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Nonspecific-interstitial -pneumonia-restrictive-lung-diseases

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


Introduction to Restrictive Lung Disease

Diseases of the lung can be broadly classified as obstructive lung diseases, such as asthma, chronic obstructive pulmonary disease and cystic fibrosis, or restrictive lung diseases.

The two groups of diseases are mainly present with overlapping clinical features of difficulty in breathing 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 (reduced total lung capacity TLC);
  2. Decreased forced expiratory volume at 1 minute (FEV1) and forced vita capacity (FVC);
  3. Increased FEV1/FVC ratio.

These conditions could arise from pathologies of the:

  • lung parenchyma,
  • pleura,
  • chest wall
  • neuromuscular components of respiration.

They are thus classified into:

Intrinsic lung disease/interstitial lung disease which affects the lung parenchyma, leading to inflammation, scaring and fibrosis of the lung or accumulation of air spaces with debris, leading to pneumonitis. They 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 that affects the

  • chest wall
  • pleura
  • respiratory muscles.

Definition of Restrictive Lung Disease

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

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

Nonspecific interstitial pneumonia is a form of idiopathic interstitial pneumonia that follows an autoimmune reaction of the body towards the lung parenchyma.

Scleroderma/systemic sclerosis (SSc) is a group of heterogenous autoimmune diseases that induce connective tissue deposition and thus, lead to hardening of the tissues. They affect the

  • skin
  • blood vessels
  • muscles
  • internal organs.

Dermatomyositis is an autoimmune disorder that is characterized by involvement of the skin, joints and internal organs, such as the lungs, esophagus and less commonly, the heart.

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

  1. proximal muscle weakness,
  2. elevated skeletal muscle enzymes
  3. electromyographic and muscle biopsy abnormalities.

Epidemiology of Restrictive Lung Disease

NSIP is the second most common form of interstitial lung disease. Of the two subtypes, the fibrotic pattern is the common one. 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 ranging 40–50 years in age. Lung involvement is one of the most common complications of scleroderma, being evident 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 of the population. They are associated with people of all ages. Two peaks are observe:, one at young ages of 5–10 years and another one at 50 years. They have a female to male ratio of 2:1, with black women being affected more. Lung involvement precedes other system involvement in up to 30–40% of dermatomyositis and polymyositis.

Etiology of Restrictive Lung Disease

These are largely autoimmune diseases that have a genetic and environmental influence, thus, the following are true about their causes or risk factors:

  1. Family history and genetic predisposition is 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, coxsackie viruses and parvoviruses.
  5. Drugs, such as statins, have been incriminated in the development of polymyositis and dermatomyositis.
  6. Immunologic predisposition to an autoimmune reaction is evident in polymyositis and dermatomyositis where TNF-α-308A allele is associated with increase in photosensitivity.
  7. Advanced age
  8. Smoking predisposes to an autoimmune process and worsens existing interstitial lung disease.

Pathophysiology of Restrictive Lung Disease

The development of interstitial lung diseases begins with a genetically predisposed individual, such as one with HLA-DR3 or HLA-DR5 mutations.

The individual is exposed to environmental triggers, such as infections, drugs and malignancies, that trigger an autoimmune process where the body is overwhelmed by auto-antibodies against tissues of the body, such as skin in dermatomyositis and muscles in polymyositis.

In all the diseases, the common denominator is the autoimmune destruction of the lung parenchyma leading to inflammatory infiltrate into the lungs and vascular injuries within the lungs.

Endothelial cell damage causes release of endothelin-1 that activates the fibroblasts. In a similar way, alveolar epithelial injury leads to cytokine release (IL-1, LPA) and growth factors release (TGF-β and IGF-1) which also activate the fibroblasts. Fibroblast activation leads to collagen deposition in the lung parenchyma which induces solidification and fibrosis.

Besides the 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.

Classification of Restrictive Lung Disease

Nonspecific interstitial pneumonia (NSIP)

It is classified based on histological findings into:

  • Cellular type, which runs a chronic inflammation pathogenic pathway with minimal fibrosis, thus, marked with inflammatory infiltrate and type II pneumocyte hyperplasia.
  • Fibrosing type, which has interstitial fibrosis with minimal chronic inflammatory pattern.

Scleroderma with pulmonary involvement

It is classified into:

  • Direct pulmonary involvement, which may be:
    • Pulmonary hypertension that is more common with the limited cutaneous systemic sclerosis.
    • Primary interstitial lung disease that is more common with diffuse cutaneous sclerosis.
  • Airway disease
  • Pleural involvement

Dermatomyositis and polymyositis

They are classified into:

  1. Primary idiopathic polymyositis
  2. Primary idiopathic dermatomyositis
  3. Polymyositis or dermatomyositis associated with malignancy
  4. Childhood polymyositis or dermatomyositis
  5. Polymyositis and dermatomyositis associated with connective tissue diseases
  6. Inclusion body myositis
  7. Miscellaneous diseases, such as focal myositis and eosinophilic myositis
  8. Amyopathic dermatomyositis is a special form of dermatomyositis that has no evidence of muscular involvement but a fulminant interstitial lung disease.

Clinical features of Restrictive Lung Disease

Clinical presentation of interstitial lung diseases is marked by signs and symptoms of systemic involvement. It may begin with pulmonary/respiratory system involvement—the system involved in all the diseases.

Respiratory system involvement

  1. Cough, which is mostly dry
  2. Difficulty in breathing due to a restricted exhalation phase
  3. Fatigue
  4. Reduced gaseous exchange capacity
  5. Chest pain
  6. Pulmonary hypertension

Polymyositis and dermatomyositis

They lead to:

  1. Muscle weakness that is bilaterally symmetrical and begins with the proximal muscles.
  2. Skin rashes and features such as 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

It affects almost every system, causing:

  1. Dizziness, palpitations, Raynaud’s phenomenon, telangiectasias, hypertension and congestive cardiac failure when involving the cardiovascular system.
  2. Loss of appetite, indigestion, bloating and constipation in the digestive system.
  3. Skin patches and hardening patches mainly in the trunk and limbs.

Investigations of Restrictive Lung Disease

The diagnostic investigations include:

Laboratory tests

Systemic sclerosis

Systemic sclerosis patients have a positive ANA test and anti-topoisomerase antibodies in serum, among other markers.

Dermatomyositis and polymyositis

In dermatomyositis and polymyositis there is leukocytosis and thrombocytosis on complete blood count as well as elevated muscle enzymes such as CK and aldolase. They also exhibit positive ANA and other serum markers.

Chest x-ray

A chest x-ray may be normal in most cases but may also exhibit nodular opacities in NSIP.

CT

High resolution Chest CT-scan (HRCT) has 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. honey comb pattern.

Pulmonary function tests (PFTs)/spirometry

This is the diagnostic test which shows:

  1. Reduced lung volumes (reduced total lung capacity TLC);
  2. Decreased forced expiratory volume at 1 minute (FEV1);
  3. Forced vita capacity (FVC), increased FEV1/FVC ratio.

Bronchoscopy

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

Echocardiogram may be considered in cases of severe cardiovascular compromise where there is pulmonary hypertension and an RSVP of greater than 30–40 mmHg. 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 weakness as seen with polymyositis and dermatomyositis.

Discoid lupus erythematosus

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

Treatment of Restrictive Lung Disease

The diseases are largely untreatable, but trials have been carried out with varying degrees of success involving various medications.

Supportive management

  • Analgesics for muscle and chest pains;
  • Muscle relaxants for spasticity and rigidity;
  • Treatment of skin ulcers that develop in systemic sclerosis.

Definitive management

Corticosteroid therapy with high dose prednisone, especially in situations of lung involvement. In treatment of 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 that decrease the 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 similar patient;
  • Age of the patient with a better response anticipated in young patients;
  • Ability to comply with the medication schedule.

Lung transplant has been tried with success, especially in complications of restrictive lung disease.

Complications of Restrictive Lung Disease

Complications associated with restrictive lung disease can arise from the disease progress or problems associated with treatment:

  1. Pulmonary hypertension is the most common and dangerous complication that arises from prolonged fibrosis and vessel damage; 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 asses 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 antimycobacterial coverage is recommended.
  6. Malignancy may arise from the prolonged fibrotic states.
  7. Skin sores and ulcers that mainly arise due to peripheral vessel damage by autoimmune processes.

Course and prognosis of Restrictive Lung Disease

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 good response to treatment. Moreover, NSIP has a better prognosis than UIP.

Median survival of systemic sclerosis with lung involvement is 6–8 years.

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