Is It Idiopathic Pulmonary Fibrosis or Not?

Mary Salvatore, MD; Genta Ishikawa, MD; Maria Padilla, MD


J Am Board Fam Med. 2018;31(1):151-162. 

In This Article

Mimicker No. 1: Fibrotic NSIP


NSIP is a subtype of fibrosing IIPs and the first mimicker of UIP/IPF. In 1990s, it was reported that a subset of patients diagnosed with IPF had cellular infiltration on lung biopsy, bronchoalveolar lavage lymphocytosis, and better clinical response to anti-inflammatory therapy (ie, steroid, etc.) with a favorable long-term prognosis.[20–23] NSIP histopathologic pattern is characterized by varying degree of inflammation and fibrosis with temporal uniformity (ie, varying proportions of interstitial inflammation and fibrosis seem to have occurred over a single time span, distinct from the temporal heterogeneity observed in UIP pattern). NSIP is most common among women in their 40s to 50s and nonsmokers, in contrast with UIP/IPF. NSIP is the most common histologic finding in some forms of connective tissue disease–related ILD (CTD-ILD) which usually does not require invasive diagnostic modalities such as surgical lung biopsy for diagnosis.[24–26] Therefore, specific attention should be given to connective tissue symptoms and signs (arthralgias, arthritis, skin changes, esophageal abnormalities, fever, etc.). Obtaining a comprehensive panel of serum autoantibodies and inflammatory markers, including but not limited to antinuclear antibody, rheumatoid factor, anti-Scl-70, antisynthetase antibodies (myositis panel), anti-Ro (SS-A), anti-La (SS-B), antiribonucleoprotein, aldolase, creatine kinase, erythrocyte sedimentation rate, anticyclic citrullinated peptide, and C-reactive protein, is crucial (Table 1). Many patients present with an underlying autoimmune feature but do not meet established criteria for a CTD; therefore, ERS/ATS recently proposed the term, "interstitial pneumonia with autoimmune features" (IPAF) and offered its diagnostic criteria.[27] This new guideline suggests a possible underlying autoimmune etiology in patients with NSIP despite a lack of definitive CTD diagnosis. Moreover, since CHP and NSIP have many overlapping findings on radiography and histopathologic examination, a comprehensive environmental, occupational, and avocational history is also a critical step. After exclusion of UIP/IPF, CHP, and CTD, a clinician must confirm the histologic diagnosis obtained either by surgical lung biopsy or bronchoscopic cryobiopsy since definitive diagnosis of NSIP can only be made histologically.[28] The majority of cases are typically classified as fibrosing, with less than 20% deemed to be cellular.[29] As is the case with diagnosing UIP/IPF, the multidisciplinary discussion plays a key role in accurate diagnosis of NSIP and referring to ILD centers would be expected.

In mild or asymptomatic diseases, serial monitoring of symptom and pulmonary function tests are sufficient. If progression of disease is seen, treatment with immunosuppressants is thought to be beneficial.[30,31] Steroids are the predominant agent of choice, whereas other immunosuppressants (azathioprine, cyclophosphamide, cyclosporine, and mycophenolate mofetil) are used to supplant steroid therapy. The prognosis for NSIP is generally favorable compared with UIP/IPF, although there is an approximate 20% mortality rate in 5 years.[24]


NSIP is a lower lobe–predominant fibrosis like UIP. However, in contrast with UIP, which is heterogeneous, NSIP is homogeneous.[32] It also differs from UIP in that it is not subpleural but instead follows the bronchovascular bundles and in fact often spares the exact periphery of the lung.[33] There are basically 3 types of NSIP radiographically, cellular, fibrotic, and mixed. Cellular NSIP is associated with ground glass opacities and has minimal volume loss. Cellular NSIP is more likely to respond to steroid treatment (Figure 4).

Figure 4.

Cellular nonspecific interstitial pneumonitis (NSIP) is associated with ground glass opacities and has minimal volume loss. Cellular NSIP is more likely to respond to steroid treatment.

Fibrotic NSIP has less ground glass opacity and more volume loss displacing the major fissures posteriorly (Figure 5). This pattern can be confused with UIP. Fibrotic NSIP is less likely to respond to steroid treatment. In reality most cases of NSIP are mixed cellular and fibrotic with ground glass opacity and volume loss.

Figure 5.

Fibrotic nonspecific interstitial pneumonitis (NSIP) has less ground glass opacity and more volume loss then cellular NSIP. The dilated esophagus in this photograph points to the cause of fibrosis, which was scleroderma.

Differentiation Pearl

  • NSIP and UIP are both lower lobe–predominant diseases; however, NSIP is distinctively different radiographically from UIP because of its homogeneity and its subpleural sparing.

  • IPAF presents most common radiographically as a lower lobe–predominant fibrosis that follows the bronchovacular bundles, but unlike NSIP it is more heterogeneous.