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

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

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

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):277-304 Travis WD, et al. Am J Respir Cnt Care Med 2013; 188 (6); 733-748

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

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. 1994 Feb. 18(2):136-47

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

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. 2003 Jan 13. 163(1):17-29

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

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

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

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. 2002 Oct. 22 Spec No:S151-65

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

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. 9-44.

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

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

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%

Non Specific Interstitial Pneumonia CT features 50 patients with biopsy-proven NSIP Ground glass attenuation 76% Irregular Linear opacities 46% Honeycombing 30% Consolidation 16% Nodular opacities 14% Interlobular septal thickening 6% Traction bronchiectasis 36% Wide variety of CT findings Hartman TE et al. Radiology 2000; 217:701-705

Ground glass opacities NSIP DIP HP PCP PAP Pulmonary edema

NSIP as the first manifestation of HIV infection

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

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

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

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

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

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

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

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?

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

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

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

Interstitial Lung Disease Advisory Group Hotel Ramada Islamabad