INTRODUCTION — Nonspecific interstitial pneumonia (NSIP) can be idiopathic or can be seen in association with connective tissue disease, HIV infection, a variety of drugs, and hypersensitivity pneumonitis. When idiopathic, NSIP is considered one of the idiopathic interstitial pneumonias (IIPs), which also 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), and cryptogenic organizing pneumonia (COP) (table 1) . Idiopathic NSIP can present alone or in combination with one of the other IIPs.
The treatment and prognosis of NSIP will be reviewed here. The clinical manifestations, evaluation, and diagnosis of NSIP and the diagnosis and management of the other IIPs are discussed separately. (See "Causes, clinical manifestations, evaluation, and diagnosis of nonspecific interstitial pneumonia" and "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)".)
OVERVIEW OF TREATMENT — The treatment of NSIP depends on the cause, disease severity, and rate of progression. While the discussion in the sections that follow will emphasize the treatment for idiopathic NSIP, much of the support for treatment selections is based on experience in connective tissue associated NSIP.
●Drug or inhalational exposure – For patients with NSIP associated with a drug or inhalational exposure, the first step is to remove the inciting exposure. This alone may be adequate treatment. (See "Causes, clinical manifestations, evaluation, and diagnosis of nonspecific interstitial pneumonia", section on 'Definition'.)
●Connective tissue disease – For patients with NSIP complicating a known connective tissue disease (eg, polymyositis/dermatomyositis, rheumatoid arthritis, systemic sclerosis), specific therapies for those diseases may guide treatment of the NSIP. (See "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis" and "Overview of pleuropulmonary diseases associated with rheumatoid arthritis" and "Interstitial lung disease associated with Sjögren's disease: Clinical manifestations, evaluation, and diagnosis" and "Overview of pulmonary complications of systemic sclerosis (scleroderma)" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)
●HIV infection – For patients with HIV infection, case reports suggest that NSIP may improve spontaneously . Others have responded to systemic glucocorticoids in combination with antiretroviral therapy (ART). In the absence of more definitive data, a reasonable approach, after careful exclusion of infection (eg, Pneumocystis jirovecii, Histoplasma, mycobacteria, cytomegalovirus), is to initiate ART and reserve systemic glucocorticoids for patients who fail to improve [3,4].
Supportive care — In terms of supportive care, current smokers should be strongly advised to stop smoking; pneumococcal, coronavirus 2019 (COVID-19), and seasonal influenza vaccination should be offered as appropriate. (See "Overview of smoking cessation management in adults" and "Pneumococcal vaccination in adults" and "COVID-19: Vaccines" and "Seasonal influenza vaccination in adults".)
OBSERVATION FOR MILD STABLE DISEASE — Some patients with NSIP (less than 20 percent) improve or stabilize without therapy. These patients typically have few symptoms (eg, dyspnea with moderate exertion) and minimal impairment on pulmonary function testing. For these patients, it may be reasonable to defer therapy until there is evidence of disease progression. This approach has not been formally studied and should be limited to patients with mild, stable disease with close follow-up [5-8].
INITIAL THERAPY FOR MODERATE TO SEVERE DISEASE — For the majority of patients with NSIP who have moderate symptoms and impairment on pulmonary function testing, and also diffuse abnormalities on high resolution computed tomography (HRCT), we suggest initiation of systemic glucocorticoids. This advice is based on observational data and our clinical experience. As the experience treating NSIP in patients with a known connective tissue disease is greater than for idiopathic NSIP, some of the choices are based on extrapolation.
For most such patients, addition of a second immunosuppressive agent is deferred for three to six months, so the response to glucocorticoid therapy can be assessed. However, for patients with more severe initial disease, we often initiate oral glucocorticoids and an additional immunosuppressive agent together. The usual choices for initial therapy are azathioprine and mycophenolate [5,8-18]. Cyclophosphamide, rituximab, and calcineurin inhibitors are generally reserved for patients with disease that is refractory to initial therapy. (See 'Refractory disease' below.)
Glucocorticoids — The optimal dose and duration of glucocorticoid therapy is not known, and most studies of patients with idiopathic NSIP consist of a small number of patients and a variety of regimens [5,8-11,13-19].
●Dose and administration – We typically begin with prednisone 0.5 to 1 mg/kg ideal body weight per day up to a maximum of 60 mg/day for one month followed by 30 to 40 mg/day for an additional two months. Dosing for patients presenting with impending or actual respiratory failure is described below. (See 'Pulse methylprednisolone' below.)
For patients who respond or stabilize with treatment, the prednisone dose is gradually tapered. While the optimal treatment duration is unknown, we aim to reach 5 to 10 mg daily or on alternate days, by the end of six to nine months, with attempted cessation after at least one year of therapy [6,19]. In one series, relapse was associated with shorter duration of therapy (4.7 compared with 7.7 months) . In another series, the average treatment length was 17.4 +/- 12.1 months .
For patients who relapse when prednisone is tapered or discontinued, low-dose prednisone can be maintained for a longer period [10,20]. Or, if relapse occurs at higher prednisone doses, another immunosuppressive agent can be added as a glucocorticoid-sparing agent. (See 'Additional immunosuppressive drugs' below.)
●Adverse effects – Glucocorticoid treatment is associated with a variety of adverse effects . Thus, careful and ongoing assessment of risks and benefits is essential. (See "Major side effects of systemic glucocorticoids".)
Pneumocystis jirovecii pneumonia (PCP) prophylaxis is not routinely recommended for all patients taking glucocorticoids. However, in patients with underlying lung disease such as NSIP, it is reasonable to administer prophylaxis in patients on moderate to high doses of glucocorticoids (eg, prednisone 20 mg daily and above for >1 month) since PCP could significantly worsen lung function. In addition, it can be difficult to differentiate worsening of underlying NSIP from intercurrent PCP, if the patient experiences worsening symptoms. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
●Efficacy – A number of case series have described the response to glucocorticoids in NSIP, but no randomized trials have been performed.
•Among 35 patients with biopsy-proven NSIP, who received initial systemic glucocorticoids (median dose prednisolone 0.54 mg/kg per day) alone, 30 patients (86 percent) responded (>10 percent increase in forced vital capacity [FVC] and diffusing capacity for carbon monoxide [DLCO]) . Seven patients subsequently received cytotoxic agents because of disease progression or glucocorticoid dependence.
•A series of 83 patients with idiopathic and rheumatic disease-related NSIP were followed for a mean of 17.4 ±12.1 months; the histopathologic pattern was fibrotic in 72 and cellular in 11 . All but four patients received initial treatment with oral prednisolone (approximately 50 mg/day), which led to an improved FVC (defined as >10 percent increase) in 36 (53 percent) and a stable FVC in 19 (28 percent). The extent of disease on HRCT scan appeared to correlate with lung function results.
•Among a total of 47 patients from a number of smaller series (both idiopathic and secondary NSIP), treatment with glucocorticoids alone resulted in improvement in 35, stabilization in 6, and deterioration or death in 6 [5,8,10,11,14]. Despite an initial response, some patients subsequently experienced progressive worsening of lung function .
Pulse methylprednisolone — For patients with severe NSIP requiring hospitalization, pulse intravenous methylprednisolone may be preferred for initial therapy . A typical regimen is 1000 mg/day for three days followed by oral prednisone as dosed above (see 'Glucocorticoids' above). Rarely, patients need additional pulse doses [17,18].
Additional immunosuppressive drugs — For patients with more severe initial disease or an inadequate response to or intolerance of glucocorticoids, therapy is usually expanded to include an additional immunosuppressive drug, such as azathioprine or mycophenolate [5,8,10,11,17,22,23]. As these agents have not been assessed in clinical trials of idiopathic NSIP, the optimal choice of which agent to select and what time to initiate therapy is not known.
Due to their substantial adverse effects, cyclophosphamide, calcineurin inhibitors, and rituximab are usually reserved for refractory disease that has not responded to prednisone in combination with azathioprine or mycophenolate.
No randomized trials have assessed these therapies. All series have included concurrent glucocorticoid therapy. The specific choice of an additional agent varies with the clinical setting.
Azathioprine — Several regimens have been described for initiation of azathioprine (AZA). A common regimen is to start with 25 to 50 mg/day and increase by 50 mg increments every 7 to 14 days up to 1.5 to 2 mg/kg per day, but not exceeding a maximum total dose of 200 mg/day. A lower dose is indicated in renal insufficiency.
The most common side effects of AZA at these doses include gastrointestinal intolerance, bone marrow suppression, and infection. Divided doses may be used to decrease gastrointestinal toxicity. These and other side effects should be discussed with the patient and are reviewed separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)
The toxicity of AZA is predominantly related to the activity of thiopurine methyltransferase (TPMT) . Both genotyping and functional assays for this enzyme are now available commercially. Many clinicians perform one test or another before initiating azathioprine therapy. These issues are discussed in detail separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and azathioprine toxicity' and "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease".)
AZA has been associated with an increased risk of bacterial and opportunistic infections, but some of the increased risk may be attributable to concomitant glucocorticoid therapy . Based on guidance from the American Thoracic Society, we suggest prophylaxis during combined therapy with prednisone ≥20 mg daily and AZA . (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
Mycophenolate mofetil — Mycophenolate mofetil (MMF) is an inhibitor of lymphocyte proliferation that is often used in the treatment of systemic rheumatic disease and has shown efficacy in the treatment of interstitial lung disease associated with systemic sclerosis (scleroderma). (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Choice of initial agent'.)
●Dose and administration – The target dose of MMF is generally between 1.5 and 3 g daily, usually in two divided doses (eg, 0.75 to 1.5 twice daily). Starting with lower doses, such as 500 mg twice daily, and increasing to the target dose over three to four months may improve a patient's gastrointestinal tolerance of MMF. Dose adjustments for renal insufficiency and drug interactions are described separately. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)
The optimal duration of MMF therapy for NSIP is unknown.
●Efficacy – In a retrospective study of 56 patients with interstitial pneumonia with autoimmune features (IPAF) and HRCT scans most consistent with NSIP or NSIP with organizing pneumonia, the most common treatment regimen was the combination of glucocorticoids and MMF . Pulmonary physiology was stable and no deaths were reported with this regimen over approximately six years of follow-up.
●Adverse effects – Gastrointestinal symptoms and dose-related bone marrow suppression are the most commonly observed adverse effects, but these usually resolve with dose adjustments. Pneumocystis pneumonia has been described in patients with connective tissue disease taking MMF and glucocorticoids . The indications for PCP prophylaxis are discussed separately. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Adverse effects' and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
REFRACTORY DISEASE — A minority of patients have progressive respiratory impairment despite therapy with systemic glucocorticoids and an additional immunosuppressive agent (see 'Additional immunosuppressive drugs' above). Therapeutic choices for these patients are based on the experience with connective tissue disease-related interstitial lung disease, as randomized trials have not been done in patients with idiopathic NSIP. The antifibrotic agent nintedanib may be an option for patients with evidence of progressive fibrotic lung disease.
Cyclophosphamide — For patients who have rapidly progressive initial disease or have progressed despite glucocorticoids and a second line immunosuppressive agent, treatment with cyclophosphamide (CYC) may have a beneficial effect, based on limited data from case series and clinical experience in lung disease associated with connective tissue diseases (eg, systemic sclerosis). Some authors have used a combination of cyclophosphamide with initial pulse dose glucocorticoids for rapidly progressive initial disease [17,18].
●Dose and administration – When using CYC for NSIP, we prefer monthly intravenous dosing over daily oral dosing, due to the lower risk of bladder toxicity, based on the protocol used for interstitial lung disease (ILD) in systemic sclerosis. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Cyclophosphamide' and "General toxicity of cyclophosphamide in rheumatic diseases".)
The initial dose is based on body surface area (BSA) and adjusted for age, obesity, and renal impairment. Subsequent dosing is based on response to therapy and monitoring of hematologic toxicity.
Adequate hydration should be given prior to and for 24 hours after infusion of CYC to reduce the risk of hemorrhagic cystitis. Mercaptoethane sulfonate (mesna), which binds and detoxifies acrolein, may be used to minimize the risk of bladder toxicity, although data in support of using mesna in this setting are limited. (See "General principles of the use of cyclophosphamide in rheumatic diseases".)
A trial of at least three to six months of cyclophosphamide is needed to ensure an adequate opportunity for clinical response. Because of toxicity with long-term use, cyclophosphamide is usually discontinued after 6 to 12 months or transitioned to a less toxic agent for maintenance.
Cyclophosphamide has important hematologic, bladder, and gonadal toxicity. These potential effects should be fully discussed with the patient. CYC has also been reported to be a risk factor for Pneumocystis pneumonia, so we suggest administering prophylaxis . (See "General toxicity of cyclophosphamide in rheumatic diseases" and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
●Efficacy – The use of monthly intravenous CYC was examined in a series of 54 patients with known or suspected idiopathic NSIP; all but two patients received concomitant prednisolone (mean dose 11±5 mg/day) . After six months of CYC, pulmonary function was stable in 25 (46 percent) after previously declining, worsened in six, and led to death in one. A substantial variability in response was noted with a borderline improvement in diffusing capacity for carbon monoxide (DLCO) of 6.8 percent (-74.6 to 92 percent) and a borderline decrease in forced vital capacity (FVC) of -0.5 percent (-22 to 102.2 percent), but broad confidence intervals.
Rituximab — Rituximab, the chimeric immunoglobulin G1 (IgG1) monoclonal antibody to CD20-positive B cells, has shown mixed results in case series of connective tissue disease-associated interstitial lung disease (CTD-ILD).
●Dose and administration – A variety of rituximab dosing regimens have been used; in rheumatic diseases, such as rheumatoid arthritis and polymyositis/dermatomyositis, the trend is to administer two doses of 1 g, intravenously, one or two weeks apart. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis" and "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults".)
Adverse effects of rituximab include infusion reactions, development of antibodies to rituximab, viral and fungal infections, and hypogammaglobulinemia. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab'.)
●Efficacy – Support for the use of rituximab in NSIP comes primarily from its use in patients with connective tissue disease-interstitial lung disease (CTD-ILD) and imaging consistent with an NSIP pattern.
•In one trial, 122 patients with NSIP pattern on CT (including 37 patients with NSIP, 43 with CT-ILD, and 36 with interstitial pneumonia with autoimmune features) were randomized to rituximab and mycophenolate mofetil or mycophenolate mofetil and placebo for six months . Approximately 75 percent of patients had been previously treated with glucocorticoids and 30 percent with other immunosuppressants. Compared with mycophenolate mofetil alone, the addition of rituximab resulted in a 3.6 percent improvement in FVC (95% CI 0.4-6.8) and improved progression free survival at six months, although other clinical outcomes were not changed. Infectious complications were more common in the rituximab group.
•In a series of 24 patients with CTD-ILD (mostly associated with rheumatoid arthritis) and a pattern consistent with NSIP on HRCT, the response to rituximab was variable, but overall rituximab did not have a glucocorticoid-sparing effect .
•In a separate series, 24 patients with CTD-ILD were treated with rituximab because of continued decline in pulmonary function with other immunosuppressive agents . After rituximab, FVC improved or stabilized (mean change 4.1 percent, 95% CI 0.9-7.2). Imaging showed improvement or stability in 11 patients and deterioration in 9. Four patients with antisynthetase syndrome experienced improvement in FVC >10 percent.
•A series of 10 patients with systemic sclerosis-ILD experienced a 19 percent improvement in DLCO and a 13 percent increase in FVC .
Calcineurin inhibitors — Data on the use of the calcineurin inhibitors, cyclosporine and tacrolimus, for NSIP are limited to observational series. Until more data are available, use of cyclosporine and tacrolimus is generally reserved for refractory disease.
●Dose and administration – The dose and target trough levels of calcineurin inhibitors vary with the disease being treated. Cyclosporine and tacrolimus should be administered at a consistent time of day. In a series of patients with acute interstitial pneumonia, the dose of cyclosporine was 50 to 200 mg/day, trough level 100 to 150 ng/mL . In a study of interstitial lung disease associated with polymyositis/dermatomyositis (PM/DM), cyclosporine was titrated to a trough level of 150 ng/mL and two hour peak level of 1000 ng/mL . For tacrolimus, a starting dose of 1 to 3 mg/day, targeting a trough level of 5 to 20 ng/mL, has been reported [35,36]. (See "Pharmacology of cyclosporine and tacrolimus".)
•In two small observational series, the addition of cyclosporine led to stabilization or clinical improvement in seven of nine patients who had not responded to prednisone alone and one patient who was refractory to both prednisone and cyclophosphamide [8,23].
•Tacrolimus was associated with longer progression-free survival compared with conventional therapy in patients with interstitial lung disease due to polymyositis/dermatomyositis , but use of tacrolimus for idiopathic NSIP has not been reported.
Nintedanib — Nintedanib has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for use in patients with idiopathic pulmonary fibrosis (IPF), systemic sclerosis-interstitial lung disease (SSc-ILD), and progressive chronic fibrosing ILD of other origin (eg, rheumatoid arthritis, fibrotic hypersensitivity pneumonitis) . The role of nintedanib in NSIP remains controversial, as much of the supportive evidence is indirect. UpToDate contributors are divided on the use of nintedanib in progressive fibrosing NSIP, with some favoring limited use in patients who meet the criteria used in the INBUILD study and others preferring to await additional supportive data.
The benefit of nintedanib in progressive chronic fibrosing ILD was demonstrated in a randomized trial that included 663 patients with various fibrotic interstitial lung diseases affecting at least 10 percent of the lung on high resolution computed tomography (HRCT) . Additionally, participants met at least one of these three criteria in the preceding two years: a decrease in FVC of at least 10 percent of predicted value, a decrease in FVC of 5 to 10 percent of predicted value with worsening symptoms and/or increased extent of HRCT fibrosis; or worsening symptoms and increased extent of HRCT fibrosis. Idiopathic NSIP was present in 19 percent of the subjects. After 52 weeks, nintedanib slowed the overall adjusted rate of decline in FVC with a between-group difference of 107 mL/year (95% CI 65.4 to 148.5). The results of this trial were not able to show a benefit for subjects with NSIP. Additional details of the trial and the use of nintedanib in IPF and SSc are described separately. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Treatment, prognosis, and prevention", section on 'Antifibrotic agents' and "Treatment of idiopathic pulmonary fibrosis", section on 'Nintedanib' and "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Nintedanib'.)
ONGOING MONITORING — The response to therapy should be assessed at one month, and then at three to six month intervals, or sooner, if the patient has more severe initial disease or reports worsening symptoms.
We monitor respiratory symptoms (eg, dyspnea, exercise tolerance, cough), development of extrapulmonary symptoms suggestive of connective tissue disease, and pulmonary function tests (eg, spirometry, diffusing capacity for carbon monoxide, oximetry, six-minute walk test) [39,40]. Interval high resolution computed tomography (HRCT) is performed when changes in the clinical assessment and/or pulmonary function tests suggest worsening disease or an intercurrent process. (See "Overview of pulmonary function testing in adults".)
For patients with more severe disease or a sudden decrease in exercise tolerance, we assess for development of pulmonary hypertension, thromboembolic disease, infection, and other comorbid diseases (eg, heart failure, muscle weakness).
For patients on immunosuppressive therapy, monitoring includes assessment for drug-related adverse effects, such as bone marrow suppression, impaired renal function, and liver inflammation, and depends on the specific agent(s) being used. Most patients on glucocorticoids plus additional immunosuppressive agent will be candidates for Pneumocystis jirovecii prophylaxis. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
Acute exacerbations — Acute exacerbations, similar to those seen in idiopathic pulmonary fibrosis, can occasionally complicate the course of NSIP. While the diagnosis and management of acute exacerbations have not been specifically described for NSIP, we manage these patients similarly to acute exacerbations of IPF, pending NSIP-specific guidance. (See "Acute exacerbations of idiopathic pulmonary fibrosis".)
LUNG TRANSPLANTATION — Patients with severe NSIP that is progressive and disabling despite immunosuppressive therapy may be considered for lung transplantation . Between 2004 and 2015, 189 patients with idiopathic NSIP underwent lung transplantation according to the International Society for Heart and Lung Transplantation . Patients with interstitial lung disease have a median survival after lung transplantation of 4.8 years, which is slightly less than the median survival of 5.6 years for patients with COPD . The indications for lung transplantation for NSIP are similar to those for other interstitial lung diseases. (See "Lung transplantation: General guidelines for recipient selection" and "Treatment of idiopathic pulmonary fibrosis", section on 'Indications and choice of procedure'.)
PROGNOSIS — The overall prognosis and response to therapy for idiopathic NSIP is favorable compared to idiopathic pulmonary fibrosis/usual interstitial pneumonitis (IPF/UIP) [1,13,43], although substantial heterogeneity is noted . Approximately two-thirds of treated patients with idiopathic NSIP are stable or improved in long-term follow-up, but a 15 to 26 percent mortality at five years is noted [1,8,19,44].
The prognosis of histopathologic NSIP appears to be influenced by the underlying cause. In a retrospective study, survival was similar for NSIP associated with undifferentiated connective tissue disease (UCTD) and known CTD and better for UCTD-NSIP than for idiopathic NSIP (p = 0.02) . A pattern of NSIP with an overall clinical diagnosis of chronic hypersensitivity pneumonitis was an independent predictor of mortality (hazard ratio 2.17, 95% CI 1.05–4.47).
The results on serial pulmonary function testing may be a better prognostic indicator than baseline histopathology [46-48]. In a series of patients with IPF/UIP (n = 61) and NSIP (n = 43), the patients with NSIP had a longer median survival than those with UIP/IPF (56 versus 33 months), but this difference did not appear until after two years of follow-up . Histopathology (UIP versus NSIP) predicted prognosis as a baseline factor and at six months when changes in pulmonary physiology were examined. After 12 months of follow-up, performance on pulmonary function tests predicted subsequent mortality while histopathology was no longer predictive. Change in diffusing capacity for carbon monoxide (DLCO) was the strongest determinant of mortality at 12 months of follow-up.
FUTURE DIRECTIONS — The antifibrotic agents pirfenidone and nintedanib slow disease progression in idiopathic pulmonary fibrosis (IPF), raising the possibility that they might be beneficial in patients with progressive fibrotic NSIP [38,49]. Further study is needed to determine the efficacy of pirfenidone and nintedanib in progressive fibrotic NSIP and to clarify the patients most likely to benefit. (See 'Nintedanib' above and "Treatment of idiopathic pulmonary fibrosis", section on 'Medical therapies'.).
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
●Overview – The treatment of nonspecific interstitial pneumonia (NSIP) depends on the cause, disease severity, and rate of progression. While the discussion in the sections that follow will emphasize the treatment for idiopathic NSIP, much of the support for treatment selections is based on experience in connective tissue-associated NSIP. (See 'Overview of treatment' above.)
In terms of supportive care, current smokers should be strongly advised to stop smoking; pneumococcal, coronavirus 2019 (COVID-19), and seasonal influenza vaccination should be offered as appropriate. (See 'Supportive care' above.)
●Avoidance of contributory exposures – Patients with exposure to potential culprit drugs (eg, amiodarone, methotrexate, nitrofurantoin, statins) or inhalational agents (eg, organic dusts) should avoid further exposure. This alone may be adequate treatment. (See 'Overview of treatment' above.)
●Observation for mild disease – Patients who have mild disease based on minimal symptoms and near normal pulmonary function may be observed for a period of time without treatment. Symptoms and pulmonary function should be reassessed every three to six months, and therapy initiated if there is progression. (See 'Observation for mild stable disease' above.)
●Glucocorticoids for moderate to severe disease – For the majority of patients with moderate to severe NSIP or with mild disease that has progressed, we suggest initial treatment with systemic glucocorticoids (Grade 2C). The usual regimen is the equivalent of oral prednisone 1 mg/kg (eg, 40 to 60 mg/day) per day for the first month. Initial pulse methylprednisolone may be used for more severe disease. For patients who respond, prednisone is gradually tapered, as tolerated, to 5 to 10 mg daily or on alternate days by the end of 6 to 9 months with attempted cessation after one year. (See 'Initial therapy for moderate to severe disease' above.)
●More severe or worsening disease – For patients with more severe disease at presentation, worsening lung function despite glucocorticoids, or inability to taper glucocorticoids, we suggest addition of another immunosuppressive agent (Grade 2C), such as mycophenolate or azathioprine; data are insufficient to guide selection between these. Calcineurin inhibitors are a rarely used alternative. (See 'Additional immunosuppressive drugs' above.)
●Refractory disease – For patients who do not respond to the combination of glucocorticoid therapy and azathioprine or mycophenolate, changing the immunosuppressive agent to cyclophosphamide, rituximab, or a calcineurin inhibitor may be beneficial, although data are limited. UpToDate contributors have differing opinions about the use of nintedanib for NSIP that meets criteria for progressive chronic fibrosing ILD. (See 'Refractory disease' above.)
●Monitoring – The response to therapy should be assessed at one month, and then at three to six month intervals, or sooner, if the patient reports worsening symptoms. Assessment usually includes symptoms (eg, dyspnea, exercise tolerance, cough), physical examination, spirometry, lung volumes, diffusing capacity for carbon monoxide (DLCO), and six-minute walk testing with oximetry. Interval high resolution computed tomography (HRCT) is performed less often, depending on changes in the clinical assessment and pulmonary function tests. (See 'Ongoing monitoring' above.)
●Pneumocystis prophylaxis – We suggest Pneumocystis prophylaxis for any patient with NSIP receiving moderate to high dose glucocorticoid (≥20 mg per day) and a second immunosuppressive agent (Grade 2C). Some experts also administer Pneumocystis prophylaxis to patients on monotherapy with moderate to high dose glucocorticoids. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis' and "Major side effects of systemic glucocorticoids".)
●Lung transplantation – Rarely, patients will develop advanced lung disease despite immunosuppressive therapy and are potential candidates for lung transplantation. (See 'Lung transplantation' above and "Lung transplantation: General guidelines for recipient selection".)
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