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Nonspecific-interstitial -pneumonia-restrictive-lung-diseases

Image: “Neumonia intersticial no especifica” by Mluisamtz11. License: CC BY-SA 3.0


Introduction

Chronic lung diseases are broadly classified as:

  • Obstructive lung diseases, for example, asthma and chronic obstructive pulmonary disease
  • Restrictive lung diseases, for instance, pneumoconiosis, interstitial lung diseases, and sarcoidosis

These two groups present with overlapping clinical features of dyspnea and other pulmonary manifestations, but they are easily differentiated based on pulmonary function testing.

Restrictive lung diseases have a hallmark of:

  1. Reduced lung volumes, also called diminished total lung capacity (TLC)
  2. Decreased forced expiratory volume at 1 minute (FEV1) and forced vital capacity (FVC)
  3. Increased or near-normal FEV1/FVC ratio

These conditions could arise from pathologies of the lung parenchyma or outside the lung parenchyma (such as the pleura, chest wall, or neuromuscular components of respiration). Thus, they are classified into:

Intrinsic/interstitial lung disease affects the lung parenchyma, leading to inflammation, scarring, and fibrosis of the lung. It may also cause debris or fluid to accumulate in air spaces, leading to pneumonitis. These diseases include:

  • Connective tissue diseases associated with interstitial lung diseases (CT-ILD)
  • Fibrotic lung diseases
  • Primary interstitial lung diseases, such as sarcoidosis
  • Idiopathic interstitial lung diseases

Extrinsic/extrapulmonary lung disease affects the

  • Chest wall
  • Pleura
  • Respiratory muscles and nerves

Connective tissue diseases associated with interstitial lung diseases (CT-ILD)

Multiple connective tissue disorders affect lung function. These include:

  • Scleroderma/systemic sclerosis
  • Dermatomyositis and polymyositis
  • Nonspecific interstitial pneumonia (NSIP)
  • Rheumatoid arthritis
  • Sjogren syndrome
  • Systemic lupus erythematosus (SLE)
  • Mixed connective tissue disease (MCTD)

Scleroderma/systemic sclerosis (SSc) is an autoimmune connective tissue disorder with a heterogeneous presentation. It induces excess collagen production, which changes the skin’s appearance and texture. Other symptoms include vasculopathy and inflammation affecting the blood vessels, muscles, internal organs, and lungs.

Nonspecific interstitial pneumonia (NSIP) is a form of idiopathic interstitial pneumonia that follows an autoimmune reaction of the body towards the lung parenchyma. Depending on histological findings, NSIP is classified as one of two types.

  • The cellular type is a chronic inflammation of the cells of the interstitium. Its pathogenic pathway has minimal fibrosis with inflammatory infiltrate and type II pneumocyte hyperplasia.
  • The fibrosing type causes thickening and scarring of lung tissue, known as fibrosis. When the lung tissue thickens or becomes scarred, it does not function as effectively. Breathing becomes less efficient, and there are lower levels of oxygen in the blood. The condition is irreversible.

Polymyositis is an idiopathic inflammatory myopathy that is characterized by the triad of:

  1. proximal muscle weakness on both sides
  2. elevated skeletal muscle enzymes
  3. electromyographic and muscle biopsy abnormalities

Dermatomyositis is similar to polymyositis. Also, these patients have characteristic skin rashes involving sun-exposed areas such as the face, neck, upper chest, and hands.

In polymyositis and dermatomyositis, lung involvement is more common with anti-synthetase antibodies.

Epidemiology

NSIP is the second most common form of interstitial lung disease. It mainly affects adults aged 40–50 years, with a slight female predilection.

Systemic sclerosis, on the other hand, affects three people per 100,000 in the general population. The disease has a slight predilection for women between 40 and 50 years of age. Lung involvement is one of the most common complications of scleroderma, occurring in 53 % of patients with systemic sclerosis and 35% of patients with cutaneous sclerosis.

Dermatomyositis and polymyositis are rare diseases with a prevalence of 0.5–8.4 cases per million people. They are associated with people of all ages. Two peaks are observed: the first peak is around 5–10 years of age and the second peak is around 50 years.

They have a female to male ratio of 2:1, and African-American women are more likely to be affected. Lung involvement precedes other system involvement in up to 30–40% of dermatomyositis and polymyositis.

Etiology

Connective tissue disorders are mostly autoimmune disorders that have a genetic and environmental influence. Certain risk factors have been linked to these disorders:

  1. Family history and genetic predisposition are more pronounced in dermatomyositis and polymyositis, where there is an association with HLA-DR3/5/7 mutations.
  2. Environmental toxins, such as exposure to silica, chlorinated toxins, and welding fumes, induce and maintain the autoimmune process.
  3. Malignancy is also a trigger for autoimmune processes.
  4. Infection processes that trigger an autoimmune process include HTLV-1, coxsackieviruses, and parvoviruses.
  5. Drugs, such as statins, have been implicated in the development of polymyositis and dermatomyositis. Drug-induced lupus is another common occurrence.
  6. Immunologic predisposition to an autoimmune reaction is evident in polymyositis and dermatomyositis, where a TNF-α-308A allele is associated with increased photosensitivity.
  7. Advanced age
  8. Smoking increases the risk of an autoimmune process and worsens existing interstitial lung disease.

Pathophysiology

When a genetically predisposed individual is exposed to environmental triggers, such as infections, drugs, or malignancies, an autoimmune process is triggered that affects multiple tissues, including the lungs. This leads to progressive destruction of lung parenchyma due to persistent inflammation, fibrosis, and vascular injury.

Further, alveolar epithelial injury leads to cytokine release (IL-1, LPA) and growth factors release (TGF-β and IGF-1), which activate the fibroblasts. Fibroblast activation leads to collagen deposition in the lung parenchyma, which induces solidification and fibrosis.

Besides lung parenchyma inflammation and fibrosis, the airway, pulmonary vasculature, and chest wall may also be involved, leading to:

  • airflow limitation
  • pulmonary hypertension
  • vasculitis
  • extrapulmonary restriction

Clinical features

These patients have clinical features affecting the respiratory system as well as systemic involvement.

Respiratory system involvement

  1. Cough
  2. Shortness of breath
  3. Fatigue
  4. Chest pain
  5. Pulmonary hypertension

The systemic features depend upon the underlying connective tissue disorder.

Polymyositis and dermatomyositis

  1. Bilateral symmetrical proximal muscle weakness
  2. Skin rashes (in dermatomyositis) commonly consist of heliotrope rash in the periorbital region, shawl sign due to clavicular and shoulder skin involvement, Gottron papules, and plaques.
  3. Esophageal and pharyngeal involvement leads to weakness and dilatation that causes aspiration pneumonia and worsens existing interstitial pneumonia.

Scleroderma/Systemic Sclerosis

It affects almost every system, causing:

  1. Tightened skin especially around the fingers (sclerodactyly)
  2. Raynaud’s phenomenon
  3. Telangiectasias
  4. Dizziness, palpitations, hypertension and congestive cardiac failure
  5. Dysphagia, GERD

Systemic lupus erythematosus (SLE)

  1. Photosensitivity and skin rash, characteristically the butterfly rash around the cheeks
  2. Oral ulcers
  3. Joint pain
  4. Muscle weakness
  5. Neuropsychiatric symptoms
  6. Thrombotic state (abortions or deep vein thromboses)

Investigations

The diagnostic investigations include:

Laboratory tests

  • Systemic sclerosis patients have a positive ANA test and anti-topoisomerase antibodies in serum, among other markers.
  • In dermatomyositis and polymyositis, a complete blood count will reveal leukocytosis and thrombocytosis, as well as elevated muscle enzymes, such as CK and aldolase. They also exhibit positive ANA and other serum markers.
  • SLE patients may have positive ANA and anti-dsDNA along with autoimmune-related pancytopenia.

Imaging

  • A chest x-ray may be normal in most cases but may also exhibit nodular opacities in NSIP.
  • High-resolution CT-scan (HRCT) of the chest may show the characteristic ground-glass opacities appearance in most of the disease with associated:
    1. pruning (loss of pulmonary vasculature)
    2. loss of pulmonary volume
    3. enlarged right pulmonary artery >1.1cm
    4. honeycomb pattern.

Pulmonary Function Tests / Spirometry

Pulmonary function tests (PFTs) are important in diagnosing restrictive lung diseases. They show:

  1. Reduced lung volumes (reduced total lung capacity TLC, tidal volume, residual volume)
  2. Decreased forced expiratory volume at 1 minute (FEV1) and forced vital capacity (FVC)
  3. Increased or near-normal FEV1/FVC ratio

Bronchoscopy

Lung biopsy and histology show a mixed pattern of inflammation and fibrosis.

Echocardiogram

An echocardiogram may be considered in cases of severe cardiovascular compromise. It helps in diagnosing the associated pulmonary hypertension. Cardiac catheterization can be done to confirm the pressures.

Differential diagnosis of Restrictive Lung Disease

Usual interstitial pneumonia (UIP)

  • Has similar imaging findings of opacification as in NSIP but lacks the restrictive and fibrotic lung injury pattern

Eosinophilic fasciitis

  • An autoimmune disease with eosinophilia and connective tissue involvement like scleroderma

Mycosis fungoides

  • A cutaneous form of cancer that is marked by skin rashes like those seen in scleroderma

Fibromyalgia

  • Presents with muscle pain and stiffness and sometimes mimic polymyositis and dermatomyositis

Discoid lupus erythematosus

  • Has skin involvement with a shawl sign, as seen with scleroderma

Treatment

The treatment is mainly symptomatic because the pulmonary changes are mostly irreversible. Effective therapies for connective tissue disease-associated interstitial lung disease (CTD-ILD) are still lacking, but multiple clinical trials have been carried out with varying degrees of success.

Supportive management

  • Long-term continuous oxygen therapy
  • Analgesics for muscle and chest pains
  • Muscle relaxants for spasticity and rigidity
  • Treatment of skin ulcers that develop in systemic sclerosis
  • Pharmacological agents to reduce pulmonary hypertension

Definitive management

Corticosteroid therapy with high dose prednisone should be initiated, especially in situations of lung involvement. To treat dermatomyositis and polymyositis, the drug is administered for 4–8 weeks, and in that time, muscle enzymes must have returned to normal levels.

Immunosuppressive therapy with methotrexate, azathioprine, and cyclophosphamide decreases autoimmune activity within the body. These drugs are considered when the disease is refractory to high dose steroids. The need is based on:

  • Disease progression at a faster rate
  • Severe lung disease
  • Likelihood of the response, based on prior experience of a similar patient
  • Age of the patient with a better response anticipated in young patients
  • Ability to comply with the medication schedule

Lung transplant is successful, especially in complications of restrictive lung disease.

Complications

Complications associated with restrictive lung disease can arise from the disease progression or problems related to treatment:

  1. Pulmonary hypertension is the most common and dangerous complication that occurs from prolonged fibrosis and vessel damage; It may cause ischemia-induced revascularization.
  2. Cor pulmonale is the final pathway for pulmonary hypertension that leads to right heart strain and, ultimately, right heart failure.
  3. Respiratory failure arises from the restriction of exhalation and compromised volume that may be worsened by medications such as methotrexate. Serial pulmonary function tests are done to assess for this complication.
  4. Renal failure
  5. Infections arise due to prolonged use of immunosuppressive therapy. Close monitoring of the patient’s immunity alongside a broad spectrum of antimycobacterial coverage is recommended.
  6. Malignancy may arise from prolonged fibrotic states.
  7. Skin sores and ulcers that mainly arise due to peripheral vessel damage by autoimmune processes.

Prognosis

The five-year survival rate for NSIP ranges from 86–92% for the fibrosing type and up to 100% for the cellular intervention due to its excellent response to treatment.
The median survival of systemic sclerosis with lung involvement is 6–8 years.

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