1. Non-specific Interstitial Pneumonia What is it? Who knows?
Ali Bin Sarwar Zubairi; MBBS, FCCP

2. Disclosure
I have no financial interest or other relationship with the manufacturers of any product that I intend to discuss in this presentation

3. Outline NSIP: A distinct entity or an overlap?
Clinical, radiologic and pathologic features of NSIP
Treatment options for NSIP
NSIP in summary

4. Diffuse Parenchymal Lung Diseases (DPLD)
DPLD of known etiology (HP, drugs, collagen-vascular)
Idiopathic interstitial pneumonia (IIP)
Granulomatous DPLDs (Sarcoidosis)
Other forms of DPLD (eosinophilic pneumonia, LAM, PLCH etc.)
Chronic fibrosing
Smoking related
Acute/sub-acute
IPF
NSIP
RBILD
DIP
AIP
COP
Rare IIPs:
Idiopathic lymphocytic interstitial pneumonia (LIP)
Idiopathic pleuroparenchymal fibroelastosis (PPFE)
Unclassifiable IIP
Spagnolo P. et al. Multidiscip Respir Med 2012;7(1):42
American Thoracic Society. Am J Respir Cnt Care Med. 2002;165(2):
Travis WD, et al. Am J Respir Cnt Care Med 2013; 188 (6);

5. Classification based on etiology
Interstitial Lung Disease
Exposure-related
Mold, bacteria, birds, medications XRT dusts cigarette smoke
CTD-related RA
Systemic
sclerosis
Genetic
FPF
Idiopathic
IIP
Idiopathic interstitial pneumonias (IIP)
Major IIP
Idiopathic pulmonary fibrosis (IPF)
Non-specific interstitial pneumonia (NSIP)
Respiratory bronchiolitis-ILD (RB-ILD)
Desquamative interstitial pneumonia (DIP)
Cryptogenic organizing pneumonia (AIP)
Rare IIP
Idiopathic lymphoid interstitial pneumonia (LIP)
Idiopathic pleuroparenchymal fibroelastosis (IPPFE)
Unclassifiable IIP

7. IPF and NSIP
Before the era of histopathologic classification of IIP’s (Katzenstein, 1994), IPF and NSIP were considered the same disease
Re-evaluation of biopsies of IIP’s diagnosed before 1998 led to 14% of previous IPF/UIP being re-classified as NSIP
Katzenstein AL, Fiorelli RF. Nonspecific interstitial pneumonia/fibrosis. Histologic features and clinical significance. Am J Surg Pathol Feb. 18(2):136-47

8. IPF and NSIP Is this clinically relevant?
Yes: The 2 entities have different prognoses
Latsi PL et al. Am J Respir Crit Care Med, 2003

9. Definition and epidemiology of NSIP
NSIP is a form of interstitial lung disease that cannot
be classified into one of the other categories of
idiopathic interstitial pneumonia  
The true incidence is unknown. It constitutes 14%-
36% of cases of idiopathic interstitial pneumonia,
which is less common than UIP (50%-60%) but more
common than DIP/RB-ILD (10%-17%) and AIP (0%-
2%)
Collard HR, King TE Jr. Demystifying idiopathic interstitial pneumonia. Arch Intern Med Jan (1):17-29

10. Is NSIP really a unique entity?
First described as a unique subunit of IIP’s in 1994
There is now sufficient evidence to justify several clinico-pathologic syndromes (overlaps) for NSIP
NSIP with IPF-like profile (NSIP/IPF)
NSIP with OP profile (NSIP/OP)
NSIP with hypersensitivity profile (NSIP/HP)
Wells AU. Thorax 2008

11. NSIP pattern
Second most common morphological and pathological pattern of the ILD’s
Subtypes:
Cellular 
Fibrotic
Mixed

12. Clinical associations of NSIP
Idiopathic NSIP
CTD’s HP
Drugs
HIV
Immunodeficiency

13. NSIP-CTD
NSIP is the most common manifestation of certain collagen vascular disease in the lung (DM/PM, SS, MCTD)
Diagnosis of NSIP may precede the diagnosis of collagen vascular disease by months or even years
Kim EA, Lee KS, Johkoh T, et al. Interstitial lung diseases associated with collagen vascular diseases: radiologic and histopathologic findings. Radiographics Oct. 22 Spec No:S151-65

14. Clinical presentation of NSIP
Younger age (40-50 years), more often in women, non-smokers
Insidious onset of dyspnea and dry cough
Systemic signs and symptoms
Digital clubbing and crackles are less frequent

15. In a normal finger, the length of the perpendicular dropped from point A to point B should be greater than a similar line from C to D. In clubbing, the relationships are reversed - that is, the distance C-D is greater than the distance A-B. The other important change is the angle described by A-C-E. In the normal finger this is usually <180 degrees whereas in clubbing it is >180 degrees. Redrawn from DeRemee, RA. Facets of the algorithmic synthesis. In: DeRemee, RA, (Ed), Clinical profiles of diffuse interstitial pulmonary disease, Mount Kisco, NY, Futura Publishing Company, Inc, 1990, pp

17. Bronchoscopy
BAL lymphocytosis (cannot be utilized to differentiate NSIP from other IIPs)
BAL may be helpful in excluding other causes of interstitial opacities, such as hemorrhage, infection and malignancy

18. Pulmonary Function Testing
Restrictive pattern of decreased lung function and a decrease in gas transfer and/or desaturation during ambulatory pulse oximetry
PFT is not essential for making the diagnosis of NSIP
Monitoring FVC and DLCO is helpful for assessing disease progression, response to therapy, and prognosis

19. CT features of NSIP Diffuse distribution Relatively symmetric
Subpleural sparing
Ground glass opacities
Reticular lines
Traction bronchiectasis
Consolidation +/-
Honeycombing rare
The diagnosis of NSIP remains one of the biggest challenges; studies showed correct diagnosis by chest radiologist varies between 65-85%

20. Non Specific Interstitial Pneumonia CT features
50 patients with biopsy-proven NSIP
Ground glass attenuation 76%
Irregular Linear opacities 46%
Honeycombing %
Consolidation %
Nodular opacities 14%
Interlobular septal thickening %
Traction bronchiectasis 36%
Wide variety of CT findings
Hartman TE et al. Radiology 2000; 217:

21. Ground glass opacities
NSIP
DIP HP
PCP
PAP
Pulmonary edema

22. NSIP as the first manifestation of HIV infection

24. Pathologic features of NSIP
Homogeneous inflammation/fibrosis
Little or no honeycombing
Few if any fibroblastic foci

25. NSIP Pattern CT Features Pathologic features Little or no honeycombing
Traction bronchiectasis
Reticular abnormalities
Ground glass opacities
Pathologic features
Little or no honeycombing
Traction bronchiolectasis
Fibrosis of interlobular septa
Homogenous inflammation/fibrosis

26. Differential diagnosis
Usual interstitial pneumonitis (UIP) pattern
Overlap pattern
Look for findings such as joint changes, esophageal dilatation, pleural and pericardial effusion etc.

27. Differences b/w UIP and NSIP
Features
UIP
NSIP
Clinical Onset
Chronic
Sub acute
Fever
Absent
1/3 of patients
Clubbing
60-90%
10-40%
Age
Older
Younger
Gender
Male predominance
Female predominance
BAL cell count
Neutrophilia
Lymphocytosis
HRCT features
Honeycombing
Subpleural
Rare GGO’s
Bilateral GGO’s
Absent or minimal
honeycombing
Subpleural sparing
Prognosis
Poor
Good
Association with smoking
Yes
Not established
Treatment with
corticosteroids
Not responsive
Responsive

28. Clinical history, time course of disease, exposures, and radiographic findings should all be correlated before idiopathic NSIP is diagnosed

29. Treatment of NSIP
iNSIP usually responds well to anti-inflammatory treatment i.e. corticosteroids or eventually in combination with cytotoxic drugs/ immunosuppressants
In cases of NSIP with CTDs, combined immunosuppressive treatment should be considered
Antifibrotic treatment?
Wells AU, Hirani N. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracicc Society of Australia and Hew Zealand and the Irish Thoracic Society, Thorax 2008

30. Prognosis In general NSIP carries a more favorable prognosis
90% 5 years survival rate for cellular
45-90% 5 years survival in fibrotic subtype 
NSIP in CTDs usually responds better to corticosteroid treatment and has a better prognosis than iNSIP
Correct and early diagnosis has significant impact on patient’s outcome

31. Unanswered questions
Is NSIP really a clinical and pathological entity, or only a pattern of healing?
Is NSIP an unrecognized autoimmune disease?
Can fibrotic or mixed NSIP be treated by anti-fibrotic treatment?

32. Emerging concept of Idiopathic NSIP
Idiopathic NSIP is a ‘group of separate disorders’
and it is time to be more specific
Preceding defined
CTD’s
NSIP
Variant of CTD
Confined to lung
NSIP/OP overlap
IPF-like phenotype

33. NSIP in summary Better prognosis than IPF Responds to steroids
Overlap in CT appearance
Surgical biopsy recommended in atypical cases

34. MULTIDISCIPLINARY DIAGNOSTIC TEAM
PULMONOLOGIST
RADIOLOGIST
MULTIDISCIPLINARY DIAGNOSTIC TEAM
HISTOPATHOLOGIST
Correct IIP Diagnoses need team work and experience
Flaherty KR, AJRCCM 2004;170:904-10

35. Interstitial Lung Disease Advisory Group
Hotel Ramada Islamabad