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Idiopathic Pulmonary Fibrosis and Sarcoidosis
Day 13
46
Biology
10/22/2012

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Term
What are Idiopathic interstitial pneumonias (IIP)?
Definition
Interstitial disease with no evident cause involving accumulation of inflammatory cells, fibroblasts and fluid in the interstitial with impaired gas exchange.

1) Acute interstitial pneumonia (AIP)

2) Nonspecific interstitial pneumonia (NSIP)

3) Desquamative interstitial pneumonia/respiratory bronchiolitis with interstitial lung disease (DIP/RBILD)

4) Idiopathic pulmonary fibrosis
Term
What is the typical clinical presentation of IIP?
Definition
Older white males with intermittent cough and loud inspiratory crackles at lung bases.

1) Progressive dyspnea on exertion
2) Paroxysmal, non-produtive cough on exertion/irritant

on PE
- Loud (Velcro) inspiratory crackles at lung bases
- Clubbing of fingers and toes 25-50%
Term
What radiological findings would you expect to find on a 69 year old white male who presents complaining of progressive dyspnea on exertion and intermittent non-productive cough.

The patient has "clubbing" of his hands and toes and you detect loud inspiratory crackles at both lung bases
Definition
Patient as IPF

1) CXR
- Reticulonodular infiltrates

2) CT
- sub-pleural infiltrates with honeycoming fibrosis
- areas of "traction bronchectasis"
Term
You are a radiologist and you discover the following findings.

1) CXR
- Reticulonodular infiltrates
2) CT
-sub-pleural infiltrates with honeycoming fibrosis
- areas of "traction bronchectasis"

What PFT findings would you expect to see from the pulmonary division?
Definition
Classic IPF, which is a restrictive-type condition.

1) Decreased VFC and FEVI
2) Normal/Increased VFC/FEVI ratio
3) Decreased DLco (circulation)
4) Widened AA gradient, particularly on EXERTION
Term
Which of the following findings is NOT characteristic of moderate IPF?

1) Decreased VFC and FEVI
2) Normal/Increased VFC/FEVI ratio
3) CO2 retention
4) Decreased DLco (circulation)
5) Widened AA gradient, particularly on exertion
Definition
3- CO2 retention is ONLY seen in very advanced disease.

Restrictive picture with wide AA gradient (V/Q mismatch) and decreased oxygen saturation on exertion is classic
Term
If you take a lung biopsy of a patient with IPF and it shows diffuse alveolar damage superimposed on the UIP (geographic and temporally irregular) pattern, what does that tell you?
Definition
Acute exacerbation of IPF (formally "Hamman-Rich syndrome").

Death by respiratory failure in weeks/months
Term
Which of the following is the most frequent cause of mortality in patients with IPF?

1) Ischemic heart disease
2) Respiratory failure
3) Infection
4) PE
5) Bronchogenic carcinoma
Definition
ALL are seen, but respiratory failure is most common.
Term
What is the "Usual Interstitial Pneumonia" pattern of pathology?
Definition
1) Geographic (normal and abnormal areas) heterogenity
- Hyperplasia of smooth msucle within interstitial space
- Epithelial hyperplasia/metaplasia in alveoli and small airways
** MOST destructive lesions are in subplueral and paraseptal areas**

2) Temporal heterogenity (different levels of inflammation in same specimen)
- PMNs, macrophages, lymphocytes, plasma cells

3) Early "fibroblastic focus" of replication at air-tissue interfaces and at normal-scarred junctions.
Term
True or False:

The prognosis of IPF patients is about 3.5 years, but will improve with therapy.
Definition
False!

Therapy is ineffective! 3.5 years no matter what
Term
What is the current model of pathogenesis in IPF?
Definition
Repetitive injury to the alveolar surface with abnormal regulation of wound repair

1) Progressive loss of alveoli due to scarring, perhaps due to oxidative stress (exposures)

2) Innate and Adaptive immune-mediated inflammation (Th1:Th2 imbalance may produce fibrosis)

3) Fibroblast regulation balance from TGF-B, CTGF and MMPs (angiogenic:angiostatic balance)
Term
What genetic abnormality is associated with familiar IPF?
Definition
Surfactant C
Term
What treatment options are available for IPF?
Definition
Nothing yet.

- Multi-kinase inhibitor, Nintenanib is in phase III trials
- LUNG transplant is only currently available option.
Term
What are the major Fibrogenic Pneumoconioses? What populations of people are affected by each?
Definition
Occupational Interstitial Lung Disease NOT including neoplasm, asthma, bronchitis and emphysema.

1) Silicosis (simple or complicated)
- Miners, Quarrying, Foundry workers, Ceramic workers

2) Asbestosis
- Old clothing or household exposure

3) Coal Worker's (simple or complicated)
- self-explanatory

Term
What is the difference between simple (chronic) and complicated silicosis?
Definition
Silicosis has gradual onset of dyspnea over 10-20 years

1) Simple
- diagnosed by nodules <1cm on CXR
- largely asymptomatic

2) Complicated ("Progressive Massive Fibrosis")
- > 1cm
- Respiratory failure and death

**progression may be due to Mycobacterial infection because of alveolar macrophage abnormality*

3) Can be acute with MASSIVE exposure, with rapid progression and death
Term
Why do patients with silicosis tend to get more Mycobacterial infections than the average individual?
Definition
Defect in alveolar macrophage function due to silica ingestion.
Term
A patient who presents with dyspnea and symptoms of respiratory failure gets a lung biopsy.

You detect nodules with cell-free central areas and surrounding concentrically arranged collagen fibers, giving it an "onion like" appearance. You find these in LN and in the lung parenchyma.

PFT shows elevated FEV1/FVC ratio, but decreased FEV1 and FVC.

You order a CXR and see......
Definition
Complicated silicosis

1) hilar calcification (LN involvement)

2) Rounded opacities indicating ischemic necrosis
Term
A patient presents complaining of insidious dyspnea and an intermittent dry cough.

On CXR you see evidence of pulmonary fibrosis in subpleural regions, mostly in the lower lobes.

You don't see lymph node involvement.

What is on your ddx and what do you think/how do you confirm?
Definition
Could be IPF, Silicosis or Asbestosis based upon dyspnea and cough.

Silicosis would probably have LN involvement.

To tell between IPF and Asbestosis, LOOK FOR ASBESTOSIS BODIES (1 – Ferruginous bodies, 2 – Iron laden macrophage) in lung and sputum.
Term
How can you distinguish Coal Worker's Pneumoconiosis from Silicosis?
Definition
Similarly asymptomatic in simple case, with <1cm rounded nodules.

1) h/x of exposures
2) CWP is often less severe
3) COAL MACULE in respiratory bronchioles (TBR), producing focal emphysema.
Term
True or False:

Sarcoidosis predominantly affects intra-thoracic organs with infectious granulomas.
Definition
False!

Its all true except they are not infectious.
Term
What are the definitive geographic and racial differences in those affected by Sarcoidosis?
Definition
Peak incidence between 25-40

1) Increase with degrees latitude from the equator

2) African americans 10X more likely ONLY in US
2b) High in asians living in london

3) Higher in health care workers
Term
What organs are most commonly affected in Sarcoidosis?
Definition
1) Lungs (>90%)
2) Hilar LN (72%)
3) Liver (50-80%)
4) Eyes (11-80%)
Term
What is the basic immune cells involved in pathogenesis of Sarcoidosis?
Definition
Th1-dominant response suggests presence of specific "sarcoidosis antigens"

**Low Th2 response may experience lack of cleared antigens**

1) CD4+ Th1 cells are activated
- Express high affinity IL-2 receptors
- Express MHC II antigens
- CD45RO+ (primed for specific antigens)
- Produce IFN-y, IL-2, IL-12 and IL-15

2) Macrophages
- Produce IL-12 (activate T cells)
- Become "epithelioid" via IL-1 and TNF-a

3) B cells (hypergammaglobulinemia)
Term
What is the supposed pathogenesis of Sarcoidosis?
Definition
1) CD4+, Th1 cells are activated by MHC-II APCs (B cells and macrophages) that interact with TCR

2) Clonal expansion of stimulated Th1 cells occurs (specific variable regions) and inflammation ensues

**see gamma and delta chains that recognize TB bacteria**

3) SNPs in TNF-a, TGF-b, complement receptors and Ig light chains have all been identified.

**small contribution of HLA haplotypes to risk**
Term
How is Sarcoidosis staged using CXR?
Definition
Remember, acute exacerbations in some, and spontaneous remission on most.

Based on 1) appearance of LN and 2) presence or absence of pulmonary infiltrates.

Stage 1) Hilar and/or mediastinal adenopathy without pulmonary infiltrates
- Most go into remission

Stage 2) Adenopathy and variable infiltrate, with "bronchovascular bundles" on CT

- 50% will remit and 25% will have some relapse (not bad)

Stage 3) NO hilar adenopathy, with upper lobe infiltrate
- Extrathoracic disease is the rule with poor prognosis (end stage lung disease in 5-10 years)

Stage 4) Diffuse infiltrate without lymphadenopathy, but with SIGNIFICANT volume loss and definitive fibrosis

- Restrictive disease on PFT with Mycetomas due to aspergillus.
Term
A patient presents with fatigue, fever, chills and night sweats.

They have arthralgias in their elbows and knees and they show you a painful red nodule over their tibia.

You also notice conjunctivitis.

What do you see on CXR and what is the prognosis?
Definition
Painful nodule, arthralgia and fever/chills fits Lofgren's Syndrome as part of Acute Sarcoidosis.

1) On CXR you see bilateral hilar lymphadenopathy without infiltrates on parenchyma (stage 1)

2) May feel miserable, but prognosis is GOOD and arthralgia can be treated with NSAID or corticosteroid (if severe).
Term
True or False:

Evidence of non-infectious granulomatous inflammation in a lung biopsy is diagnostic of Sarcoidosis.
Definition
False! It is a clinical diagnosis (you don't want to worsen other conditions like cancer or infection).
Term
How can you tell between stage III and stage IV sarcoidosis?
Definition
Both have infiltrates without lymphadenopathy

1) Stage IV will have significantly decreased lung volume, with low PFT tests and tendency to get Mycetomas from aspergillus infection.

2) Stage III is associated with extrathoracic disease and will have normal lung volume, despite infiltrates.
Term
How is Sarcoidosis treated?
Definition
1) Corticosteroids

2) If CS side effects are a problem, may try immunosuppression (Methotrexate or Azothioprine)

- Can also try TNF-a inhibitor or Infliximab

3) **Transplant is option (granulomatous inflammation develops in allograft, but doesn't impair function!)
Term
What are the major causes of mortality due to Sarcoidosis?
Definition
10% in AA and only 1-3% in whites!

1) Respiratory failure
2) Massive hemoptysis from mycetoma
3) RHF from pulmonary HTN
4) LVH from cardiac involvement
5) Renal failure.

**Transplant is option (granulomatous inflammation develops in allograft, but doesn't impair function!)
Term
What major compartments should be considered when considering pulmonary pathology?
Definition
1) Airspaces (= distal airspace)
2) Interstitum (= mostly alveolar septum)
3) Bronchovascular bundles (= vessels)
4) Airways (= conducting airways)
5) Pleura
Term
What are the 3 most common reaction patterns to injury in the lung?
Definition
1) Airspace organization (organizing Pneumonia)
2) Inflammatory infiltrates (interstitial Pneumonia)
3) Fibrosis
Term
What is the most common radiographic abnormality in pulmonary fibrosis?
Definition
"Honeycombing"

Uneven scarring/remodeling with less-involved bronchioles being stretched by scar contraction
Term
What are the 5 major categories of interstitial lung disease?
Definition
1) Infection
2) Inorganic dust exposure (Pneumoconioses)
3) Organic dust exposure (Hypersensitivity pneumonitis)
4) Idiopathic (IIP)
5) Drug-induced
Term
Distinguish between what is meant by "Idiopathic pulmonary fibrosis" and "Usual Interstitial Fibrosis."
Definition
1) IPF is a "clinical term" characterizing chronic, progressive fibrosis with poor prognosis in older people.

2) UIP is a pathology term used to refer to "geographically" and "temporally" heterogenous fibrosis with a "honeycomb" pattern

- Fibroblastic foci at normal-pathological junctions stain red on H & E and represent "young" fibrosis, as opposed to "mature scar tissue with dense collagen"

**ALL IPF will have features of UIP on pathology, but not all UIP will be idiopathic**
Term
What pathological features does a physician have to document in order to make the diagnosis of IPF?
Definition
CXR findings are not enough.

1) Fibrosis of lung with distortion of lung architecture (honeycomb changes).

2) Geographical heterogeneity (Normal and remodelled areas)

3) Temporal heterogeneity (Fibroblastic foci and mature scarring)
Term
What pathological features does a physician have to document in order to make the diagnosis of IPF?
Definition
CXR findings are not enough.

1) Fibrosis of lung with distortion of lung architecture (honeycomb changes).

2) Geographical heterogeneity (Normal and remodelled areas)

3) Temporal heterogeneity (Fibroblastic foci and mature scarring)
Term
What is the current, speculative model of IPF pathogenesis?
Definition
1) Multiple microinjuries to alveolar epithelial cells induce fibrosis, with growth factors released from damaged cells recruiting fibrblasts.

2) Initial site of fibrosis is "fibroblastic foci".
Term
What are the primary pathological findings in sarcoidosis?
Definition
1) Granulomatous inflammation with well formed non-necrotizing granulomas (looks for epithelioid histiocytes, giant cells and fibrous rim) in a LYMPHANGITIC distribution (follows both bronchovascular bundles and veins along septa and pleura)

2) "Schaumann bodies" (laminated concretions composed of calcium and proteins"

3) "Asteroid bodies" (stellate inclusions containing degraded cytoskeletal protein enclosed in multi-nucleated giant cell.
Term
What 3 features are often seen in the non-nectrotizing granulomas of Sarcoidosis?
Definition
1) Epithelioid histiocytes

2) Fibrous rim

3) Multinucleated giant cells
Term
What is "Hypersensitivity Pneumonitis"? What histopathological features are characteristic of HP?
Definition
1) Diffuse inflammatory lung disease seen in patients exposed to organic dusts (Extrinsic allergic alveolitis).

- Farmer's lung
- Bird-fancier's lung

2) Airway-centered cellular interstitial pneumonia with poorly formed non-nectrotizing granulomas (Type IV hypersensitivity)
Term
How can you distinguish Hypersensitivity Pneumonitis from Sarcoidosis histologically?
Definition
Since both involve type IV hypersensitivity (T-cell mediated) with non-necrotizing granulomas, it can be confusing.

1) Sarcoid granulomas are WELL-formed, with epithelioid histiocytes, multi-nucleated giant cells and a clear fibrous ring.

2) HP granulomas are loosely formed will few inflammatory cells.
Term
What is the most essential diagnostic finding for IPF?
Definition
UIP pathology with temporal and geographical heterogenity.

If you can't get a biopsy, look for sub-pleural fibrosis and honeycombing on CT
Term
What is the most common cancer caused by asbestosis?
Definition
Adenocarcinoma
Term
What is Berylliosis and what are its major clinical manifestations?
Definition
1) Acute- chemical injury
2) Chronic- immune reactions (steroid resistant)
Term
Why might you use tracheobronchoscopy vs. mediastinoscopy to diagnose sarcoid?
Definition
- Tracheobronchoscopy is preferred and has good sensitivity for granulomas in > stage 2

- Mediatstinoscopy is 100% sensitive in experienced has, but has more risks.

1) Bleeding
2) Longer hospital stay
3) Keloid formation in suprasternal notch
Term
How should you treat Cardiosarcoidosis
Definition
1) Cardio gets immunosuppressives and Corticosteroids

Present with massive hemoptosis