Pulmonary Fibrosis

Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. The diagnosis is made by characteristic imaging findings, pulmonary function testing that indicates restrictive lung disease, and (if necessary) lung biopsy. Options are limited for therapies to slow progression. Lung transplantation is the only curative intervention if the patient is a candidate for one.

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Definition and Epidemiology

Definition

Idiopathic pulmonary fibrosis (IPF) is the most common type of interstitial lung disease (ILD) and is characterized by chronic, progressive, irreversible fibrosis of the lung parenchyma.

Epidemiology

IPF has been difficult to study because of its rarity and evolution in diagnostic practices.

  • Incidence and prevalence:
    • Uncommon
    • Higher in North America and Europe than in the rest of the world
    • Estimated prevalence in the United States: 10–60 per 100,000
    • Likely underappreciated in terms of its occurrence and public health impact (e.g., health care costs and resource utilization)
  • Occurs primarily in elderly individuals (> 65 years) 
  • More often seen in men

Etiology and Pathophysiology

Etiology

The cause of IPF remains largely unclear. However, in the current hypothesis regarding the pathogenesis of IPF, the following exposures may lead to the initial alveolar epithelial injury:

  • Tobacco smoke (most common)
  • Environmental pollutants and dust
  • Viral infections
  • GERD 
  • Chronic microaspiration 
  • Obstructive sleep apnea

Pathophysiology

The underlying mechanism is poorly understood.

  • Environmental exposure and possible genetic predisposition → recurrent alveolar epithelial damage
  • Migration and activation of fibroblasts → myofibroblast transformation
  • Failure of normal myofibroblast apoptosis → exaggerated extracellular matrix accumulation → lung parenchyma destruction and scarring
  • Additional mediators of profibrotic changes include:
    • Transforming growth factor beta
    • Fibroblast growth factor 2
    • Platelet-derived growth factor (PDGF)
    • Matrix metalloproteinase 7 (MMP-7)
  • Consequence: ↓ gas exchange → chronic hypoxic respiratory failure

Clinical Presentation

Symptoms

Patients with IPF can have variable presentations, and early in its course, IPF can be asymptomatic. 

  • Presentation of symptoms suggests a moderate to advanced stage:
    • Chronic dyspnea: 
      • Initially exertional (nearly universal)
      • Progressive, eventually occurring at rest
    • Chronic nonproductive cough
    • Reduced exercise tolerance
  • Associated systemic symptoms are uncommon but can include:
    • Fatigue
    • Low-grade fever
    • Weight loss
    • Myalgias

Physical exam

General findings:

  • Bibasilar fine inspiratory (“Velcro-like”) crackles on auscultation 
  • End-inspiratory “squeaks” in advanced disease with bronchiectasis
  • Digital clubbing 

Patients can present with pulmonary hypertension (PH) and cor pulmonale: 

  • Pitting edema (pedal or sacral)
  • Jugular venous distention
  • Cyanosis 
  • Split second heart sound with dominant P2 component

Diagnosis

Idiopathic pulmonary fibrosis is diagnosed by a combination of radiologic, pathologic, and clinical investigations.

Important patient history

It is critical to obtain the following on top of a complete medical history to ensure that other causes of ILD are excluded: 

  • Occupational history
  • Recreational history
  • Environmental history
  • Risk factors for HIV 
  • Radiation exposure
  • Notable medications associated with pulmonary fibrosis:
    • Amiodarone
    • Bleomycin
    • Nitrofurantoin
    • Methotrexate

Pulmonary function tests

Typical findings:

  • Restrictive ventilatory defect
  • ↓ Diffusing capacity of the lung for carbon monoxide (DLCO)

Measurements:

  • Static lung volumes using body plethysmography typically reveal ↓ lung volumes (restriction) such as:
    • Vital capacity
    • Functional residual capacity (FRC)
    • Total lung capacity (TLC)
    • Forced vital capacity (FVC)
  • Normal or ↑ forced expiratory volume in 1 second (FEV1)/FVC ratio
  • Static pressure–volume curve shifted downward and to the right → ↓ lung compliance

Imaging

Chest X-ray:

  • May look normal in early disease
  • Reticulonodular infiltrates
    • Bilateral
    • Basal
    • Symmetrical

High-resolution CT (HRCT) scan:

  • Significantly more sensitive and specific for the diagnosis of IPF
  • Features (predominantly seen in the lower lobes):
    • Peripheral and subpleural reticular septal thickening
    • Traction bronchiectasis
    • Honeycombing cysts
    • Lung architectural distortion
    • Superimposed ground-glass opacities may be seen.

CT image from a patient with pulmonary fibrosis:
A basilar reticular pattern is seen.

Image: “Patient with pulmonary fibrosis” by Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, #1 Shuaifuyuan Street, Beijing, Dongcheng District 100730, China. License: CC BY 2.0

Lung biopsy

Surgical specimens can be obtained using video-assisted thoracoscopic surgery (VATS). Patients with IPF may show a pattern of usual interstitial pneumonia:

  • Alternating zones of normal and abnormal lung tissue
  • Fibrosis
  • Fibroblast foci (areas of active fibroproliferation)
  • Honeycombing patterns

Bronchoscopy

  • Bronchoscopy with bronchoalveolar lavage (BAL) and/or transbronchial biopsy is often of limited benefit in the diagnosis of IPF.
  • Patients with severe hypoxia may not be able to tolerate bronchoscopy.
  • May be used to:
    • Exclude alternative diagnoses if imaging is indeterminate.
    • Evaluate for coexisting infection.

Supporting laboratory evaluation

The following can be performed to exclude other causes of ILD and will be guided by clinical suspicion:

  • Erythrocyte sedimentation rate and CRP
  • Antinuclear antibodies
  • Rheumatoid factor and anti–cyclic citrullinated peptide antibodies
  • Aldolase and CK
  • Myositis-specific antibodies
  • Anti-SSA/Ro and anti-SSB/La antibodies
  • Serum ACE level

Management

Pharmacologic therapy

There are limited options for pharmacologic treatment in patients with IPF, and none provide a cure.

Antifibrotic agents:

  • Approved for delaying progression
  • Do not significantly improve mortality
  • Options:
    • Pirfenidone 
    • Nintedanib

PH management:

  • Inhaled prostacyclins (treprostinil)
  • Diuresis is used to maintain euvolemia in the presence of right heart failure.

GERD management:

  • Proton pump inhibitors
  • H2 antagonist

Nonpharmacologic therapy

  • Long-term oxygen therapy when patients resting or ambulatory saturations are < 88% 
  • Pulmonary rehabilitation:
    • Alleviate the overt symptoms.
    • Improve functional status.
    • May include: 
      • Exercise training
      • Smoking cessation
      • Psychosocial assistance
      • Supportive care
  • Vaccinations:
    • Influenza
    • Pneumonia
  • Lung transplantation:
    • The only definitive treatment 
    • Bilateral lung transplantation is more commonly used than single lung transplantation.
    • Early referral should be considered.
  • Palliative care:
    • Focus on reducing symptoms and improving comfort.
    • Use is not limited to end-of-life care.

Complications and Prognosis

Complications

  • Respiratory infections
  • Thromboembolic disease
  • Lung cancer
  • Type 3 PH and cor pulmonale
  • Respiratory failure

Prognosis

IPF progression is associated with an estimated median survival time of up to 5 years following the diagnosis.

  • The rate of decline and progression to death in patients with IPF may take several clinical forms: 
    • Slow physiologic deterioration with worsening severity of dyspnea
    • Rapid deterioration and progression to death
    • Periods of relative stability interposed with periods of acute respiratory decline
  • Acute respiratory failure is a common cause of hospital admission and death, and can result from:
    • Disease progression
    • Pneumonia
    • Pulmonary hypertension 

Differential Diagnosis

  • Sarcoidosis: granulomatous disorder affecting multiple organ systems without a known etiology: The most common presenting findings include pulmonary reticular opacities, bilateral hilar adenopathy, and skin, joint, or eye lesions. Patients are often asymptomatic, though may present with cough, dyspnea, fever, and malaise. Diagnosis involves imaging, elevated serum ACE levels, and BAL and often requires a biopsy. Management is usually with glucocorticoids.
  • Hypersensitivity pneumonitis: immunologically induced inflammatory disease affecting the alveoli, bronchioles, and lung parenchyma resulting from exposure to inhaled antigens: Patients may develop cough, dyspnea, and fatigue. HRCT will show diffuse, poorly defined centrilobular micronodules or ground-glass opacities. Pulmonary function tests are variable. Management includes avoiding the inciting agent and administering steroids in subacute and chronic cases.
  • Pneumoconiosis: occupational disease that results from inhalation of inorganic particles into the lungs: In the lungs, these particles can cause chronic inflammation and fibrosis. Patients will have progressive dyspnea and dry cough. Chest X-ray findings can vary depending on the causative particle, but may include ground-glass opacities, calcifications, lung nodules, and pleural irregularities. Management is mainly symptomatic.
  • Chronic obstructive pulmonary disease (COPD): lung disease characterized by progressive, largely irreversible airflow obstruction: Symptoms include progressive dyspnea and chronic cough. Prolonged expiration, wheezing, and/or diminished breath sounds may be noted on physical exam. Unlike IPF, pulmonary function testing is consistent with obstruction. Management includes smoking cessation, pulmonary rehabilitation, and pharmacotherapy.
  • Congestive heart failure: inability to produce normal cardiac output to meet metabolic needs: Patients present with dyspnea, hypoxia, and peripheral edema. BNP will be elevated, and pulmonary edema may be seen on X-ray examination. Echocardiography will confirm the diagnosis. Management relies on diuresis and medical optimization of cardiac function with beta-blockers and ACE inhibitors.

References

  1. Maher, T. M., Strek, M. E. (2019). Antifibrotic therapy for idiopathic pulmonary fibrosis: time to treat. Respiratory Research 20(1). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731623/
  2. Weerakkody, Y. (n.d.). Usual interstitial pneumonia: radiology reference article. Retrieved April 2, 2021, from https://radiopaedia.org/articles/usual-interstitial-pneumonia?lang=us
  3. Lederer, D. J., Martinez, F. J. (2018). Idiopathic pulmonary fibrosis. New England Journal of Medicine 378:1811–1823.
  4. Waxman, A., Restrepo-Jaramillo, R., Thenappan, T., Ravichandran, A., Engel, P., Bajwa, A., Nathan, S. D. (2021). Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. New England Journal of Medicine 384:325–334.
  5. Godfrey, A. M. K., Ouellette, D. R. (2019). Idiopathic pulmonary fibrosis (IPF). In Soo Hoo, G. W. (Ed.), Medscape. Retrieved April 13, 2021, from https://emedicine.medscape.com/article/301226-overview
  6. Lee, J. (2019). Idiopathic pulmonary fibrosis. MSD Manual Professional Version. Retrieved April 13, 2021, from https://www.msdmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/idiopathic-pulmonary-fibrosis
  7. Krishna, R., Chapman, K., Ullah, S. (2020). Idiopathic pulmonary fibrosis. StatPearls. Retrieved April 13, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK448162/
  8. King, T. E., Jr. (2021). Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis. In Hollingsworth, H. (Ed.), UpToDate. Retrieved April 13, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-idiopathic-pulmonary-fibrosis
  9. King, T. E., Jr. (2020). Treatment of idiopathic pulmonary fibrosis. In Hollingsworth, H. (Ed.), UpToDate. Retrieved April 13, 2021, from https://www.uptodate.com/contents/treatment-of-idiopathic-pulmonary-fibrosis
  10. Raghu, G. (2019). Pathogenesis of idiopathic pulmonary fibrosis. In Hollingsworth, H. (Ed.), UpToDate. Retrieved April 13, 2021, from https://www.uptodate.com/contents/pathogenesis-of-idiopathic-pulmonary-fibrosis

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