Nonspecific Interstitial Pneumonia

Etiology

Nonspecific interstitial pneumonia can be idiopathic or associated with connective tissue disease, HIV infection, toxins, or numerous other causes. Secondary causes of nonspecific interstitial pneumonia NSIP include:

1. Connective tissue disease (CTD): NSIP is a common pattern due to underlying connective tissue disease which includes systemic sclerosis, polymyositis/dermatomyositis, rheumatoid arthritis, and Sjogren syndrome.
2. Drug-induced: Amiodarone, methotrexate, nitrofurantoin, chemotherapeutic agents, and statin therapy have been associated with an NSIP pattern.
3. HIV infection: Less common now after the widespread use of the antiretroviral therapy. 
4. Interstitial pneumonia with autoimmune features: those patients have NSIP on lung biopsy, and features of autoimmune disease that don’t match specific connective tissue disease.
5. Hypersensitivity pneumonitis: In some patients, the lung biopsy lacks granuloma, and multinucleated giant cells through the histopathology have an appearance of NSIP.
6. Others: Such as an IgG4-related systemic disease, familial interstitial pneumonia, and graft versus host disease

Epidemiology

NSIP is rare. It constitutes 14% to 36% of cases of idiopathic interstitial pneumonia which is less common than usual interstitial pneumonia (UIP) (50% to 60%) but more common than desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease (DIP/RB-ILD) (10-17%) and acute interstitial pneumonia (AIP) (0% to 2%). Idiopathic NSIP occurs mostly in middle-aged women who are non-smokers, while NSIP due to connective tissue disease is equal in men and women.

Pathophysiology

Pathophysiology of the NSIP includes epithelial injury, dysregulated repair, involvement of the immune system based in the presence of lymphocyte in the alveolar septae and bronchoalveolar lavage, and abnormal fibroblast/myofibroblast function leading to excess collagen deposition.[6][7][8]

Histopathology

For the diagnosis of diffuse interstitial lung disease, surgical biopsy via VATS or thoracotomy is the gold standard. Transbronchial cryobiopsy can be used as well. Traditional transbronchial forceps lung biopsies have been reported to have a low diagnostic yield. Ideally, biopsy samples should be obtained from more than one lobeNSIP is a diagnosis of exclusion. Nonspecific gross findings may be observed on wedge biopsy, including increased stiffness of the pulmonary parenchyma secondary to interstitial inflammation and fibrosis. The histopathology of NSIP is characterized by a temporally homogeneous inflammatory and fibrosing interstitial process. Fibroblastic foci and peripheral accentuation are typically absent, which helps to differentiate it from usual interstitial pneumonia (UIP). NSIP is also characterized by diffuse alveolar wall thickening by uniform fibrosis, but with the preservation of the alveolar architecture. Three separate groups within NSIP have been described:

1. Group 1: Mainly interstitial inflammation 
2. Group 2: Inflammation and fibrosis 
3. Group 3: Mainly fibrosis

History and Physical

History

• The most common symptoms are dyspnea and cough that are progressive over weeks to months 
• Fever
• Weight loss 
• Flu-like symptoms 
• If CTD is present, the patient may have dry mouth, dry eyes, arthralgias, joint swelling, myalgias, dysphagia, skin changes, or other features

Physical Exam

• Fine crackles, especially at the bases, may be noted 
• Clubbing is present in 10% to 35%, though this may be a non-specific finding
• Exam features of rheumatological disease such as skin changes, joint swelling may also be noted

Evaluation

The evaluation of the patients with possible NSIP include: 

1. Clinical evaluation: Detailed history and physical exam are important. Patients should be asked about exposure to airborne antigens, medication list, history of exposure to radiation, HIV risk factors, CTD symptoms, as well as family history.
2. Laboratory test: If CTD is suspected, one should perform an appropriate serological evaluation. One may also consider HIV testing if there are risk factors. 
3. Pulmonary function testing (PFT): Includes spirometry to determine whether the symptoms are associated with an obstructive or restrictive pattern, lung volumes, diffusing capacity for carbon monoxide (DLCO) to check for gas exchange, and 6-minute walk test to check for hypoxia at rest or exertional hypoxia. Monitoring forced vital capacity (FVC) and DLCO is helpful to monitor for progression and correlate with clinical symptoms as well as to monitor response to treatment and offer additional information on prognosis. Patients with NSIP typically have a spirometric restrictive pattern on the PFTs with reduced TLC and DLCO.
4.  Imaging: (1) Chest x-ray may show increased basilar markings and/or interstitial prominence bilaterally; (2) High-resolution Computed Tomography (HRCT) of the chest is the gold standard for imaging diagnosis. Most common findings may include increased reticular markings, traction bronchiectasis, volume loss, and ground glass opacification mainly in the lower zones. Honeycomb changes are more common with UIP and usually absent in NSIP. 
5. Lung biopsy may assist in definitive diagnosis, though may not always be needed. The need for biopsy must be evaluated within the clinical context, including whether there is an identified underlying process or not, and the severity of lung injury. For example, in the case of an associated CTD or drug-induced NSIP, a biopsy may not be needed. Conversely, in those cases where an associated etiology is not discovered, a lung biopsy may be needed for diagnosis.

Treatment / Management

Treatment of NSIP depends on the cause and the severity of the disease:

• Mild disease: These patients usually have mild symptoms and minimal impairment on their pulmonary functions tests. Close follow up and observation for evidence of disease progression may be adequate.
• Moderate to severe disease: These patients have moderate to severe symptoms, with significant impairment on their pulmonary function tests as well as diffuse changes on HRCT chest scan. In this scenario, we typically start with systemic steroid therapy (prednisone) at a dose of 0.5 to 1 mg/kg ideal body weight (IBW) up to a maximum dose of 60 mg per day for 1 month, followed thereafter by a dose of 30 to 40 mg per day for an additional 2 months. For those who respond/stabilize with this treatment, the prednisone should be gradually tapered over 6 to 9 months to a dose of 5 to 10 mg per day or every other day with a goal of potential cessation in therapy after 1 year. Typically, patients are monitored on prednisone for 3 to 6 months to assess for response to treatment and tolerance prior to consideration for a second immunosuppressive agent like azathioprine or mycophenolate. However, for patients with a more severe initial disease, clinicians may start systemic steroid therapy along with a second immunosuppression agent together.
• More severe disease may require hospitalization: These patients may require pulse methylprednisolone at a dose of 1000 mg per day for 3 days, followed by systemic prednisone therapy as outlined above. Rarely is an additional pulse therapy needed.
• Refractory disease despite systemic steroid and immunosuppressive agents: Consideration may be given for cyclophosphamide, rituximab, or calcineurin inhibitors. Those that are not responsive may be considered for lung transplantation.
• It is important to be mindful of potential adverse effects to steroid therapy and continue to assess the risks and benefits of steroid therapy. Further, consideration should be given to Pneumocystis jirovecii pneumonia (PJP) prophylaxis in those patients on greater than 20 mg prednisone daily for more than 1 month, or those on multiple immunosuppressive agents, as this infection may significantly worsen lung function.[9]

 Treatment of the secondary causes:

• Drug induced: Removal from the exposure may be sufficient.  
• Connective tissue disease: Treatment is focused on the underlying cause. Coordination with a rheumatology specialist may be helpful as well.
• HIV infection: Exclude infections and then start antiretroviral therapy. Systemic steroids can be used for those who fail to improve.

Differential Diagnosis

• Other idiopathic interstitial pneumonia: The histopathology of usual interstitial pneumonia (UIP) can be seen in both idiopathic pulmonary fibrosis (IPF) as well as NSIP.  Given the potential for clinical and histopathological overlap between these two entities, differentiating the two may be challenging. Fibrotic NSIP should be distinguished from IPF as it has a better prognosis and possible response to steroid therapy.
• Hypersensitivity pneumonitis: Typical imaging features in the acute or subacute phase include findings of centrilobular nodules as well as the predominance of upper lung zone involvement. On histopathology, there is the bronchiolocentric distribution of giant cells and poorly formed granulomas. Chronic hypersensitivity pneumonitis may have more fibrotic features, and thus an attempt should be made to discern this disease state by clinical history and potential further evaluation.
• IgG-related systemic disease: Some patients with IgG4 have interstitial lung disease. Histopathology may demonstrate infiltration of the lung interstitium with IgG4-positive plasma cells, which helps to differentiate this entity.

Prognosis

The prognosis of NSIP is significantly better than that of UIP. Five and 10-year survival is 43% and 15% respectively among patients with UIP, compared to 86% to 92% 5-year survival and 26% to 40% 10-year survival rates among patients with NSIP with the fibrotic component. Fibrotic NSIP is thought to have a worse prognosis than inflammatory, cellular NSIP.