1. Interstitial Lung Disease
Kunwar Sohal, PGY3
2/3/2010

2. Idiopathic Interstitial Pneumonias
Subset of diffuse interstitial lung diseases of unknown etiology characterized by expansion of the interstitial compartment w/an infiltrate of inflammatory cells sometimes accompanied by fibrosis, either in the form of abnormal collagen deposition or proliferation of fibroblasts capable of collagen synthesis
All under umbrella of IPF? Or separated based on histological appearance? Matter of debate

3. Averill Liebow
Pioneered the notion that morphologic characteristics are useful in separating idiopathic interstitial pneumonias into clinically and histologically distinct groups
These processes were histological patterns rather than free standing diagnostic entities, and that each could occur in a variety of clinical contexts
Maintained that precise histological classification of interstitial pneumonias provides clues to etiology, pathogenesis, natural history, and prognosis (helps limit differential dx and lead to treatment options and response)
The biopsy is intended not only to confirm the suspicion of an interstitial pneumonia, but also to exclude various IPF mimics such as sarcoidosis, hypersensitivity pneumonitis, and pulmonary Langerhans' cell histiocytosis

4. UIP-Usual Interstitial Pneumonia
IPF - a specific form of chronic fibrosing interstitial pneumonia limited to the lung and associated with the histologic appearance of usual interstitial pneumonia (UIP) based on surgical biopsy
IPF has an estimated prevalence of 14 to 43 per 100,000
Most cases are sporadic and present with slowly progressive dyspnea and nonproductive cough
Prevalence and incidence increase with age
HRCT demonstrates a characteristic pattern of peripheral (subpleural) and bibasilar reticulonodular opacities associated with architectural distortion, including honeycomb changes and traction bronchiectasis

5. Histo
Histologic hallmark and chief diagnostic criterion is a heterogeneous appearance with alternating areas of normal lung, interstitial inflammation, fibroblast foci, and honeycomb change
The tissue is stained with hematoxylin (purple dye) and eosin (pink dye) to make it visible. The pink areas in this picture represent lung fibrosis (patchwork fibrosis)

6. Honeycombing, traction bronchiectasis, predominance in bases, mild mediastinal LAD

7. RB-ILD Respiratory bronchiolitis-associated interstitial lung disease
Also uncommon, accounting for only 2 percent of biopsied Mayo Clinic patients who were suspected of having IPF
DIP and RB-ILD show significant clinical, radiologic and histologic overlap, and in some patients the distinction is arbitrary and of uncertain clinical significance
Clinical features are non-specific, usually males, smokers, 30+ pk year hx, symptoms are usually mild and not disabling
Chest radiographs are abnormal in 80 percent of patients and show diffuse fine reticular or reticulonodular opacities in a bibasilar distribution

8. Histo
The main feature that distinguishes DIP from RB-ILD is that DIP affects the lung in a more uniform and diffuse manner, lacking the bronchiolocentric distribution of macrophages seen in RB-ILD
It is likely that DIP and RB-ILD are highly related if not identical lesions, differing only in the severity and extent of the abnormality (ie, RB-ILD = mild/early DIP).
Pertinent NEG findings: Lack of diffuse macrophage accumulation, and interstitial fibrosis and/or honeycomb fibrosis

9. Diffuse ground glass abnormality, with some associated cystic changes
Bronchial wall thickening (arrow-thickened interlobular septa)

10. DIP-Desquamative Interstitial Pneumonia
It is relatively uncommon, comprising 8 percent of biopsied Mayo Clinic patients suspected of having IPF
The vast majority (>90 percent) of patients with DIP are smokers, a small percentage of cases are associated with connective tissue diseases
Glucocorticoids are beneficial in the majority of patients, and the overall survival is about 70 percent after 10 years 
Radiographic abnormalities: less severe than UIP, HRCT shows ground glass opacities without the peripheral reticular and reticulonodular opacities characteristic of UIP
One review of HRCT findings found no evidence of progression from DIP to UIP, further supporting the concept that DIP and UIP are separate and distinct entities (Chest, 1996)
DIP differs histologically from UIP in that the changes tend to be much more uniform at low magnification
The most striking feature is the presence of numerous mononuclear cells within most of the distal air spaces. These mononuclear cells represent smokers' macrophages rather than desquamated pneumocytes, as had been originally proposed

11. Histo
The alveoli are filled with macrophages containing brown pigment in this disease of smokers.
Tx: smoking cessation, steroids

12. AIP-Acute Interstitial Pneumonia
Etiology: neutrophil mediated lung injury
Initial stage: inc capillary permeability, leads to organizing stage with fibroblast prolif (can progress to severe fibrosis)
Presents with the explosive onset of respiratory symptoms and is characterized by rapidly progressive respiratory failure associated with diffuse infiltrates on chest radiographs (versus chronic nature of others)
This acute variant is analogous to the acute respiratory distress syndrome (ARDS), differing only in that it is not preceded by a catastrophic event, it is idiopathic
Other terms have been proposed: including Hamman-Rich syndrome and accelerated interstitial pneumonia
AIP has the same poor prognosis as ARDS, and the majority of patients die of respiratory failure
Digital clubbing is limited to patients with acute exacerbation of underlying fibrotic lung disease and serves as a helpful clue to separate such patients from those with AIP

13. Histo
AIP is identical to the organizing or proliferative stage of diffuse alveolar damage (DAD)
The main finding is extensive interstitial fibroblast proliferation within an edematous-appearing stroma

14. Classical histopathology of DAD is evident with prominent hyaline membranes (hm) lining alveolar spaces.
Note that the interstitium of the lung is thickened and hypercellular. While hyaline membranes are still present, 1-4 days after the acute injury event, the interstitium is edematous and has sparse inflammatory cells

15. HRCT Characteristics are diffuse or patchy consolidation
HRCT findings in AIP are indistinguishable from ARDS
Sometimes bilateral areas of airspace consolidation in a predominantly subpleural distribution. Mild honeycombing, usually affecting < 10% of the lung, may be present
Traction bronchiectasis is often seen as a delayed manifestation in the areas of air-space consolidation or ground-glass attenuation

16. NSIP-Nonspecific Interstitial Pneumonia
Chronic interstitial pneumonia that lacks the histopathologic features typical of UIP, DIP, RB-ILD or AIP
In studies of idiopathic pulmonary fibrosis, NSIP has been described as "early" or "cellular" UIP (“fibrosing” NSIP behaves like IPF-more fibrotic foci, worse outcome)
The most important clinical characteristics that distinguish NSIP from UIP are a subacute rather than insidious onset of symptoms, associated fever in about one-third of patients, lack of a strong male predominance, relative absence of clubbing in NSIP, and increased frequency of features suggestive of connective tissue disease
As the name implies, the histological findings in patients with NSIP are variable
The main change in all cases is an interstitial pneumonia characterized by expansion of alveolar septa by a variably dense infiltrate of predominantly mononuclear inflammatory cells with or without associated fibrosis

17. HRCT
HRCT findings include bilateral patchy ground-glass attenuation, bilateral areas of consolidation, irregular lines, and bronchial dilatation. Ground-glass attenuation is the predominant finding in most cases and is the sole abnormality in about 1/3 of cases
Bilateral subpleural ground-glass opacities (arrowhead) and irregular linear opacities (arrow)

18. NSIP contd
Groups: I, II: majority of patients had a prominent inflammatory component either without (Group I) or with (Group II) concomitant fibrosis; biopsies showing predominantly fibrosis (Group III) were the least common
As noted in other studies, the most compelling distinction between NSIP and UIP was related to outcome: NSIP had a significantly better prognosis than UIP

19. Treatment and Prognosis of Idiopathic Interstitial Pneumonias
Idiopathic pulmonary fibrosis: Possibly lung transplantation, Mortality rate: 50–70% in 3 yr
NS-IP: Corticosteroids, Mortality rate: < 10% 5yr
RB-ILD: Smoking cessation, Mortality: rare
DIP: Smoking cessation, Mortality rate: 5% in 5 yr
AIP: Best tx unknown, Mortality rate: 60% in <6 mo (Corticosteroid therapy is generally used, but efficacy has not been established)

20. BOOP/COP?
Cryptogenic organizing pneumonitis (COP), which is the name applied to the idiopathic form of organizing pneumonia (idiopathic BOOP), is a distinct clinical entity with features of a pneumonia rather than a primary airway disorder

21. Approach
History, family history, occupational hx, exposures, syms, labs, rads, PFTs, etc.
Role of lung biopsy: Not possible to make a definitive diagnosis or to stage the disease without careful examination of lung tissue
Indications for performing a lung biopsy:
To provide a specific diagnosis, especially in a patient with atypical or progressive symptoms and signs, or rapid clinical deterioration or sudden change in radiographic appearance
To assess disease activity
To exclude neoplastic and infectious processes that occasionally mimic chronic, progressive interstitial disease
To identify a more treatable process than originally suspected
To establish a definitive diagnosis and predict prognosis before proceeding with therapies which may have serious side effects
Transbronchial lung biopsy: Normal tissue or nonspecific changes on transbronchial lung biopsy may result from a sampling error, need larger sample (VATS preferred method)