Causes, clinical manifestations, evaluation, and diagnosis of nonspecific interstitial pneumonia

INTRODUCTION — Nonspecific interstitial pneumonia (NSIP) is one type of idiopathic interstitial pneumonia (IIP). The other IIPs include usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), acute interstitial pneumonia (AIP), lymphocytic interstitial pneumonia (LIP), and cryptogenic organizing pneumonia (COP) (table 1) [1].

NSIP can be idiopathic or can be seen in association with HIV (human immunodeficiency virus) infection, connective tissue diseases, a variety of drugs, and hypersensitivity pneumonitis. It can also present in combination with the other IIPs.

The etiology, pathogenesis, clinical manifestations, and diagnosis of NSIP will be reviewed here. The treatment and prognosis of NSIP, and the pathology, clinical manifestations, diagnosis, and treatment of the other IIPs are discussed separately. (See "Idiopathic interstitial pneumonias: Classification and pathology" and "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis" and "Treatment of idiopathic pulmonary fibrosis" and "Respiratory bronchiolitis-associated interstitial lung disease" and "Cryptogenic organizing pneumonia" and "Acute interstitial pneumonia (Hamman-Rich syndrome)".)

DEFINITION — Nonspecific interstitial pneumonia (NSIP) is a chronic interstitial pneumonia (IIP) that is called "nonspecific" because it lacks the histopathologic features that characterize usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), or acute interstitial pneumonia (AIP). The histopathology of NSIP is characterized by a homogeneous appearance of dense or loose interstitial fibrosis with mild to moderate chronic interstitial inflammation (table 2) and rare or absent fibroblast foci, dense alveolar septal fibrosis, organizing pneumonia, granulomas, conspicuous infiltration of lymphocytes or eosinophils, and temporal heterogeneity, which are features of other chronic interstitial pneumonias.

CAUSES — NSIP can be idiopathic; it has also been associated with many medical conditions, although the specific causal link has not been identified.

Connective tissue disease — NSIP is a common pattern in patients with interstitial lung disease (ILD) that arises in the context of connective tissue disease (CTD, also referred to as systemic rheumatic disease), including polymyositis-dermatomyositis, rheumatoid arthritis, Sjögren's disease, and systemic sclerosis (scleroderma) [2-11]. Of note, the exact ILD histopathology is not always known in patients with CTD, as a lung biopsy is not always obtained.

●Polymyositis-dermatomyositis – In an observational study of 70 patients with polymyositis-dermatomyositis (PD-DM) and ILD, the most common pulmonary presentation was presumed acute or subacute antibiotic resistant community acquired pneumonia [5]. NSIP was identified in 18 of 22 patients (81 percent) who underwent lung biopsy. (See "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis".)

●Rheumatoid arthritis – NSIP is less common than usual interstitial pneumonitis among patients with rheumatoid arthritis (RA) [10,12]. Among 96 patients with RA and ILD, HRCT interpretation found definite UIP in 21 percent, probable UIP in 20 percent, indeterminate for UIP in 30 percent, NSIP in 14 percent, and an alternative diagnosis in 15 percent [12]. (See "Interstitial lung disease in rheumatoid arthritis".)

●Sjögren's disease – NSIP is the most frequent histopathologic pattern in patients with ILD and Sjögren's disease (close to 50 percent) [9,13]. (See "Interstitial lung disease associated with Sjögren's disease: Clinical manifestations, evaluation, and diagnosis".)

●Systemic sclerosis – NSIP is the most common ILD pattern in patients with systemic sclerosis [7,8,14,15]. Among 80 patients with ILD associated with systemic sclerosis, NSIP was identified in 62 (78 percent) [7]. (See "Overview of pulmonary complications of systemic sclerosis (scleroderma)".)

Systemic sclerosis sine scleroderma (a rare illness characterized by the typical vascular features and visceral fibrosis of systemic sclerosis but without skin sclerosis) can present with dyspnea with radiographic features of NSIP or UIP [16]. Patients usually have subtle physical exam findings such as scattered telangiectasia, Raynaud's phenomenon, esophageal reflux, pericardial effusion, and abnormal nailfold capillaroscopy. Antinuclear antibodies are typically of the nucleolar pattern. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Systemic sclerosis sine scleroderma'.)

●ANCA-associated vasculitis – NSIP is described in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (often microscopic polyangiitis), although a pattern of usual interstitial pneumonia is more common [17]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement", section on 'Interstitial lung disease'.)

Interstitial pneumonia with autoimmune features — Some patients with idiopathic interstitial pneumonia on lung biopsy (eg, NSIP, UIP/IPF) have features of autoimmune disease, but the findings are insufficient for definitive diagnosis of a specific CTD [11,18,19]. A multidisciplinary task force has proposed criteria for this entity, under the name "interstitial pneumonia with autoimmune features (IPAF)" [19]. IPAF is not considered a diagnosis, but a way of unifying patients with these characteristics for clinical research. Several terms had previously been used to describe these patients, including undifferentiated CTD-ILD, lung-dominant CTD, and autoimmune-featured ILD. The preference for the term "autoimmune features" over "undifferentiated CTD" is that the latter has the connotation of a defined disease, while "autoimmune features" describes the possibility of an underlying autoimmune process centered on the lung.

Proposed criteria for IPAF are organized around three domains: a clinical domain composed of extrapulmonary clinical features, a serologic domain of specific autoantibodies, and a morphologic domain that includes pulmonary physiologic, chest imaging, and histopathologic features (table 3) [19]. To meet criteria for IPAF, a patient must manifest at least one feature from at least two domains.

●Clinical features – Distal digital fissuring or tip ulceration, unexplained digital edema, inflammatory arthritis or polyarticular morning stiffness ≥60 minutes, palmar telangiectasia, Raynaud phenomenon, unexplained rash on the extensor surfaces of digits (Gottron sign).

●Serologic features – Antinuclear antibody (ANA) ≥1:320 (diffuse, speckled, homogeneous), ANA any titer with a nucleolar pattern, ANA any titer with a centromere pattern; rheumatoid factor ≥2 times upper limit of normal; antibodies to cyclic citrullinated peptide (anti-CCP), double-stranded (ds) DNA, Ro (SS-A), La (SS-B), ribonucleoprotein (RNP), Smith, topoisomerase (Scl-70), tRNA synthetase (eg, Jo-1, PL-7, PL-12), PM-Scl, or melanoma differentiation-associated gene 5 (MDA-5).

●Morphologic features – Morphologic features include the following:

•High-resolution computed tomography (HRCT) appearance suggestive of NSIP or other idiopathic interstitial pneumonia (IIP) (table 4). (See 'Chest imaging studies' below.)

•Histopathologic patterns or features of NSIP or another IIP. (See "Idiopathic interstitial pneumonias: Classification and pathology".)

•Multicompartment involvement such as unexplained pleural thickening or effusion, unexplained pericardial thickening or effusion, unexplained intrinsic airways disease (by pulmonary function testing, HRCT, or pathology), and unexplained pulmonary vasculopathy.

Several studies have noted that a high portion of patients with NSIP have underlying features suggestive of CTD [18,20-22]. In a case-control study of 28 patients with NSIP who had no clear underlying disease, 88 percent had laboratory or clinical features of undifferentiated connective tissue disease (autoimmune features) [18]. These features included arthralgias, gastroesophageal reflux disease (GERD), Raynaud's, sicca symptoms, and dysphagia, in addition to positive serologic studies (eg, rheumatoid factor, ANA, or antibodies to SSA, SSB, RNP, Jo-1, Scl-70). A larger study with prospectively collected data is needed to better define the relationship between "idiopathic" and "connective tissue disease-related" NSIP. (See "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes".)

Hypersensitivity pneumonitis — In some patients with hypersensitivity pneumonitis (also called extrinsic allergic alveolitis), surgical lung biopsy lacks the characteristic poorly formed granulomata and multinucleated giant cells and has an appearance more typical of NSIP [23]. In patients with chronic bird fancier's lung, 13 of 26 had NSIP; most had some multinucleated giant cells, but only one-fourth had granulomas [24]. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis".)

Drug-associated NSIP — Many drugs, including but not limited to flecainide, amiodarone, methotrexate, carmustine, nitrofurantoin, statins, and chlorambucil have been associated with an NSIP pattern [25-31].

HIV infection — NSIP is less frequently identified in patients with HIV-infection since the widespread use of antiretroviral therapy (ART), but still occurs [32,33]. In one observational study of 110 patients with AIDS and interstitial lung disease, NSIP was detected in 38 percent [34]. A study performed since the introduction of ART found that 7 percent of HIV patients admitted with ILD had NSIP [35]. Nearly half of these patients had normal chest radiographs.

Other — NSIP has also been associated with immunoglobulin G4 (IgG4)-related systemic disease [36,37], familial interstitial pneumonia [38,39], and graft versus host disease (GVHD) [40]. Cigarette smoking may also be a factor [41-43]. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

PATHOGENESIS — The understanding of the pathogenesis of idiopathic NSIP and other idiopathic interstitial pneumonias (IIPs) is evolving. A potential relationship between NSIP and usual interstitial pneumonia (UIP) is suggested by the commonality of associated diseases, exposures (eg. cigarette smoking), and genetic mutations, in addition to the observation that individual patients can harbor histopathologic lesions of both UIP and NSIP [44,45]. The exact nature of this association is not known.

Potential contributors to the development and perpetuation of NSIP include epithelial injury and disregulated repair, involvement of the immune system (based on autoimmune features of idiopathic NSIP and the presence of lymphocytes in alveolar septae and bronchoalveolar lavage), and abnormal fibroblast/myofibroblast function leading to excess deposition of collagen. Some of these processes are discussed in the context of UIP/idiopathic pulmonary fibrosis (IPF). (See "Pathogenesis of idiopathic pulmonary fibrosis".)

CLINICAL FEATURES — NSIP that is not clearly associated with an underlying cause typically occurs in middle-aged females (67 percent) who are never smokers (69 percent) [46]; NSIP associated with connective tissue disease (CTD) has an equal distribution between males and females. As noted above, some patients with NSIP have idiopathic disease, while others have a predisposing underlying disease or exposure. In a given patient, the clinical features can be limited to those attributable to NSIP or may reflect extrapulmonary manifestations of the associated process. As an example, a known CTD may be present, or features suggestive but not diagnostic of CTD may be present. (See 'Interstitial pneumonia with autoimmune features' above.)

●History – The most common symptoms of NSIP are dyspnea and cough that have developed subacutely over weeks to months [3,4,47]. About one-third of patients have fever or flu-like symptoms. Depending on whether an underlying CTD is present, patients may also report dry mouth or eyes, joint pain or swelling, muscle tenderness or weakness, Raynaud phenomenon, rash or other skin changes, or neurologic symptoms.

Occasional patients with apparent idiopathic NSIP may develop CTD after the diagnosis of NSIP. In a series of 35 patients initially diagnosed with idiopathic NSIP, 17 percent were subsequently diagnosed with dermatomyositis, Sjögren's disease, or rheumatoid arthritis [48].

●Physical examination – The majority of patients have bibasilar crackles, but only 10 to 35 percent have clubbing [49]. Careful attention should be paid to identifying stigmata of rheumatic disease. Nail bed capillaroscopy may be helpful if systemic sclerosis is suspected.

EVALUATION — NSIP is typically suspected in patients with subacute onset of dyspnea and cough and radiographic evidence of interstitial lung disease. The assessment of patients with suspected NSIP requires a synthesis of clinical, laboratory, pulmonary function, radiographic, and (sometimes) histopathologic data [46,50]. An important component of the evaluation is determining whether the patient has any predisposing conditions or exposures [51,52]. (See 'Definition' above and "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing" and "Idiopathic interstitial pneumonias: Classification and pathology".)

As cigarette smoking is associated with a number of idiopathic interstitial pneumonias (IIPs), patients who smoke should be advised to stop smoking even prior to making a diagnosis.

Clinical review — Given the broad differential diagnosis of interstitial lung disease, a detailed history is important to narrow the possibilities. Patients should be asked about exposure to airborne organic antigens (eg, barns, birds, hot tubs, humidifiers, mold, plastic/epoxy manufacture) [53]. A complete list of current and recent medications should be reviewed for agents associated with NSIP; patients should be asked about any history of radiation therapy; and risk factors for HIV infection should be assessed. (See "Approach to the adult with interstitial lung disease: Clinical evaluation", section on 'History' and 'Drug-associated NSIP' above.)

As with any patient being evaluated for interstitial lung disease, nonpulmonary symptoms and signs should be assessed, as described in the table (table 5) [52].

Laboratory tests — No laboratory tests are specific for NSIP. However, in the evaluation of patients with dyspnea, cough, and pulmonary radiographic opacities, the usual laboratory tests include a complete blood count and differential, blood urea nitrogen, creatinine, hepatic function tests, brain natriuretic peptide, and urinalysis (table 6). (See "Approach to the adult with interstitial lung disease: Diagnostic testing".)

For patients without a known CTD, we typically obtain an antinuclear antibody, rheumatoid factor, and anti-citrullinated peptide antibodies, early in the course of the evaluation of ILD. If a systemic rheumatic disease is suspected on the basis of extrathoracic symptoms or signs, we also obtain serologic testing appropriate to those findings (table 6) [18,54,55]. A broader panel of serologic tests is obtained, as needed, based on results of initial testing and after a diagnosis of NSIP has been made.

The utility of screening panels for hypersensitivity pneumonitis (HP) is unclear due to problems with specificity. We typically reserve serologic testing for HP for patients with a historical risk factor (eg, occupational or environmental exposures). (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis", section on 'Laboratory tests'.)

Testing for HIV infection should be performed unless it can be excluded on the basis of clinical history [52]. (See "Screening and diagnostic testing for HIV infection".)

Pulmonary function tests — Pulmonary function tests (PFTs) are obtained in most ambulatory adults with dyspnea and cough to determine whether the symptoms are associated with an obstructive or restrictive impairment and whether a gas transfer defect is present. Generally, testing includes spirometry, lung volumes, diffusing capacity for carbon monoxide (DLCO), and a six-minute walk test with assessment of oxygen saturation. While pulmonary function testing is not essential for making the diagnosis of NSIP, monitoring forced vital capacity (FVC) and DLCO is helpful for assessing baseline respiratory impairment, disease progression, response to therapy, and prognosis [56].

In patients with NSIP, PFTs typically demonstrate a restrictive ventilatory defect (decreased FVC and total lung capacity [TLC]) and impaired gas transfer manifested by a decrease in DLCO and/or desaturation during ambulatory oximetry [53]. Mild resting hypoxemia may be present at diagnosis [52]. (See "Overview of pulmonary function testing in adults".)

Chest imaging studies — A chest radiograph is obtained in virtually all adults with persistent symptoms of dyspnea and cough, particularly in the presence of fever. High-resolution computed tomography (HRCT) scans should be obtained in all patients suspected of having NSIP on the basis of an abnormal conventional chest radiograph or impaired gas transfer. In addition to aiding the diagnosis, serial HRCT scans may be useful to assess disease improvement or progression [57-62]. (See "High resolution computed tomography of the lungs".)

●Chest radiograph – Chest radiographs of NSIP typically show bilaterally increased markings with a basilar predominance [63].

●High-resolution computed tomography – HRCT scans should be noncontrast with images obtained at full inspiration, unless expiratory views are needed to look for areas of air trapping (eg, in hypersensitivity pneumonitis). Prone views are often obtained in addition to supine to make sure that dependent atelectasis is not mistaken for interstitial disease.

The most frequent HRCT findings in NSIP are increased reticular markings (87 percent), traction bronchiectasis (82 percent), lobar volume loss (77 percent), and ground glass opacification (GGO, 42 percent), predominantly in the lower lung zones (92 percent) [46,64]. Other studies have found GGO in up to 94 percent of NSIP [65]. Bibasilar GGO that spares the subpleural region is the most characteristic HRCT appearance in NSIP, but is not pathognomonic and was only observed in 21 percent of one series [65]. When present, it is often associated with manifestations of fibrosis such as volume loss, reticular pattern, and/or traction bronchiectasis.

The HRCT features of idiopathic NSIP compared to CTD-related NSIP are similar [2-4,9,23,47,57-61,66-76].

Honeycomb change is rare with NSIP; a predominance of honeycombing relative to ground glass attenuation suggests UIP [77-79].

Unlike UIP/IPF where HRCT can at times supplant the need for a surgical lung biopsy, the ability of HRCT to make an accurate diagnosis of NSIP is more limited [80]. This is in part related to variable inter-reader interpretations of HRCT [81]. Several series have evaluated the ability of HRCT to make a diagnosis of NSIP (as confirmed by surgical lung biopsy). The accuracy ranges from 66 to 68 percent [71,79].

Bronchoalveolar lavage — Bronchoalveolar lavage (BAL) findings in NSIP are nonspecific, and BAL cell counts cannot be utilized to differentiate NSIP from other IIPs [82]. The main role of BAL in patients with imaging findings suggestive of NSIP is to exclude other causes of diffuse opacities, such as hemorrhage, infection and malignancy. As a result, BAL is not typically used for the evaluation of suspected IIP unless hypersensitivity pneumonitis, malignancy, or opportunistic infection is likely. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

In some reports, a higher percentage of lymphocytes was noted in bronchoalveolar lavage (BAL) from patients with NSIP compared with UIP [3,4,47,66]; however, this is not always the case [67,82]. In addition, several other ILDs have BAL lymphocytosis, making this a nonspecific finding. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Lymphocytic BAL'.)

DIAGNOSIS — A definitive diagnosis of NSIP requires histopathologic analysis of a surgical lung biopsy specimen, accompanied by a multidisciplinary assessment when possible [52,54]. However, a surgical lung biopsy is not always needed to guide management. The need for a surgical lung biopsy to confirm the diagnosis of NSIP largely depends on the presence or absence of an underlying process known to be associated with NSIP and the severity of lung disease.

Clinical diagnosis based on multidisciplinary discussion (MDD) — Often a confident clinical diagnosis can be achieved through a MMD that reviews the clinical findings, evidence of associated diseases or exposures, laboratory data, and high-resolution computed tomography (HRCT) features. MDD is helpful to optimize diagnostic accuracy and ensure that subtle clinical and morphologic features and potential inciting drugs and exposures are not overlooked.

●Patients with a known connective tissue disease (CTD) and a clinical course and HRCT pattern consistent with NSIP generally do not need a lung biopsy. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Interstitial lung disease associated with systemic rheumatic disease'.)

●If drug-induced NSIP is suspected (eg, nitrofurantoin, flecainide, amiodarone, methotrexate, carmustine, statins), the culprit drug should be discontinued and lung biopsy deferred pending the response to drug discontinuation.

●Patients with exposure to agents associated with hypersensitivity pneumonitis (HP) should be evaluated with directed serologic tests, examination of HRCT for features of HP (table 7), and a trial of exposure avoidance (if feasible). Flexible bronchoscopy may be helpful if bronchoalveolar lavage fluid is lymphocytic (>20 percent), particularly if the CD4/CD8 lymphocyte ratio is <1. If confident exclusion of HP is not possible noninvasively, a lung biopsy (transbronchial, surgical) is often needed. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis".)

Surgical lung biopsy — When a confident clinical diagnosis remains unclear after MDD, the decision to proceed with surgical lung biopsy often depends on the severity of lung disease. Patients with mild respiratory impairment may prefer to wait for evidence of progression prior to lung biopsy. At the other end of the spectrum for patients with severe respiratory impairment, the benefits of a secure diagnosis need to be carefully weighed against the risks of surgical biopsy in the patients with severe respiratory impairment. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

For definitive diagnosis of diffuse interstitial lung disease, surgical lung biopsy via VATS or thoracotomy is the standard; transbronchial cryobiopsy (cryo-TBB) is gaining acceptance, but is not considered to be a replacement for surgical lung biopsy. Transbronchial lung biopsy (TBLB) has a low diagnostic yield in the IIPs and is generally avoided when NSIP is suspected. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

Ideally, when evaluating interstitial lung disease, surgical samples are obtained from more than one lobe and are greater than 4 cm in the greatest dimension when inflated and include a depth from the pleural surface of 3 to 5 cm. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Specimen collection'.)

Histopathology and interpretation — Histopathologic examination by an experienced lung pathologist is essential, and most cases require careful clinical and pathological correlation to arrive at the most accurate final diagnosis [83-85]. Although the histopathologic features of NSIP are well defined, the differentiation of NSIP from other IIPs, particularly idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP), is difficult and even expert pathologists may disagree on a particular biopsy [86,87]. (See "Role of lung biopsy in the diagnosis of interstitial lung disease" and "Interpretation of lung biopsy results in interstitial lung disease".)

The histopathology of NSIP is characterized by the following features (picture 1A-B and table 2) [1,53]:

●Diffuse alveolar wall thickening by uniform fibrosis

●Preservation of the alveolar architecture when examined with elastin stains

●Expansion of alveolar septa by variably dense infiltrate of predominantly mononuclear inflammatory

●Overall pattern suggests temporal homogeneity

The histopathologic features do not fit the patterns of other IIPs such as UIP, desquamative interstitial pneumonia, respiratory bronchiolitis interstitial lung disease, cryptogenic organizing pneumonia, acute interstitial pneumonia, or lymphocytic interstitial pneumonia. While a few fibroblast foci and focal areas of organizing pneumonia may be present in NSIP, dense alveolar septal fibrosis, granulomas, conspicuous infiltration of lymphocytes or eosinophils, and temporal heterogeneity are absent. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Nonspecific interstitial pneumonia'.)

NSIP was initially divided into three groups, based upon the presence and extent of interstitial fibrosis: Group I with primarily interstitial inflammation (picture 1A), Group II with both inflammation and fibrosis, and Group III with primarily fibrosis (picture 1B). Group III is distinguished from UIP by the absence of fibroblast foci and the presence of temporal homogeneity [2]. However, later studies found no prognostic difference between Groups II and III, so the subgroups were merged into two, cellular and fibrotic. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Pathology'.)

The classification of NSIP is further complicated by the fact that areas of both NSIP and UIP can be identified in the same patient when biopsies are taken from multiple locations. Studies evaluating patients with multiple lobe biopsies found a pattern of UIP in one lobe and NSIP in another lobe in 13 to 26 percent of patients [44,45]. These mixed NSIP/UIP cases had a similar prognosis to patients with UIP/IPF in all lobes.

Interstitial pneumonia with autoimmune features — Part of the role of interdisciplinary assessment is to determine whether NSIP is associated with an underlying CTD. In this process, some patients will be identified who do not meet criteria for a specific CTD, but have some subtle "autoimmune" features. An international consensus task force has proposed classifying such patients as having "interstitial pneumonia with autoimmune features" [19]. (See 'Interstitial pneumonia with autoimmune features' above.)

If not already performed, the serologic testing outlined in the table can help identify patients with IPAF (table 3). (See 'Interstitial pneumonia with autoimmune features' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of NSIP includes the other idiopathic interstitial pneumonias (IIPs), other diseases with histopathologic features of NSIP, such as rheumatic diseases (eg, rheumatoid arthritis, systemic sclerosis), chronic hypersensitivity pneumonitis, asbestosis, and certain drug-induced lung diseases.

●Other idiopathic interstitial pneumonias – Usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) is the IIP that has the greatest overlap with NSIP. The imaging findings and histopathology of UIP/IPF and the differentiating features of the various IIPs are discussed separately (table 4). (See "Idiopathic interstitial pneumonias: Classification and pathology" and "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis", section on 'Histopathology'.)

●Hypersensitivity pneumonitis – Certain imaging features help to differentiate hypersensitivity pneumonitis (HP) from NSIP. High-resolution computed tomography (HRCT) findings of centrilobular nodules, mosaic air-trapping, and upper lung zone distribution suggest HP rather than NSIP [1,64]. On histopathology, bronchiolocentric distribution of mononuclear and giant cell inflammation and poorly formed granulomas suggest HP. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis".)

●Immunoglobulin G4 (IgG4)-related systemic disease – A portion of patients with IgG4-related systemic disease have interstitial lung disease [36,37]. While some features are similar to NSIP, histopathology demonstrates infiltration of the lung interstitium with IgG4-positive plasma cells.

●Familial interstitial pneumonia – Among patients with familial interstitial pneumonia (FIP), a small portion have HRCT and histopathologic features consistent with NSIP, while the majority have features of UIP/IPF [38]. In a study of HRCT characteristics of FIP, patients with FIP were more likely to have a diffuse craniocaudal distribution of opacities, whether reticular or mixed reticular-ground glass, while UIP/IPF and NSIP are typically basilar predominant [39]. (See "Pathogenesis of idiopathic pulmonary fibrosis", section on 'Genetic predisposition'.)

●Hermansky-Pudlak syndrome – Hermansky-Pudlak syndrome is a rare genetic defect associated with oculocutaneous albinism, abnormal platelets, and fibrotic interstitial lung disease. While the lung disease is similar to UIP/IPF in most patients, some patients have features more typical of NSIP, such as onset at an earlier age (eg, thirties) reticular and ground glass opacities on HRCT, and on histopathology, temporal homogeneity, sparse mononuclear cell infiltration, and diffuse collagen deposition [88]. Foamy swelling of type II pneumocytes is a clue to the underlying HPS. (See "Hermansky-Pudlak syndrome".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Interstitial lung disease".)

SUMMARY AND RECOMMENDATIONS

●Definitions – Nonspecific interstitial pneumonia (NSIP) is one type of idiopathic interstitial pneumonia (IIP) (table 1). (See 'Introduction' above.)

●Histopathology – The histopathologic lesion characteristic of NSIP is thickening of the alveolar septum with varying degrees of inflammatory (mononuclear) cell infiltration and fibrosis in a pattern suggesting temporal homogeneity. The fibroblast foci and temporal heterogeneity typical of usual interstitial pneumonia (UIP) are rarely seen. (See 'Histopathology and interpretation' above.)

●Etiology – NSIP may be idiopathic or may be associated with connective tissue disease (CTD), certain drugs, human immunodeficiency virus infection, and hypersensitivity pneumonitis. (See 'Evaluation' above.)

●Clinical features – The onset of idiopathic NSIP is typically in the fifth or sixth decades of life, with both sexes affected equally. Most patients present with the insidious onset of dyspnea and cough. (See 'Clinical features' above.)

●Evaluation

•Laboratory studies – Laboratory testing is similar to that of other patients with suspected ILD (table 6). For patients with radiographically suspected or histologically determined NSIP without a known CTD, we typically obtain an antinuclear antibody, rheumatoid factor, and anticitrullinated peptide antibodies early in the course of the evaluation. Additional serologic testing is guided by extrathoracic symptoms or signs and results of initial testing. (See 'Laboratory tests' above.)

•Pulmonary function testing (PFTs) – PFTs generally include spirometry, lung volumes, diffusing capacity for carbon monoxide (DLCO), and a six-minute walk test with oximetry. NSIP is typically associated with a restrictive ventilatory defect and a low diffusing capacity with or without exertional oxygen desaturation. (See 'Pulmonary function tests' above.)

•Chest imaging – Bibasilar diffuse ground glass or reticular opacities are typical findings on chest radiograph. High-resolution computed tomography (HRCT) usually shows ground glass and reticular opacities, predominantly in the lower lung zones. Traction bronchiectasis and lobar volume loss may be present, but honeycombing is generally absent. (See 'Chest imaging studies' above.)

●Diagnosis

•Patients with connective tissue disease or HIV – For patients with known underlying connective tissue disease or HIV infection AND HRCT findings consistent with NSIP, histopathologic confirmation of NSIP is generally not necessary. (See 'Diagnosis' above.)

•Other patients – For most patients without an underlying process known to be associated with NSIP, lung biopsy obtained by thoracoscopy or thoracotomy and multidisciplinary clinicopathologic correlation are needed to confirm a diagnosis of NSIP. (See 'Diagnosis' above.)

For patients with confirmed or radiographically suspected NSIP, every effort should be made to identify any exposure or concomitant systemic disease that may be contributory. (See 'Histopathology and interpretation' above.)

●Differential diagnosis – The differential diagnosis of NSIP includes the other IIPs (table 1), chronic hypersensitivity pneumonitis, asbestosis, and certain drug-induced lung diseases. (See 'Differential diagnosis' above.)