Definition and Epidemiology

Definition

Idiopathic pulmonary fibrosis (IPF) is the most common type of interstitial lung disease ( ILD ILD Interstitial lung diseases are a heterogeneous group of disorders characterized by the inflammation and fibrosis of lung parenchyma, especially the pulmonary connective tissue in the alveolar walls. It may be idiopathic (e.g., idiopathic pulmonary fibrosis) or secondary to connective tissue diseases, medications, malignancies, occupational exposure, or allergens. Interstitial Lung Diseases) 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 GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease 
• Chronic microaspiration 
• Obstructive sleep apnea Obstructive sleep apnea Obstructive sleep apnea (OSA) is a disorder characterized by recurrent obstruction of the upper airway during sleep, causing hypoxia and fragmented sleep. Obstructive sleep apnea is due to a partial or complete collapse of the upper airway and is associated with snoring, restlessness, sleep interruption, and daytime somnolence. 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 Gas exchange Human cells are primarily reliant on aerobic metabolism. The respiratory system is involved in pulmonary ventilation and external respiration, while the circulatory system is responsible for transport and internal respiration. Pulmonary ventilation (breathing) represents movement of air into and out of the lungs. External respiration, or gas exchange, is represented by the O2 and CO2 exchange between the lungs and the blood. Gas Exchange → chronic hypoxic respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure

Clinical Presentation

Symptoms

Patients with IPF can have variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables presentations, and early in its course, IPF can be asymptomatic. 

• Presentation of symptoms suggests a moderate to advanced stage:
  • Chronic dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). 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 Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Weight loss
  • Myalgias

Physical exam

General findings:

• Bibasilar fine inspiratory (“Velcro-like”) crackles on auscultation 
• End-inspiratory “squeaks” in advanced disease with bronchiectasis Bronchiectasis Bronchiectasis is a chronic disease of the airways that results from permanent bronchial distortion. This results from a continuous cycle of inflammation, bronchial damage and dilation, impaired clearance of secretions, and recurrent infections. Bronchiectasis
• Digital clubbing 

Patients can present with pulmonary hypertension Pulmonary Hypertension Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies. Pulmonary Hypertension (PH) and cor pulmonale Cor Pulmonale Cor pulmonale is right ventricular (RV) dysfunction caused by lung disease that results in pulmonary artery hypertension. The most common cause of cor pulmonale is chronic obstructive pulmonary disease. Dyspnea is the usual presenting symptom. Cor Pulmonale: 

• Pitting edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema (pedal or sacral)
• Jugular venous distention
• Cyanosis 
• Split second heart sound with dominant P2 component

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 GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease 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 Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/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 Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer
• Type 3 PH and cor pulmonale Cor Pulmonale Cor pulmonale is right ventricular (RV) dysfunction caused by lung disease that results in pulmonary artery hypertension. The most common cause of cor pulmonale is chronic obstructive pulmonary disease. Dyspnea is the usual presenting symptom. 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 Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
  • Rapid deterioration and progression to death
  • Periods of relative stability interposed with periods of acute respiratory decline
• Acute respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure is a common cause of hospital admission and death, and can result from:
  • Disease progression
  • Pneumonia
  • Pulmonary hypertension 

Differential Diagnosis

• Sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, joint, or eye lesions. Patients are often asymptomatic, though may present with cough, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and malaise. Diagnosis involves imaging, elevated serum ACE levels, and BAL and often requires a biopsy. Management is usually with glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids.
• Hypersensitivity pneumonitis Hypersensitivity Pneumonitis Hypersensitivity pneumonitis (HP), previously called extrinsic allergic alveolitis, is an immunologically induced inflammatory disease affecting the alveoli, bronchioles, and lung parenchyma. It is caused by repeated inhalation of an inciting agent in a susceptible host that triggers first a type III (complement-mediated) hypersensitivity reaction in the acute phase and then a type IV (delayed) reaction in the subacute and chronic phases. Hypersensitivity Pneumonitis: immunologically induced inflammatory disease affecting the alveoli, bronchioles, and lung parenchyma resulting from exposure to inhaled antigens: Patients may develop cough, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, and fatigue. HRCT will show diffuse, poorly defined centrilobular micronodules or ground-glass opacities. Pulmonary function tests are variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables. Management includes avoiding the inciting agent and administering steroids in subacute and chronic cases.
• Pneumoconiosis Pneumoconiosis Pneumoconiosis is an occupational disease that results from the inhalation and deposition of mineral dusts and other inorganic particles in the lung. It can be categorized according to the type of causative particle involved or by the type of response provoked. Pneumoconiosis: occupational disease that results from inhalation of inorganic particles into the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: In the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs, these particles can cause chronic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and fibrosis. Patients will have progressive dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). 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 Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD) ( COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD)): lung disease characterized by progressive, largely irreversible airflow obstruction: Symptoms include progressive dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea and chronic cough. Prolonged expiration, wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. 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 Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure: inability to produce normal cardiac output to meet metabolic needs: Patients present with dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, hypoxia, and peripheral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema. BNP will be elevated, and pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. 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.