneumonia
Infection: Bacterial/ fungal
Bronchiolitis
Asbestosis
ARDS
Diffuse alveolar damage
What is CD4+/CD8+ > 4 on BAL indicative of ?
Highly specific for sarcoidosis (in absence of higher proportion of other cell types)
What is eosinophil >25% on BAL indicative of ?
Acute or chronic eosinophillic pneumonia
What is neutrophil count >50% on BAL indicative of ?
Acute lung injury
Aspiration Pneumonia
Suppurative infection
What is bloody fluid incr on subsequent alliquots on BAL indicative of ?
Pulmonary haemorrhage/ Diffuse alveolar damage
What is milky fluid with positive periodic acid Schiff staining and amorphous debris indicative of ?
Pulmonary Alveolar Proteinosis
What is the diagnostic test for HSP?
BAL and TBB (NB in fibrotic HSP will need to be surgical biopsy/ cryobiopsy; in non fibrotic HSP TBB and surgical biopsy )
Are serum precipitans useful in HSP?
Marker of exposure , not disease , 40% of farmers will have
How do we treat HSP?
Antigen avoidance !!!
If poor lung function, very symptomatic , evidence of fibrosis - Prednisolone 0.5 mg/kg 2-4 weeks and taper ( taper as per response , HRCT , lung function - no definitive guidance)
If steroids alone not improving things can add MMF /AZA
What makes prognosis of HSP worse?
Intensity of exposure
Age
Clubbed
Traction bronchiectasis/ honeycombing on CT
NSIP and UIP on histology
Fibroblastic foci
Unknown antigen
Talk through pulmonary langerhans cell histocytosis
Cystic lung disease strongly associated with cigarette smoking
Initially thought to be reactive but now evidence of MAPK pathway alteration in 85% and BRAVF 600 mutation in 36-50%
Sx : SOB , cough , fever
15% have PTX , 63% have recurrence. Can cause bone cysts , DI (can proceed lungs) , multi system involvement <1%
HRCT: upper and mid zone bizarrely shaped cysts, diffuse centrilobular nodules , sometimes cavitating
PFTs: mixed restrictive / obstructive
TBB- may yield dx material but often unhelpful as risk of PTX, surgical lung biopsy preferred but only if atypical ie purely cystic, purely modular
Mx : smoking cessation (rarely Cladribine) ; lung transplant if severe and pulmonary HTN
Talk through Lymphangioleiomyomatosis (LAM)
Rare
Caused by abnormal proliferation of smooth muscle cells
(termed sporadic LAM if not associated with tuberous sclerosis)
Female , epilepsy, learning difficulties , associated with tuberous sclerosis
70% have PTX , recurrence 73%
Lymphatic obstruction can lead to chylothorax
Associated with abnormal angiomyolipoma
HRCT: variable sized cysts distributed throughout lung
CT Abdo - check for angiomyolipoma
PFTs: obstructive or mixed
Dx: Consider in young/Middle Aged women who have recurrent pneumothorax and cystic lung disease / obstruction / chylous pleural effusions and angiomyolipoma and tuberous sclerosis
Mx: Mx PTX, avoid oesteogen, sirolimus
Talk through Burt Hogg Dube
Multi-system disorder characterized by :
- cutaneous manifestation , typically fibrofolliculomas (skin tags)
- multiple lung cysts
- PTX
- increased risk of renal tumours
- genetic mutation in the follicular gene
HRCT: Basal predominance, paramediastinal/ perifissural , irregular shaped , round and elongated adjacent to the interlobular septa and vessels
Talk through Lymphoid Interstitial Pneumonia
Definition: Interstitial pneumonia characterised by lymphoid infiltration and often lymphoid hyperplasia
Causes: Idiopathic (rare), CTD (Sjogrens, SLE, RA), Immunodeficiency (HIV, CVID), Infection (PCP, Hep B), AI disease, Drugs (Phenytoin)
Clinical fx: Gradual onset breathless, fever , WL , crackles on exam
Ix:
Bloods: mild anaemia, poly/monoclonal increased immunoglobulins
HRCT : Ill defined cebtrilobular and subpleural nodules cysts , scattered and thin walled. Predominant ground glass
BAL: non clonal lymphocytosis
Treatment: Steroids
What is anti synthetase syndrome?
An autoimmune disorder characterised by antibodies against an aminoacylT RNA synthetase along with one or more of the following : ILD, myositis , Raynaud’s, arthritis
Two diagnostic criteria are proposed :
- Presence of an anti amino acyl tRNA synthetase antibody
AND
One or more of the following clinical features :
Raynauds, Arthritis , ILD, Fever (not attributable to another cause) , mechanics hands
2 major / 1 major and 2 minor
Major: ILD , polymyositis/dermatomyositis
Minor Arthritis, Raynauds, Mechanic hands
A transbronchial biopsy specimen shows abundance of eosinophils and birbeck granules, what is the diagnosis ?
Pulmonary Langerhans Cell Histocytosis
What are Birbek granules?
Well demarcated cytoplasmic organelles- LCH
How do you restart Pirfenidone after interruption?
If interrupted for more than 14 days : Start with 267 mg TDS for 7 days , then 534 mg TDS for 7 days then 801 mg TDS
What is the gene mutated in Birt Hogg Dube ?
FLCN gene
What is the most common tracheobronchial abnormality in granulomatosis with polyangitis?
Subglottic stenosis
What is Heerfordt-Waldenstrom syndrome ?
Rare subtype of sarcoidosis . More common in Afro-Caribbean patients and 15% of patients have relatives who suffered from it
Characterised by : enlargement of the parotid or salivary glands , facial nerve paralysis and anterior uveitis
What are the systemic association of LCH?
Severe PHT - may be seen in the absence of significant parenchymal involvement, direct involvement of pulmonary vessels has been described
Systemic LCH- particularly diabetes insipidus from pituitary disease , skin involvement , lytic honey lesions , rarely cardiac/ GI
Lymphoma - may proceed, complicate or co-exist
What other organs are affected in LAM?
Kidney: Angiomyolipoma (Benign ; 50%) - tumour respected or embolized
Abdomen: lymphadenopathy - due to lymphatic obstruction
Pelvis: Lymphangioleiomyoma - cystic mass that enlarges
Chylous ascites (can occur in absence of chylothorax)
Skin- cutaneous swellings
What is cryptogenic organising pneumonia ?
ILD characterised by plugging of the alveolar spaces with granulomatous tissue, can expand into bronchioles
Who gets Cryptogenic Organising Pneumonia (COP)?
More common in non smokers
Male = Female
55yo mean onset
What can cause Organising pneumonia ?
Cryptogenic
or
Organising pneumonia secondary to :
Infection, Drug, CTD, Diffuse alveolar damage, Haematological malignancy , IBD, Post BMT, Pulmonary infarction, Lung malignancy /obstruction
NB often get some OP surrounding a lung cancer
What does HRCT of organising pneumonia show?
Consolidation with air bronchograms sometimes with associated ground glass or nodules. Basal, subpleural and peribronchial . May migrate. Reticulation may represent poor response to tx
How do you diagnose OP and how treat ?
Clinical + HRCT +/- Biopsy (if needed should be surgical)
Tx: Steroids (AZT/ Cyclophosphamide if poor response)
Outline Acute Interstitial Pneumonia (AIP) - formerly known as Hamman Rich
Definition: Rapidly progressive form interstitial pneumonia characterised histologically by diffuse alveolar damage
Clinical: Often proceeded by viral illness , rapid onset <3 weeks after sx onset
HRCT: Bilateral diffuse ground glass and patchy airspace consolidation , later traction bronchiectasis , cystic change and reticulation
Dx : Biopsy to exclude ARDS (practically difficult)
Tx : Nil evidence but usually high dose steroids once infection ruled out
Mortality is 50%
What is Respiratory Bronchiolitis ILD? (RB-ILD) ?
Respiratory Bronchiolitis refers to the accumulation of bronchiolar pigmented macrophages in cigarette smokers and is nearly always asymptomatic
Minority of smokers develop ILD , exact relationship between DIP and RB-ILD is unclear
What does HRCT of RB-ILD show?
Poorly defined centrilobular nodules , ground glass change , thick walled airways often associated with centrilobular emphysema
What is Desquamative Interstitial Pneumonia (DIP)?
ILD in smokers associated with pathological finding of pigmented macrophages located diffuse throughout alveolar space (more extensive form of RB-ILD)
Very rare
What does HRCT with DIP demonstrate?
Ground glass change, lower zone , peripheral predominant , Reticulation and honeycombing may be evident but are mild
Tx for RB-ILD and DIP?
Smoking cessation!
DIP often steroids also RB-ILD steroids occasionally
What are the baseline cardiac tests for sarcoid ?
ECG and echo
If abnormalities in ECG or echo suggestive of sarcoid then should get Cardiac MRI or PET
What is Lofgren’s Syndrome?
Bilateral Hilar Lymphadenopathy
Erythema Nodosum
Arthralgia
Occurs in 30% patients and remits 70-80% within 2 years ; often steroids needed for severe arthralgia but usually shorter courses with high doses 30-40mg for 1-2 weeks and tapering
Can be discharged once resolution confirmed
What is the first line agent and regimen ins sarcoid tx ?
Steroids, if acute disease 20-40mg for 4-6 weeks and then wean by 5mg every 2 weeks to maintenance of 5 or 10mg and attempt withdrawal at 6-12 months
What is the second line treatment in Sarcoid?
Methotrexate or Azathioprine
Outline issues related to Vitamin D supplementation and Sarcoid
Patients with sarcoid may have low 25-OH-Cholecalciferol (Vitamin D3) , Serum 1,25 (OH) 2 Cholecalciferol may be elevated due to granuloma macrophages over expressing 1 alpha hydroxylase which can lead to hypercalcemia or hypercalcurea. So if giving Vitamin D supplementation should be done carefully
What is the Scadding Staging of Sarcoid ?
0- Normal (5-15%)
1- Enlarged nodes only (45-65%)
2- Enlarged nodes and parenchymal changes (30-40%)
3- Parenchymal changes without enlarged nodes / fibrosis (10-15%)
4- Fibrosis (5%)
What % of patients will have radiological and clinical resolution without treatment (by stage) ?
0: n/a
1: 50-90%
2: 30-70%
3: 10-20%
4: 0%
In total around 40% of patients with sarcoid will remit within 6 months but it’s not clear which ones
What are the positive signs for cardiac sarcoid on investigations ?
CMR: late gadolinium enhancement
PET: significant FDG uptake
(NB on ECG - advanced atrioventricular block, ventricular tachycardia; Echo- LV systolic/ diastolic impairment)
What are findings associated with pulmonary htn in cardiac sarcoid ?
Reduced DLCO in setting of restrictive
Increased PA diameter (≥29mm)
Increase in PA diameters /ascending aorta diameter ratio (≥1)
O2 sats < 90% on 6MWT
Need for LTOT
What are the CT findings in sarcoid ?
LN enlargement
- Hilar +/- mediastinal
- Bilateral and symmetrical
- Well defined homogenous
LN classification
- Icing sugar
- Eggshell
Nodules:
- well defined 2-5mm
- paraseptal predominant
- fissural beading / peribronchovascular nodularity
- Colaescence
Fibrosis
- Reticular opacity
- Volume loss / architectural distortion
- Traction bronchiectasis
- Peribronchovascular air trapping / mosaic pattern
What are the 2 situations in sarcoid where you don’t require tissue biopsy (bar obviously patient choice etc) ?
Lofgren’s Syndrome
Long standing Pulmonary disease
What do you expect to see /sample on BAL for sarcoid?
Nodules 2-3mm waxy yellow mucosal lesions with mucosal cobble stone , biopsy these
BAL - lymphocytes 15-25% provide support for granulomatous disease (but seen in others)
- CD4:CD8 > 4 (in the absence of increased proportion of other inflammatory cells is highly specific
When do we treat sarcoid ?
If potential danger of fatal outcome or permanent disability
Or
Unacceptable QOL
What are the spirometric cut offs loosely applied for sarcoid for when to treat?
DLCO <65%
Spirometric <70%
FVC 10% drop
TLCO 15% drop
Caveat would be in the presence of inactive fibrotic disease which may result in irreversible but non progressive lung function loss
What are the indications for 2nd line agents ?
- Progression of pulmonary disease or an unacceptable symptom burden despite steroid treatment
- Intolerable side effects from steroids
- Inability to taper to below 10-15mg
- Presence of major comorbidities likely to be adversely affected by steroids
- Strong patient aversion
What are the second line options for Sarcoidosis?
MTX or AZT
MMF
Leflunomide
What is methotrexate induced pneumonitis?
Productive cough, dyspnoea and fever can occur acutely within days to weeks after initiation or can be insidious
On CT will get new ground glass change , particularly suggestive if changes differ from pre-existing. Poorly formed granulomas on biopsy but fibrosis is not a feature
In what settings within sarcoid is Hydroxychloroquine useful?
Mainly for fatigue, joint and skin sarcoid
What is the third line treatment in sarcoid?
Infliximab + AZT/MTX
Do ACE/ BAL lymphocytosis/Gallium scanning correlate with disease progression in sarcoid?
No
What are the fx of steroid withdrawal in presence of normal hypothalamic - pituitary - adrenal axis?
Fatigue, dizziness , headache, mood swings , athralgia , myalgia , nausea and abdo pain
What are the cut offs for early morning cortisol?
<100 Insufficient
100-450 Stimulation test, d/w Endo
>450 Sufficient
What is the GAP score ?
GAP score can be used to predict mortality in the case of Idiopathic Pulmonary Fibrosis (IPF). It uses four parameters: gender, age, and two physiological parameters of FVC and diffusion capacity of carbon monoxide (DLCO). On the basis of GAP score, patients are grouped into 3 stages with each successive stage predicting poorer prognosis.
What effect does Ciprofloxacin have on Pirfenidone ?
Ciprofloxacin enhances Pirfenidone so need to reduce dose of Pirfenidone , ideally avoid Cipro
What are the contraindications to Pirfenidone ?
eGFR < 30
Child Pugh C
Smoking
Pregnant
What are the contraindications to Nintedanib?
MI last 6/12
Unstable angina
Pregnant
Hypersensitivity to peanut /soy
What is the median survival following an exacerbation of IPF?
3 months
What are some common drugs associated with drug induced organising pneumonias ?
Amiodarone
Interferons
Minocycline
Rituximab
Statins
Drug withdrawal usually leads to improvement
