CONTENTS
abbreviations used in the pulmonary section:
- ABPA: Allergic bronchopulmonary aspergillosis 📖
- AE-ILD: Acute exacerbation of ILD 📖
- AEP: Acute eosinophilic pneumonia 📖
- AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
- ANA: Antinuclear antibody 📖
- ANCA: Antineutrophil cytoplasmic antibodies 📖
- ARDS: Acute respiratory distress syndrome 📖
- ASS: Antisynthetase Syndrome 📖
- BAL: Bronchoalveolar lavage 📖
- BiPAP: Bilevel positive airway pressure 📖
- CEP: Chronic eosinophilic pneumonia 📖
- COP: Cryptogenic organizing pneumonia 📖
- CPAP: Continuous positive airway pressure 📖
- CPFE: Combined pulmonary fibrosis and emphysema 📖
- CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
- CTEPH: Chronic thromboembolic pulmonary hypertension 📖
- DAD: Diffuse alveolar damage 📖
- DAH: Diffuse alveolar hemorrhage 📖
- DIP: Desquamative interstitial pneumonia 📖
- DLCO: Diffusing capacity for carbon monoxide 📖
- DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
- EGPA: Eosinophilic granulomatosis with polyangiitis 📖
- FEV1: Forced expiratory volume in 1 second 📖
- FVC: Forced vital capacity 📖
- GGO: Ground glass opacity 📖
- GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
- HFNC: High flow nasal cannula 📖
- HP: Hypersensitivity pneumonitis 📖
- IPAF: Interstitial pneumonia with autoimmune features 📖
- IPF: Idiopathic pulmonary fibrosis 📖
- IVIG: Intravenous immunoglobulin 📖
- LAM: Lymphangioleiomyomatosis 📖
- LIP: Lymphocytic interstitial pneumonia 📖
- MCTD: Mixed connective tissue disease 📖
- NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
- NSIP: Nonspecific interstitial pneumonia 📖
- NTM: Non-tuberculous mycobacteria 📖
- OP: Organizing pneumonia 📖
- PAP: Pulmonary alveolar proteinosis 📖
- PE: Pulmonary embolism 📖
- PFT: Pulmonary function test 📖
- PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
- PPFE: Pleuroparenchymal fibroelastosis 📖
- PPF: Progressive pulmonary fibrosis 📖
- PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
- RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
- RP-ILD: Rapidly progressive interstitial lung disease 📖
- TNF: tumor necrosis factor
- UIP: Usual Interstitial Pneumonia 📖
- NSIP is a chronic, progressive fibrotic lung disease. It correlates with characteristic histologic and radiologic patterns. It has many similarities with IPF (idiopathic pulmonary fibrosis). However, NSIP is different from IPF in several important ways:
- (1) IPF is a primarily fibrotic process that doesn't respond to immunosuppression. In contrast, NSIP involves inflammation which subsequently triggers fibrosis. Thus, NSIP responds better to steroids and immunomodulation than IPF.
- (2) IPF is often an idiopathic process, whereas NSIP is usually caused by some other underlying disease process (e.g., rheumatological disease).
- NSIP may be divided into two forms: cellular NSIP and fibrotic NSIP.
- Cellular NSIP (~20%) has a greater component of acute inflammation. It may be more responsive to steroid or immunosuppression, with a greater degree of reversibility.
- Fibrotic NSIP (~80%) has a greater component of fibrosis. It is less responsive to immunosuppression, behaving similarly to IPF.
- NSIP is the second most common idiopathic interstitial pneumonia (after IPF). However, it is quite rare overall (accounting for ~7% of all interstitial lung diseases). (31172700)
- NSIP tends to affect younger patients (e.g., <50 years old) as compared to IPF (which only rarely affects people <50 years old).
- Most patients are women.
- Most patients lack a history of smoking.
- Most patients have some sort of rheumatologic disorder.
connective tissue disease-associated ILD (CTD-ILD) (~50%).
- Explanation:
- CTD-ILD may manifest with a variety of different forms of interstitial lung disease (table above). NSIP is the most common interstitial lung disease manifestation seen among patients with CTD-ILD. Such patients have both secondary NSIP and also CTD-ILD.
- Among patients initially presenting with idiopathic NSIP, about a third will eventually be diagnosed with a connective tissue disease. (Murray 2022)
- Diseases that most frequently cause CTD-ILD with NSIP:
- Polymyositis/dermatomyositis.
- Scleroderma.
- Other causes of CTD-ILD with NSIP:
- Rheumatoid arthritis.
- Sjogren syndrome.
- Mixed connective tissue disorder.
- Inflammatory bowel disease.
- Lupus (although NSIP is rather uncommon). (32279290)
medications (complete listing at PneumoTox: 📖):
- Amiodarone.
- Aripiprazole.
- Azathioprine
- Cancer therapies:
- Chemotherapy: Bleomycin, bortezomib, busulfan, carmustine (BCNU), cyclophosphamide, docetaxel, gemcitabine, hydroxyurea, leflunomide, lenalidomide, methotrexate, mitomycin C, mitoxantrone, paclitaxel, pemetrexed, R-CHOP, vincristine).
- Targeted therapy: Crizotinib, imatinib, osimertinib, vemurafenib.
- Immune checkpoint inhibitors.
- Carbamazepine.
- Clopidogrel.
- Fluoxetine.
- Hydrochlorothiazide.
- Interferon alpha/beta.
- Mesalamine.
- Nitrofurantoin.
- Phenytoin.
- Propylthiouracil.
- Rifampicin.
- Simvastatin
- TNF (tumor necrosis factor) inhibitors (adalimumab, etanercept, infliximab).
infection
- HIV has been associated with NSIP, but this is less common with modern therapies for HIV.
idiopathic NSIP
- The existence of truly idiopathic NSIP is debatable. Most of these patients likely have some underlying autoimmune process, which may not have yet fully manifested itself. (26564810) These patients often meet criteria for IPAF 📖 (interstitial pneumonia with autoimmune features).
- For patients who are diagnosed with idiopathic NSIP, intermittent review should be performed over time to evaluate for the emergence of an underlying rheumatological disorder.
general features of presentation:
- Progressive dyspnea, which may be subacute to chronic in duration.
- Nonproductive cough.
- Fever and constitutional symptoms may occur.
- Acute exacerbations of NSIP can occur (with acute deterioration within <1 month).
some clinical features of NSIP which can help distinguish it from IPF:
- NSIP may have a subacute onset over a few weeks, whereas IPF usually has a more chronic and insidious onset. However, NSIP patients usually have symptoms for several months prior to diagnosis.
- NSIP may cause fever in about a third of patients (whereas IPF doesn't usually cause fever).
- NSIP causes clubbing in only ~20% of patients, whereas IPF causes clubbing in ~65% of patients.
clinical features of an underlying connective tissue disease:
- Clinical features of connective disease should be sought. NSIP is often associated with connective tissue disorders (as listed above). In such patients, NSIP may present before diagnosis of the connective tissue disease.
- Some more common examples include:
- Skin changes.
- Digital ischemia.
- Small joint pain or swelling.
- Raynaud phenomenon.
- Photosensitivity.
- Sicca symptoms (dry mouth/eyes).
- Muscle weakness or tenderness.
Compared to IPF, NSIP is notable for greater homogeneity, more ground glass opacities, and less honeycombing. Further discussion of the distinction between IPF vs. NSIP is here: 📖
chest radiograph
- In 15% of patients with NSIP, the chest radiograph may be normal. (Walker 2019)
- Chest radiograph findings are generally reflective of CT findings (e.g., lower lung predominant opacities which may have associated reticulation). However, findings on chest X-ray are much less specific.
CT radiology of NSIP
distribution of radiologic findings
- (1) Distribution is invariably symmetric.
- (2) Distribution is lower lung predominant in 92% of patients. (32279290)
- (3) Distribution is usually peripheral on axial images. However,
- Relative subpleural sparing may occur in ~20-50% of patients, especially sparing of the dorsal regions of the lower lobes. (Walker 2019) If subpleural sparing is encountered, this essentially excludes UIP (usual interstitial pneumonia). (Murray 2022; Shepard 2019)
- Diffuse distribution in the axial plane is also possible. (26564810)
early radiologic findings of disease (corresponds with cellular NSIP)
- Diffuse ground glass opacity is usually the initial finding.
- Generally there is some evidence of a fibrotic process going on (e.g., reticulation and/or traction bronchiectasis).
- Reticulation (~50%) is common. In some patients, reticulation will resolve following steroid therapy, so reticulation doesn't necessarily indicate fibrosis.
- Scattered micronodules may occur.
late radiologic findings (corresponds with fibrotic NSIP)
- Ground glass opacities may remain the most notable feature.
- Reticulation may be somewhat more prominent.
- Traction bronchiectasis often occurs.
- Mild honeycombing can occur (~20% of patients):
- When honeycombing is present, it tends to be a minor finding (involving <10% of the lung parenchyma). (Walker 2019, Shepard 2019)
- Cysts may be smaller than those typically encountered in IPF (“microcystic honeycombing”).
- When present, honeycombing is associated with worse prognosis. (26564810)
other findings
- Lymphadenopathy is often present, but this is usually mild (10-15 mm) and involving only one or two nodal stations. This is similar to lymphadenopathy seen in IPF. (Walker 2019)
- CTD-ILD may cause a combination of NSIP plus OP (organizing pneumonia). If some radiological features of organizing pneumonia are seen (e.g., consolidation), this may raise this possibility. (26564810; 31172700) The radiology of organizing pneumonia is discussed further here: 📖
expiratory CT scan
- Given similarities between NSIP and HP (hypersensitivity pneumonitis), an expiratory CT scan may be helpful.
- If air trapping on expiratory CT scan is seen bilaterally and in three lobes, this is strongly suggestive of HP (rather than NSIP or IPF).
- If a three-density (aka, head cheese) sign is present, this is even more strongly suggestive of HP.
radiologic differentiation between IPF vs. NSIP
distribution
- Both IPF and NSIP usually have a peripheral, basal predominance.
- IPF is very heterogeneous.
- NSIP tends to be more uniform. Homogeneous involvement without an obvious predominance of disease in the lower lung would favor a diagnosis of NSIP.
- Subpleural sparing may occasionally be seen in NSIP (but not seen in IPF).
- Straight-edge sign:
- The straight edge sign refers to an imaginary line in the coronal projection below which abnormality occurs, and above which there is normal lung tissue.
- NSIP: Often has a bilateral straight-edge sign (example below).
- IPF: Usually lacks a straight-edge sign (because reticulation creeps up the lateral edges of the lungs).
extent of GGO (ground glass opacification)
- NSIP: GGO is often a dominant feature in NSIP.
- IPF: GGO can occur, but it should be less prominent than reticulation.
- In IPF, GGO usually occurs in areas with a finely reticulated pattern and traction bronchiectasis/bronchiolectasis. This form of “textured” GGO reflects alveolar fibrosis, rather than acute alveolitis. (36630775) Over time, these areas of textured ground glass opacity usually progress to frank fibrosis (reticulation and honeycombing). (Walker 2019)
- Predominant ground glass opacities make a diagnosis of IPF unlikely. However, an exception to this is an exacerbation of IPF, wherein the amount of ground glass opacity may increase dramatically.
extent of reticulation
- Reticulation is often a dominant feature in IPF.
- NSIP may cause reticulation as well, but this is often finer than is typically seen in IPF.
honeycombing
- The extent of honeycombing is probably the single strongest differentiator between IPF and NSIP. (Walker 2019)
- If honeycombing is the predominant finding, this is strongly suggestive of IPF.
- NSIP may cause some honeycombing, but it is less prominent.
evolution over time
- NSIP may cause ground glass opacities and fine reticulations that improve with steroid therapy. A dramatic response to steroid treatment favors the diagnosis of cellular NSIP (rather than IPF). However, failure to respond to steroid is nonspecific, since this could be consistent with either IPF or fibrotic NSIP.
basic laboratory studies
- Complete blood count with differential.
- Liver function tests.
- CRP (C-reactive protein).
- HIV serology.
complete serological evaluation for an underlying rheumatologic condition
- In the absence of a defined cause of NSIP, patients should probably receive a full serological evaluation.
- Extractable Nuclear Antigens (ENA panel) – anti-RNP, anti-Sm, anti-SSa (Ro), anti-SSb (La).
- MyoMarker panel – evaluation for idiopathic inflammatory myositis. (34488971) This is a send-out test to the Mayo Clinic (test ID FMYO3).
- Antinuclear antibody (ANA).
- RF (rheumatoid factor) and anti-citrullinated protein autoantibodies (ACPA).
- Anti-topoisomerase (Scl-70) antibody.
- Anti-double stranded DNA.
- Creatinine kinase (CK).
- Aldolase.
- Anti-U1-ribonucleoprotein antibody (anti-U1-RNP).
bronchoalveolar lavage
- Bronchoscopy with bronchoalveolar lavage cannot establish a diagnosis of NSIP. However, it may help exclude some alternative diagnoses (especially in subacute cases, where infection may be a greater consideration).
- Bronchoalveolar lavage in NSIP may show an increased lymphocyte fraction, especially in cellular NSIP (~29-47% lymphocytes). (26564810) However, there are numerous other causes of lymphocytic bronchoalveolar lavage, as discussed further here: 📖
- If bronchoalveolar lavage reveals elevated neutrophils, this may be suggestive of IPF. However, fibrotic NSIP may cause this as well: 📖
transbronchial biopsy
- Transbronchial biopsy is not recommended for the diagnosis of NSIP, because the specimen size is insufficient. (31172700)
understanding the significance of “NSIP pattern” on biopsy
- NSIP pattern on biopsy refers to a histopathological finding that involves more geographically and temporally uniform inflammation (as compared to IPF). NSIP pattern should have rare or no fibroblastic foci (whereas this is a hallmark of IPF).
- NSIP pattern on biopsy may be seen in the following clinical scenarios:
- Idiopathic NSIP.
- Secondary NSIP (e.g., due to a medication).
- Hypersensitivity pneumonitis (some patients may have areas of NSIP pattern and areas of HP; this usually corresponds clinically to HP).
- Organizing pneumonia (some patients may have areas of NSIP pattern and areas of OP; this usually corresponds clinically to connective tissue disease-related ILD).
- UIP (usual interstitial pneumonia) – some patients may have areas of NSIP pattern and areas of UIP pattern. This often corresponds clinically to IPF. (26564810)
- 💡 Thus, finding an NSIP pattern on biopsy thus is not necessarily diagnostic of clinical NSIP.
risks, modalities, & contraindications of biopsy
- Different options for obtaining lung tissue are discussed in the chapter on IPF here: 📖.
most closely related disorders:
- IPF (idiopathic pulmonary fibrosis).
- HP (hypersensitivity pneumonitis).
- HP/NSIP overlap:
- Some patients may display histopathological and radiological overlap between NSIP and HP.
- This tends to correspond to a clinical diagnosis of HP.
- OP (organizing pneumonia).
- NSIP/OP overlap:
- Some patients have histopathological and radiological overlap between NSIP and OP.
- Such patients frequently have CTD-ILD (connective tissue disease related-interstitial lung disease).
- DIP (desquamative interstitial pneumonia).
- LIP (lymphocytic interstitial pneumonia).
- Infection:
- HIV
- Pneumocystis.
related differential diagnoses:
overall diagnostic process for NSIP:
- This is generally similar to IPF.
- NSIP is diagnosed based on a combination of several sources of information:
- History & physical examination.
- Laboratory studies (especially evaluation for rheumatologic disorders).
- CT scan.
- Lung biopsy (in some cases).
- When logistically feasible, the diagnosis should be reached by a multidisciplinary conference.
diagnosis of secondary vs. idiopathic NSIP
- Diagnosis of secondary NSIP: Among patients with an established underlying cause of NSIP (e.g., rheumatologic disease or a causative medication), lung biopsy is not generally required for the diagnosis. However, sufficient evidence must be obtained to reasonably exclude competing diagnoses (e.g., infection).
- 💡 Among patients with known rheumatologic diseases, the treatment is generally the same regardless of the histology (e.g., NSIP vs. OP vs. NSIP-OP overlap). (26564810) Thus, pinning down a concrete histological diagnosis is clinically unnecessary.
- Diagnosis of idiopathic NSIP: Lung biopsy is generally required to obtain a definitive diagnosis. Unlike the diagnostic process with IPF, a CT scan alone is inadequate to reach the diagnosis of idiopathic NSIP. (31172700)
NSIP is more steroid-responsive than IPF. However, there is no high-level data regarding the optimal doses and schedules for immunosuppressive therapy. For patients with an underlying rheumatological disorder, co-management with a rheumatologist may help optimize the immunosuppressive regimen to treat both pulmonary and extrapulmonary symptoms.
treatment varies depending on the clinical context
- Occasional patients may remain stable or progress very slowly. Immunosuppression may not be beneficial for such patients (risks > benefits). However, close follow-up is mandatory (with serial imaging and PFTs). (Fishman 2023)
- Some patients may have an acute exacerbation of interstitial lung disease, for which aggressive treatment is needed (this is discussed further here: 📖).
- Most patients have subacute or chronic disease progression, warranting therapy.
immunosuppression
- Steroid:
- A trial of steroid is often utilized initially (e.g., 0.5-1 mg/kg ideal body weight prednisone up to a maximal dose of 60 mg/day, for a month). Subsequently, response may be determined based on repeat CT scan and pulmonary function tests. If steroid causes improvement, then further immunosuppression may be beneficial. Steroid may be tapered off very gradually over >6 months. During this process, patients may benefit from the introduction of a steroid-sparing agent.
- For patients with a more severe and acute presentation, starting with higher steroid for ~3 days may be reasonable (similar to the regimen utilized for an acute exacerbation of interstitial lung disease, discussed here: 📖).
- Mycophenolate mofetil: 💉 The Scleroderma Lung Study II found that mycophenolate was as effective as cyclophosphamide, yet with a superior safety profile. (27469583) Mycophenolate appears effective in other forms of connective tissue-related interstitial lung disease. (23457378)
- Azathioprine: 💉 A retrospective cohort study suggests that azathioprine is relatively safe and effective among patients with connective tissue-related interstitial lung disease. (32663826)
antifibrotic therapy
- Nintedanib is arguably supported by the most robust data in NSIP:
- Pirfenidone has also demonstrated some efficacy in non-IPF patients with progressive fibrotic lung disease.
- Survival is ~80% over five years and ~73% after ten years. (32279290) This is considerably more favorable than IPF.
- Cellular NSIP has a better prognosis than fibrotic NSIP.
- Prognosis is similar among patients with idiopathic NSIP as compared to NSIP associated with a connective tissue disease. (32279290)
deterioration of PFTs over time
- Deterioration in PFTs over time is a powerful prognostic factor:
- FVC reduction >10% within a year.
- DLCO reduction >15% within a year (ideally corrected for hemoglobin).
- Over time, serial PFTs become a more powerful prognostic factor than the initial histology (i.e., cellular NSIP vs. fibrotic NSIP vs. IPF). (32279290) This emphasizes the importance of obtaining serial PFTs and pursuing aggressive therapy for patients who are deteriorating.
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References
- 25923555 Shea BS, Sharma A, Mark EJ. Case records of the Massachusetts General Hospital. Case 14-2015. A 58-year-old woman with shortness of breath. N Engl J Med. 2015 Apr 30;372(18):1749-58. doi: 10.1056/NEJMcpc1415200 [PubMed]
- 26564810 Belloli EA, Beckford R, Hadley R, Flaherty KR. Idiopathic non-specific interstitial pneumonia. Respirology. 2016 Feb;21(2):259-68. doi: 10.1111/resp.12674 [PubMed]
- 31172700 Lee J, Kim YH, Kang JY, Jegal Y, Park SY; Korean Interstitial Lung Diseases Study Group. Korean Guidelines for Diagnosis and Management of Interstitial Lung Diseases: Part 3. Idiopathic Nonspecific Interstitial Pneumonia. Tuberc Respir Dis (Seoul). 2019 Oct;82(4):277-284. doi: 10.4046/trd.2018.0092 [PubMed]
- 32279290 Teoh AKY, Corte TJ. Nonspecific Interstitial Pneumonia. Semin Respir Crit Care Med. 2020 Apr;41(2):184-201. doi: 10.1055/s-0040-1708499 [PubMed]
Books:
- Shah, P. L., Herth, F. J., Lee, G., & Criner, G. J. (2018). Essentials of Clinical pulmonology. In CRC Press eBooks. https://doi.org/10.1201/9781315113807
- Shepard, JO. (2019). Thoracic Imaging The Requisites (Requisites in Radiology) (3rd ed.). Elsevier.
- Walker C & Chung JH (2019). Muller’s Imaging of the Chest: Expert Radiology Series. Elsevier.
- Palange, P., & Rohde, G. (2019). ERS Handbook of Respiratory Medicine. European Respiratory Society.
- Murray & Nadel: Broaddus, V. C., Ernst, J. D., MD, King, T. E., Jr, Lazarus, S. C., Sarmiento, K. F., Schnapp, L. M., Stapleton, R. D., & Gotway, M. B. (2021). Murray & Nadel’s Textbook of Respiratory Medicine, 2-Volume set. Elsevier.
- Fishman's: Grippi, M., Antin-Ozerkis, D. E., Cruz, C. D. S., Kotloff, R., Kotton, C. N., & Pack, A. (2023). Fishman’s Pulmonary Diseases and Disorders, Sixth Edition (6th ed.). McGraw Hill / Medical.