sarcoidosis Flashcards
what is sarcoidosis
Systemic disorder of unknown
cause(s) characterised by formation
of noncaseating granulomas,
affecting the lung in >90% of cases
where can sarcoidosis affect
any organ: nervous cvs ocular = blindness lung most common
what is the initial event that leads to granulomas
don’t know
features of sarcoidosis and what the suggest
Accumulation of oligoclonal T cells at sites of granuloma formation
suggest antigen-specific cell-mediated immune response
Kveim-Siltzbach spleen extract skin tests suggest specific immune
response
Features resemble other antigen-induced disorders, including chronic
beryllium disease, hypersensitivity pneumonitis, and mycobacterialinduced granulomatous disease
what are the features that suggest infectious aetiology
other granulomatous diseases have infectious aetiology
• Epidemiological evidence suggesting clusters of disease in
environments linked with bioaerosol production
can be transmitted by transplant organs
difference in presence of microbe in sarcoid and control – organisms found most – P. acnes and micobacteria - however confidence intervals cross the non-significant line
results of high throughput microbe genetic typing
o Correct any microbe for the sample in the env ie contaminants – found that overall the burden of microbe in sarcoid seems larger than in healthy control
o Couldn’t find microbes that were consistently present across the tissue
o Found fungi
o Need more work
inconclusivity of finding microbes in sarcoid
heterogeneity between studies, especially the ones
on mycobacteria
only few international studies
unidentified organisms may be cause
Colonizing microbes may cause disease by their antigenic or
adjuvant properties rather than infection
RF for sarcoidosis
Agricultural exposures
Insecticides
Microbial bioaerosols (work environments with mould/damp exposure)
protective factors for sarcoid
cigarette smoking - develops when stop smoking
protective against granulomatous disorders
genetic predisposition of sarcoidosis
familial clustering in several populations
More common in monozygotic than dizygotic twins
g associations with major histocompatibility
complex region (MHC) class II alleles
• susceptibility alleles: HLA DR 11, 12, 14, 15, 17
• protective alleles: HLA DR1, DR4
Other non HLA genes: BTNL2, IL-23R, NOTCH4, 11q13 locus in common
with other immune mediated diseases (ulcerative colitis, ank spond, RA)
incidence of sarcoidosis
-Major geographical differences: prevalence highest in Northern Europe, USA, India
4x more severe and multi-organ in African-Americans than caucasians
patterns of organ involvement
- Acute uveitis and erythema nodosum in Scandinavians, Irish, Puerto Ricans
- in Japanese, eye and heart frequent, no Lofgren (Lung)
- Lupus pernio more frequent in African-Americans
variation suggests gene involvement
severity
more severe lung impairment and extrathoracic involvement in US AfricanAmerican, Afro-Caribbean patients
could sarcoidosis be a family of disease
Lofgren’s disease has very distinct genetic associations (HLA DR3,
CCR2), demographics and clinical findings
• Different HLA associations with different organ involvement
(uveitis, cardiac)
• Different HLA associations with acute (HLA-DR3) and chronic
(HLA-DR14 and 15) disease
pathogenesis of sarcoidosis
• Unknown ag – presented by APC coupled with HLA class 2 = amplification = granuloma
explain the spread of sarcoidosis
Loosely-formed granulomas follow lymphatic pathways:
bronchovascular bundles
interlobular septa
pleura
diagnosis
no test for sarcoid
need compatible findings across investigations: clinical, XR, histology
exclude alternative ie TB
histology = non caseating granulomas
histology needed, especially if immunosuppressive treatment being considered
and/or diagnostic uncertainty (tb, lymphoma, lymphangitis)
discuss whether to do bronchoscopic histological confirmation with pt
o Aim for diagnostic probability of >95%
o Symmetrical bilateral lymphadenopathy and erythema nodosum = is sarcoid
o Calcification around LN and on both sides, on TB unilaterally only
how many stages of sarcoid are there
4
done on XR
stage 1 sarcoid
Bilateral hilar (+ Rt paratracheal) lymph nodes Symmetrical
stage 2
Bilateral hilar (+ Rt paratracheal) nodes Parenchymal disease - ie white lung elargement
stage 3
Parenchymal disease
No BHL/mediastinal nodes
stage 4
fibrosis and scarring
upper lobe/hilar pulled up, trachea pulled to R by upper lobe fibrosis
why is staging important
gives broad cohort outcomes, however
Cannot distinguish between active inflammation, fibrosis and
inactive disease
• Large variability within scorers on stage IV; trivial vs end stage lung
fibrosis
• Some pts will present at stage 1 – most will stay here, some will present at stage ¾ - sometimes see switch – but can stick with the stage you present with
broad cohort outcomes of the stages
1 = good 2 = progression in one third at 5 years 3 = progression in two thirds at 5 years 4 = overt fibrotic disease, significant mortality
diagnosis with bronchoscopy and biopsy
in stage 1 or 2:
EBUS-TBNA/EUS-TBNA
• (with rapid onsite cytology if available) (80% diagnostic yield)
+- TBBx (90%)
stage 3/4 BAL: Lymphocytosis: 25-30% • +/- CD4/CD8 ratio (>4 highly specific) • Microbiological sampling • EBBx-TBBx (90%)
course of most pts
benign
epidemiology of progressive pulmonary fibrosis
significant minority of people have it Approximately 8-10% of sarcoidosis patients will have shortened life expectancy; of these roughly 70% due to pulmonary involvement
CT appearance of progressive pulmonary fibrosis
fibrotic changes with traction bronchiectesis
airway pulled apart by fibrosis and ground glass
predictors of mortality in pulmonary sarcoidosis
age
fibrosis on HRCT >20% ie extensive disease
pul HTN
what do you need to determine about the fibrosis and why
Is the fibrotic disease stable or progressive? • Aim of treatment is to prevent progression of fibrosis, but avoid toxicity in stable fibrosis • Ongoing active inflammation likely to lead to further progression of fibrosis therefore need measures of disease activity
what are the measures of disease activity
HRCT patterns • FDG-PET • -Bronchoalveolar lavage: lymphocytosis • -Serum markers: inflammatory markers, ACE, IL2R, chitotriosidase, 24- hour urinary calcium • -Serial Lung Function Tests
can you assess reversibility with CT
o Nodular sarcoids – reversible, agglomerates of sarcoid glomeroma therefore active – reversible
o Ground glass – grey attenuation of parenchyma - mostly irreversible – cant determine if still inflamm
o Irreversible – UIP pattern with honeycombing
so CT cant always distinguish
Use of FDG-PET to determine stable/progressive
FDG-PET/CT correlates with other markers of disease activity ie BAL and serum inflamm markers
• PET activity correlated with more severe lung function impairment and extensive
CT changes, including fibrosis
most have extra-thoracic PET positivity too
ie still inflammation in fibrotic changes
therefore treatment with anti-TNF (infliximab) = improvement
monitoring pulmonary sarcoidosis
Change in symptoms of breathlessness/cough
Lung function: change in FVC, FEV1 by ≥10%; DLCO ≥15% (ATS/ERS criteria)
• (isolated drop in DLCO suggesting pulmonary vascular involvement)
chest Xray
• chest HRCT better correlated with lung function changes
• (FDG-PET to assess ongoing activity when disease not responding to treatment)
serum biomarker changes
worsening in >1 domain will increase the liklihood that the changes are real
what is the major complication of sarcoidosis
chronic pulmonary aspergillosis
o 5-10% from chronic sarcoid suffering from CPA – all had advanced disease, high prev pul htn, treat with long term anti-fungal- death caused by advanced sarcoid, rather than massive haemoptysis – although concern in cavitating lesions full of fungus
o More common fungi exposure
what are the indications for management of sarcoid
major loss of quality of life (fatigue that is life changing, skin disease, joint pains – may not danger from internal organ though)
danger from disease
treatment options for QOL
discuss with pt
if dont treat - NSAIDs for joint pains as needed
if do:
Low dose prednisolone
• Hydroxycloroquine
• Less likely to use methotrexate or azathioprine (immunosuppressants), except for particular
cases
death in sarcoid
<10% of patients have a shortened life expectancy
• Respiratory failure and cardiac failure/arrhythmias the most
common
risk stratification in sarcoid
• Integration of clinical, functional and imaging features to
assess likelihood of progression of pulmonary sarcoidosis
• In cardiac disease, we need markers of accurate early
diagnosis to prevent loss of function and fatal arrhythmias
how do you identify pts at risk of progression of fibrosis and so which to treat
• Severity of pulmonary fibrosis:
• Irreversible changes present
• Integration of symptoms, lung function and imaging
Which lung function thresholds ? Lung function:
• FVC <60%
• DLCO <50%
• Major airflow obstruction
Longitudinal behaviour - if function dropping and symptoms increasing need to treat
describe cardiac sarcoid
o Should screen for involvement in all o Ask about presence of symptoms Palpations, disproportionate breathless, syncope, presyncope ECG abnormalities Echo if find things = furtehr imaging
ECG abnormalities in cardiac sarcoid
AV block, frequent premature ventricular ectopics, non-sustained/sustained ventricular tachycardia, LBBx or RBBx, Q waves, axis deviation
echo abnormalities in cardiac sarcoid
reduced LVEF, regional wall abnormalities, wall thinning or thickening, ventricular aneurysms
further investigations used if suspect cardiac sarcoidosis
cardiac MRI
FDG-PET alongside resting myocardial perfusion scan
PET tends to be more sensitive than MRI: however,
whether isolated PET positivity has prognostic significance
remains to be established
treatment of sarcoidosis
o Toxicity of steroid very diff high dose compared to low dose
o Second line immunosuppression
o Corticosteroids – mainstay of treatment – moderates doses
o High dose long term = methylprednisolone
o Aim is to go as low as possible – maintain improvement and objective lung func improvement
o 2nd line – methotrexate, azathioprine +- hydroxychloroquine
Used if low dose steroids not sufficient to allow control or need corticosteroid spearing – comorb (obesity, dm, osteoporosis), intolerance
o Biologics
3rd agent – once pt has failed steroid and 2nd line
Active and progressive disease despite non conventional or Toxicity or lack of tolerability to conventional
treatments
steroid regieme in sarcoidosis
• Corticosteroids remain mainstay of treatment:
• Induction
• Moderate dose oral prednisolone (20-40 mg od)
• Or in selected cases with severe disease
• High dose iv methylprednisolone treatment (1 Gr x 3) followed by 20 mg od, then
tapered
• Maintenance
• Low dose 7.5-10 mg od
PET
CT pick up radioactive glucose – injected into vein – goes to more active site ie inflammation or cancer- light up – wont tell sarcoid, just that there is positivity
honeycomb pattern
parallel lines of cysts that have walls
end stage fibrosis
often seen in usual interstitial pneumonitis - pattern that defines idiopathic pul fibrosis
also in sarcoid
happens because disruption of architecture -dialtion of airways, formation of aberrent airways and cystic spaces
why is the hilar pulled up in stage 4 sarcoid
all granulomatous disease go to apices because done with things inhaling eg hypersensitivity pneumonitis – fibrosis which retracts the lung and therefore pulls up the hilar
presentation of sarcoid
o Non-specific
o Extra-pul involvemenht help – erythema nodosum – painfulnothces on shin
o Classic skin lesions elsewhere
o Young pts
o Fatigue – incredible
o Joint pain – ankles most commonly involved
o Cough, breathlessness – XR will show one of the stages
what is TBNA
endobronchial aspirate – US guided – go with bronchoscopy and fine needle to biopsy LN of mediastinum
