Home Educatione-Learning Nonspecific Interstitial Pneumonia
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Nonspecific Interstitial Pneumonia

PCCSU Volume 25, Lesson 21

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

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PCCSU Volume 25 Editorial Board

Editor-in-Chief
Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Mary E. Strek, MD, FCCP; and Imre Noth, MD, FCCP

Dr. Strek is Professor and Dr. Noth is Associate Professor, Department of Medicine, The University of Chicago, Chicago, Illinois.

Drs. Strek and Noth have disclosed no significant relationships with the companies/organizations whose products or services may be discussed within this chapter.

Objectives

  1. Define nonspecific interstitial pneumonia (NSIP) as a histopathologic diagnosis and distinct clinical entity.
  2. Understand the etiology and potential pathogenesis of NSIP.
  3. Recognize the clinical presentation, radiographic manifestations, and pathologic findings of NSIP.
  4. Review the diagnostic evaluation of patients with NSIP.
  5. Describe general and specific treatment recommendations for NSIP.

Key words: idiopathic interstitial pneumonia, interstitial lung disease, nonspecific interstitial pneumonia, pulmonary disease

Abbreviations: IIP = idiopathic interstitial pneumonia; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; NSIP = nonspecific interstitial pneumonia; UIP = usual interstitial pneumonia

Interstitial lung diseases (ILDs) are a heterogeneous group of noninfectious diffuse infiltrative disorders characterized by varying degrees of inflammation and fibrosis of the lung parenchyma. There are numerous causes of ILD, including environmental exposures, connective tissue disorders, and medications. The idiopathic interstitial pneumonias (IIPs) are a subset of ILD with an unknown etiology. The American Thoracic Society/European Respiratory Society Consensus Statement from 2002 established a uniform set of definitions and criteria for the diagnosis of IIPs that includes seven clinico-radiologic-pathologic entities.1 Idiopathic pulmonary fibrosis (IPF) is the most common and causes substantial mortality. It is characterized by usual interstitial pneumonia (UIP) on lung biopsy and can also be diagnosed by distinct findings on CT scan. In contrast, nonspecific interstitial pneumonia (NSIP) requires lung biopsy for definitive diagnosis and has a more favorable prognosis. While NSIP can be idiopathic, in most cases systematic evaluation reveals an associated connective tissue disease or environmental exposure as the cause. This article will review both the rationale for NSIP as a separate clinical entity from the other IIPs and our current understanding about disease pathogenesis. The clinical presentation, radiographic manifestations, and pathologic findings of NSIP will be reviewed. An approach to the evaluation of patients with suspected NSIP and recommendations for management and treatment of both idiopathic and secondary NSIP are included.

The gaps in knowledge regarding NSIP are related to our limited understanding of this uncommon disorder. Several factors make this topic difficult: (1) accurate pathologic diagnosis requires an experienced pulmonary pathologist to review and interpret lung biopsy specimens; (2) a multidisciplinary approach to diagnosis, integrating radiology and pathology findings along with the clinical information, is optimal; and (3) idiopathic NSIP is a diagnosis of exclusion requiring a thorough evaluation to rule out an underlying cause.

The Definition of NSIP

In 1994, Katzenstein and Fiorelli2 proposed that NSIP was a specific histologic pattern characterized by varying degrees of interstitial inflammation and/or fibrosis that appeared to be temporally uniform (occurring over a single time span). While the degree of interstitial inflammation and fibrosis differed from case to case, the changes were of a similar age, appearing either recent and active or quiet and old. Katzenstein and Fiorelli divided these cases into three groups based on the degree of cellularity and fibrosis. One group (those having what was later termed cellular NSIP) was characterized by active inflammation, while another group (with fibrosing NSIP) had dense interstitial collagen deposition or scarring (Fig 1). The authors also noted patients with both inflammation and fibrosis (mixed NSIP). In this series, a number of possible etiologic factors or associated conditions were identified, prompting the authors to conclude that NSIP was not a specific clinical disease. In 1998, Katzenstein and Myers3 proposed a pathologic classification of the IIPs that included NSIP as a distinct category. They preserved their original histologic definition of NSIP: interstitial fibrosis and inflammation present in variable amounts without the more specific changes of the other IIPs including UIP. While the pathologic findings could be patchy, they appeared to have arisen in a single time span (Table 1). The pathologic findings of NSIP contrasted sharply with the temporal heterogeneity characteristic of UIP, with active fibroblastic foci noted in some areas and interstitial fibrosis, inflammation, honeycomb change, and normal lung seen in others.3 Travis and colleagues4 subsequently demonstrated that the subtype of NSIP affected prognosis; cellular NSIP was associated with improved long-term survival compared with the fibrosing variant.


L21Fig1A

L21Fig1B

Figure 1. A, Histology from a video-assisted thoracoscopic surgical lung biopsy specimen in a patient with polymyositis. Note the uniform interstitial inflammation characteristic of cellular NSIP. B, Histopathology from a video-assisted thoracoscopic surgical lung biopsy specimen. Note uniform interstitial involvement with collagen deposition characteristic of fibrotic NSIP. (Photographs courtesy of Dr. Aliya Husain.)


Table 1Histopathologic Criteria for NSIP vs UIP

Characteristic Cellular NSIP Fibrosing NSIP UIP
Chronic interstitial inflammation Lymphocytes and plasma cells Mild Mild
Lung involvement Uniform but distribution may be patchy Temporally homogeneous collagen deposition Temporal heterogeneity
Interstitial fibrosis Inconspicuous Present but fibroblastic foci rare Fibroblastic foci
Acute lung injury pattern Absent Absent Absent
Eosinophils and granulomas Absent Absent Absent

 


Despite these refinements, debate about NSIP as a distinct clinical entity persists. A recent British Thoracic Society statement from 2008 proposes that a pathologic finding of NSIP may be associated with different clinical profiles that include the following: (1) NSIP behaving clinically as IPF, (2) NSIP behaving clinically as organizing pneumonia, or (3) NSIP caused by hypersensitivity pneumonia (environmental exposure, medications, etc.).5 A recent American Thoracic Society report reviewed cases of pathologic NSIP and confirmed idiopathic NSIP as a clinical diagnosis in a minority (67/193) of patients.6 This suggests that idiopathic NSIP exists but is very uncommon.

Epidemiology and Secondary Causes

The incidence and prevalence of idiopathic NSIP are unknown but have been estimated using the updated American Thoracic Society/European Respiratory Society ILD classification scheme.1 A retrospective review of cases previously classified as IPF resulted in reclassification from IPF to idiopathic NSIP in 11% to 43% of cases.7 The authors extrapolate from these data to estimate a prevalence of idiopathic NSIP ranging from 1 to 9/100,000 compared with 3 to 20/100,000 for IPF. Patients with NSIP tend to be younger than patients with IPF and unlike in IPF, there is no sex predominance or association with cigarette smoking, except that NSIP from connective tissue disease is seen more commonly in women.

As a histopathologic finding, NSIP has been associated with several nonidiopathic causes (Table 2). These include connective tissue disorders such as polymyositis, dermatomyositis, Sjögren syndrome, rheumatoid arthritis, and systemic sclerosis.8-11 NSIP is the most common type of ILD secondary to connective tissue disorders with the exception of rheumatoid arthritis, where UIP is more often noted. NSIP has also been seen as a manifestation of hypersensitivity pneumonitis, as a result of drug hypersensitivity, and in patients with graft vs host disease.5,12 Since the introduction of antiretroviral therapy, NSIP is seen much less commonly in patients with HIV.


Table 2Causes of NSIP

Causes of NSIP
Connective tissue diseases
Hypersensitivity pneumonitis
Drug toxicity
HIV
Postinfection
Idiopathic

 


In addition, it is recognized that seemingly idiopathic NSIP may later be found to be secondary to a connective tissue disease or environmental exposure. Sato and coworkers13 reviewed cases of histologically proven NSIP associated with a connective tissue disorder and found that seven patients had presented with NSIP 6 to 35 months before the onset of their rheumatologic disease. Park and coworkers14 similarly demonstrated that a minority of patients with idiopathic NSIP (10%) were later identified as having a connective tissue disease. These studies suggest that in patients with NSIP, a vigorous search for an etiology should be conducted not only at presentation, but also during follow-up, even in the absence of classical systemic involvement.

What Is the Pathogenesis of NSIP?

The etiology and pathogenesis of NSIP are poorly understood. The root problem may be that NSIP is more of a histopathologic finding and only provisionally a disease state. It has been suggested that NSIP is a precursor to UIP, although the majority of the data do not support this contention.15 In a study by Katzenstein and colleagues16 comparing lung biopsy data prior to lung transplant to lung explants from the same patients, none of the explants with pathologic findings of UIP had a prior lung biopsy showing NSIP. There is no evidence that cellular NSIP progresses to fibrotic NSIP.5

A critical difference between UIP and NSIP is the temporal heterogeneity of UIP and temporal homogeneity of NSIP. A working hypothesis for UIP is a model of repetitive injury to the lung epithelium leading to epithelial cell apoptosis and an increase in activity and immortalization of myofibroblasts. When compared with UIP specimens, in NSIP specimens the messenger RNA expression patterns for signaling pathways important to lung development in the alveolar epithelium of human lung tissue differ.17 There is evidence for epithelial cell injury in NSIP as well, with increased epithelial cell apoptosis in NSIP compared with normal lung parenchyma.18 Elevated levels of serum KL-6, a mucin-like glycoprotein expressed by type II pneumocytes, have been correlated with the extent of fibrosis on chest CT scan in fibrotic NSIP.19

There is evidence for both inflammation and immune stimulation in NSIP even when idiopathic. Dendritic cells in lung tissue from patients with idiopathic NSIP stained for S-100 protein antibody, while this result was rarely observed in cases of UIP.20 Likewise, heat shock protein autoantibody levels are higher in NSIP than IPF.21 BAL studies reveal that NSIP is a more active inflammatory disease than UIP, with greater degrees of lymphocytosis and increased interleukin-6 levels.22 Epithelial neutrophil-activating peptide 78 and interferon-γ-inducible protein 10, which play a role in inflammatory cell recruitment, are more highly expressed in BAL fluid in patients with NSIP than in those with IPF.23

In a study examining gene expression profiles in lung tissue samples from patients with hypersensitivity pneumonitis, NSIP, and IPF, the molecular “signatures” enabled identification of potential subgroups of NSIP. One case of NSIP matched the characteristic genetic profile of hypersensitivity pneumonitis and two cases matched the genetic profile of UIP. Five cases were not classifiable; these may represent true idiopathic NSIP.24 These findings support the contention of the British Thoracic Society that NSIP is associated with different clinical phenotypes that may include NSIP/IPF and NSIP/hypersensitivity pneumonitis.

Clinical Presentation

History and Physical Examination
The most frequent presenting complaint of patients with ILD is breathlessness and cough that may be insidious in onset. Patients may be treated for asthma, recurrent pneumonia, or congestive heart failure before the presence of a chronic interstitial process is recognized. While the duration of symptoms prior to presentation may be shorter in patients with NSIP than in those with IPF, there is nothing specific about the symptoms that suggest the cause is NSIP as opposed to another IIP (Table 3). Some studies have noted fever or a flu-like syndrome in up to one third of patients with idiopathic NSIP. Lung examination usually reveals crackles but occasionally crackles are subtle or absent. Unlike patients with UIP, clubbing is infrequent in those with NSIP. Signs of right-sided heart dysfunction are uncommon in NSIP, especially at presentation.


Table 3Typical Clinical Characteristics in NSIP

Typical Clinical Characteristics in NSIP
Age 40-60 yr
Sex predominance None
Cigarette smoking Not a risk factor
Symptoms Dyspnea, cough
Physical findings Crackles; clubbing rare
Pulmonary function test findings Total lung capacity, FVC, and diffusing capacity of the lung for carbon monoxide all reduced
Chest CT scan findings Ground-glass opacities, reticular opacities

 


Pulmonary Physiology
Pulmonary function tests typically show restriction with a reduced diffusing capacity. Obstruction may be noted in patients with hypersensitivity pneumonitis and in cigarette smokers; if these patients also have emphysema, the only abnormality may be a reduced diffusing capacity because the hyperinflation from emphysema may “normalize” lung volumes. Six-minute walk testing may show reduced exercise distance and exercise-induced arterial oxygen desaturation.

Radiographic Findings
The chest radiograph often shows ground-glass opacities or reticular changes, but radiographic findings may be normal. Characteristic findings on CT scan in patients with NSIP include ground-glass opacities, reticular abnormalities, and traction bronchiectasis.25 These findings are typically bilateral and symmetric with lower lobe predominance; subpleural sparing may be seen (Fig 2). Upper zone predominance suggests hypersensitivity pneumonitis. Honeycombing may be seen but should not be the predominant radiographic abnormality.


L21Fig2A

L21Fig2B

Figure 2. A, Chest CT scan showing typical findings in a patient with biopsy-proven cellular NSIP from polymyositis. Note patchy ground-glass opacities in the lung parenchyma bilaterally. B, Chest CT scan showing typical findings in a patient with fibrotic NSIP on lung biopsy. Note subpleural reticular changes, ground-glass opacities, and traction bronchiectasis. There is no honeycomb change. (Both CT scan images courtesy of Dr. Steven Montner.)


While a UIP pattern on thin-section CT strongly correlates with UIP on biopsy, the radiographic findings do not correlate as strongly with NSIP. CT findings suggestive of NSIP may correspond to pathologic findings of UIP on surgical lung biopsy. Therefore, chest CT scan alone cannot be relied on for diagnosis of NSIP. In one study of CT scan in 53 patients with NSIP on biopsy, CT had a sensitivity of 70% and specificity of 63% in the diagnosis of NSIP.26 In a study evaluating serial CT scans in patients with biopsy-proven NSIP, a decrease in extent of ground-glass opacities, increase in reticulation, and greater chance of peripheral distribution was noted in the majority of patients over time.27 Thus, unlike findings from lung pathology, serial chest CT scans suggest that over time progressive interstitial fibrosis may occur in some patients with NSIP.

Pathology
Lung biopsy by the video-assisted thoracoscopic surgical approach is the procedure of choice, as transbronchial biopsy will not provide a large enough tissue sample for accurate diagnosis. Biopsy samples should be obtained from multiple lobes and reviewed by an experienced pulmonary pathologist. As noted above, NSIP is characterized by variable interstitial inflammation and collagen deposition. When present, fibrosis is diffuse with few, if any, fibroblastic foci; honeycombing is uncommon.3 The hallmark of NSIP is that the changes are temporally homogeneous and appear to have occurred at a single time. The pathologic description should note if cellular or fibrotic NSIP is seen (Table 1, Fig 1).

Foci of organizing pneumonia are seen in nearly half the cases but are small and inconspicuous, constituting <10% of the overall findings. Prominent organizing pneumonia should prompt a search for a connective tissue disorder, such as polymyositis. Other pathologic findings that suggest the presence of connective tissue disease-related ILD include the following: lymphoid aggregates with germinal centers, prominent plasmacytic infiltration, extensive pleuritis, and dense perivascular collagen.28 More than a few loosely formed granulomas or multinucleated giant cells suggests hypersensitivity as the cause of NSIP.29 Both NSIP and UIP may be found on lung biopsy in the same patient. Studies show that in these cases, the prognosis is similar to that of IPF.15

Lung biopsy may not be necessary in cases where a well-characterized connective tissue disease is present or a definite environmental or medication exposure is noted. Lung biopsy should be strongly considered in idiopathic cases and in cases where multiple underlying etiologies are possible (eg, a patient with rheumatoid arthritis who is taking methotrexate and has a pet bird).

Diagnostic Evaluation

The diagnosis of NSIP requires a multidisciplinary approach integrating the clinical, radiographic, and pathologic findings.5 The cause of NSIP must be sought with a thorough environmental, occupational, and medication history. A retrospective analysis of patients with IIP suggested that the majority of patients with NSIP on lung biopsy (88%) might have an undifferentiated connective tissue disease.30 A connective tissue disease is suggested by arthralgias, gastroesophageal reflux, or sicca symptoms, while a careful physical examination may reveal rash, alopecia, Raynaud phenomenon, synovitis, or mechanic’s hands.31 There is not a consensus on the number or extent of serologic tests to be performed.5 At a minimum, an antinuclear antibody titer and pattern and rheumatoid factor should be ordered. At our institution, we also test for anti-cyclic citrullinated peptide, Scl-70, and Jo-1 antibodies. If the antinuclear antibody titer is positive, SS-A, SS-B, Smith, and ribonuclear protein antibodies should be sent. Esophageal, pleural, or pericardial involvement on chest CT scan or pathology findings suggests connective tissue disease.28,31 Tests for unusual serologic markers, such as anti-Th/To antibody, and a myositis panel may be ordered in certain circumstances.31 Antigen tests for hypersensitivity pneumonitis may identify a potential exposure but the sensitivity and specificity of these tests are not high and they cannot be used alone to rule hypersensitivity in or out as a cause. The diagnosis of idiopathic NSIP is made only after the above evaluation is unrevealing.

Prognosis and Natural History

Patients with NSIP have a better prognosis than those with UIP that is idiopathic (IPF) or secondary to another process. Prognosis is especially good for patients with cellular NSIP, with minimal mortality in these patients.5,32 Park and colleagues14 demonstrated a reasonably good prognosis for idiopathic fibrotic NSIP with 74% survival at 5 years; however, the presence of honeycombing on chest CT scan was a predictor of poor long-term outcome. As has been noted in patients with IIP, progressive dyspnea, honeycombing on chest CT scan, and desaturation on a 6-min walk test may identify patients at risk of a poor outcome.5 In patients with underlying connective tissue disease, the lung disease may progress independently of the activity of their rheumatologic disease. Rapid progression or acute exacerbations of NSIP are reported, especially in patients with poly- and dermatomyositis, and may respond to aggressive therapy.5

Treatment

General Overview
Whether treatment alters the natural history of either idiopathic or secondary NSIP is not known. Patients with an exposure-related NSIP should have the medication discontinued or offending antigen removed from their environment. Methotrexate should be stopped and is best avoided in patients with IIPs.33 Systemic corticosteroids have been the mainstay of therapy. In patients who respond to corticosteroids but whose dose cannot be reduced sufficiently to avoid side effects, an additional nonsteroidal immunosuppressive agent is recommended (Table 4), but immunosuppressants should only be prescribed by physicians who have experience using these agents or in collaboration with a rheumatologist. In patients with NSIP related to a connective tissue disorder, treatment may be tailored to the specific rheumatologic disease, although the course of the ILD does not always parallel that of the connective tissue disease. Novel antifibrotic agents tested in clinical trials in patients with UIP/IPF may one day have a role to play in the treatment of fibrotic NSIP but they are not approved for use in the United States at this time. Patients with mild or stable ILD or with contraindications to corticosteroid therapy may be followed closely and treated if deterioration occurs.


Table 4Medications Used to Treat NSIP

Medication Dose Precautions
Corticosteroids (prednisone) 1 mg/kg/d to start, then taper Lower doses should be used in patients with scleroderma and the elderly
Azathioprine 1-2 mg/kg/d, 150 mg maximum dose Check thiopurine methyltransferase level
Cyclophosphamide 1-2 mg/kg/d orally, 200 mg maximum dose or 750 mg/m2 body surface area IV dosing is associated with less toxicity; reduce dose in elderly and those with renal dysfunction
Mycophenolate mofetil 1,000-3,000 mg/d in divided doses Expensive

These agents should only be used by practitioners experienced with their use or in consultation with the rheumatology service.


Patients should be informed of the numerous potential side effects of systemic corticosteroids and immunosuppressive agents.34 In women of childbearing potential, screening for pregnancy and use of appropriate contraception is essential. All patients should be vaccinated against pneumococcus and influenza. In patients taking moderate- to high-dose prednisone (>20 mg/d) and/or immunosuppression, prophylactic treatment to prevent infection with Pneumocystis jiroveci is advised.

Patients with exercise limitation may be candidates for pulmonary rehabilitation. Oxygen should be prescribed for patients who experience arterial oxygen desaturation at rest or with exercise. Diagnosis and treatment of right heart dysfunction has not been studied in idiopathic NSIP, but such treatment may particularly benefit those with connective tissue disease-related ILD.5

Corticosteroids
Controlled trials are lacking but case series and expert opinion support a trial of corticosteroids in patients who have either idiopathic or secondary NSIP with symptomatic and/or progressive lung disease. The usual dosage is 1 mg/kg/d (maximum dose, 60 mg daily) but no more than 20 mg daily should be given to patients with scleroderma because of the risk of precipitating a renal crisis.5 Lower doses might be safer in the elderly as well. Both acute exacerbations and rapid deterioration of NSIP may be seen, especially in those with polymyositis- or dermatomyositis-related NSIP. Case reports suggest that IV methylprednisolone (up to 1 g daily for 3 days) along with cyclophosphamide may be effective in this situation.5

Azathioprine
The initial studies of therapy for IIP showed benefit for a subset of patients treated with prednisone and azathioprine.5 Many of the patients who improved in those studies may have had fibrotic NSIP. The typical starting dose is 50 mg daily, increased in 25- to 50-mg increments every 14 days to a dosage of 1 to 2 mg/kg/d (maximum dose, 150 mg daily) as long as blood counts and hepatic function remain normal with therapy. Most experts measure the enzyme thiopurine methyltransferase prior to starting therapy. If this enzyme level is low, more gradual dose adjustments and more frequent monitoring of complete blood counts and liver function tests are advised.

Cyclophosphamide
In a small, prospective study comparing patients with NSIP and patients with UIP/IPF, patients with biopsy-proven fibrotic NSIP showed a more favorable response to intermittent-pulse therapy with methylprednisolone for 4 weeks followed by low-dose prednisone and cyclophosphamide for 1 year.35 After pulse therapy, 33% of patients with NSIP had improved lung function vs 15% with IPF. After 1 year of combination therapy, 66% of patients with NSIP had improved, vs 15% of the IPF group.

A retrospective study of patients with known (n=7) or suspected NSIP (n=47), excluding scleroderma, received IV cyclophosphamide.36 There were two withdrawals and the four deaths were not therapy related. Stable lung function was noted at 6 months. A greater response was noted in those in whom the chest CT scan suggested organizing pneumonia. In patients with scleroderma ILD, NSIP is the predominant pathologic finding. In a large, multicenter, placebo-controlled prospective study in patients with scleroderma ILD, treatment with cyclophosphamide for 12 months resulted in improvements in lung function (FVC), dyspnea, skin-thickness score, and disability index that persisted or increased for several months after stopping therapy. Except for dyspnea, the improvements were no longer apparent at 24 months.37 A treatment-related improvement in fibrosis score on chest CT was seen at 12 months.38 Cyclophosphamide has serious potential acute and long-term side effects so it should be used only in patients with severe or progressive ILD and only by experienced practitioners.

Mycophenolate Mofetil
This agent is generally well tolerated.34 A study of a small number of patients with scleroderma ILD showed this was a safe and possibly effective agent.39 A prospective study with this agent for patients with scleroderma lung disease is currently underway.40 This drug is highly teratogenic and must be stopped prior to pregnancy.

Calcineurin Inhibitors
Tacrolimus has been reported to be of benefit in patients with refractory ILD from polymyositis or dermatomyositis.41 There is a case report of a patient with ARDS secondary to cellular NSIP who did not respond to high-dose corticosteroids but improved with tacrolimus and low-dose prednisone.42 The authors have had success using this medication in patients with progressive ILD from poly- and dermatomyositis.43 It is important to monitor serum levels and aim for a trough level <10 mg/mL. Renal toxicity may be serious and can lead to renal insufficiency or renal failure. Renal complications are more likely with high serum levels or long-term use.

Conclusions

NSIP is a histopathologic diagnosis associated primarily with connective tissue disorders and hypersensitivity pneumonitis. It is less commonly a clinical entity with an idiopathic origin. It is likely that with time and further study, recognition of additional causes of NSIP will further decrease the identification of truly idiopathic cases. While rigorous studies of treatment are lacking, there is some evidence that treatment may improve outcomes.

Acknowledgment: The authors would like to thank Ms. Nancy Jackson for her assistance in the preparation of this manuscript.


References

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  12. Ohtani Y, Saiki S, Kitaichi M, et al. Chronic bird fancier's lung: histopathological and clinical correlation. An application of the 2002 ATS/ERS consensus classification of the idiopathic interstitial pneumonias. Thorax. 2005;60(8):665-671.
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