Idiopathic Pulmonary Fibrosis

Specific Form of Fibrosing Interstitial Pneumonia

Lung-limited Disease

Exclusion of Alternative Diagnoses

• Other idiopathic interstitial pneumonias (e.g., nonspecific interstitial pneumonia)
• Environmental exposures (e.g., metal, wood, or agricultural dust)
• Drug-induced lung injury (e.g., from amiodarone, nitrofurantoin)
• Systemic autoimmune diseases (e.g., systemic sclerosis, rheumatoid arthritis, polymyositis)

Radiological and Histopathological Pattern of UIP

Overview of Aetiological Concepts

• IPF is a chronic, progressive fibrosing interstitial lung disease with no known definitive cause.
• The leading hypothesis is that repetitive alveolar epithelial injury in genetically predisposed individuals triggers a dysregulated repair response.
• This process is characterised by persistent fibroblast activation, myofibroblast accumulation, and excessive extracellular matrix (ECM) deposition.
• Unlike classic inflammatory lung diseases, IPF is driven by aberrant wound healing rather than persistent inflammation.

Environmental and Occupational Exposures

• Inhaled environmental agents are strongly implicated as risk factors.
• Cigarette smoke is the most consistent exposure, found in up to 70–80% of cases; it promotes oxidative stress and epithelial apoptosis.
• Occupational dusts such as metal, stone, and pine wood dust are associated with increased risk.
• Vapours, gases, dusts, and fumes (VGDF) contribute to repeated micro-injury of the alveolar lining.
• Agricultural settings (e.g. livestock farming, bird handling) are associated with higher prevalence of IPF.
• Chronic aspiration of gastric contents, especially in gastro-oesophageal reflux disease (GORD), may result in repetitive alveolar injury.

Demographic Risk Modifiers

• Age is a major risk factor, with most diagnoses occurring after age 60.
• The disease is more common in men than women.
• A history of tobacco smoking is frequent among affected individuals.
• IPF is rare in children or young adults unless associated with familial pulmonary fibrosis.

Genetic Susceptibility

Telomerase-related gene variants

• Mutations in TERT, TERC, and RTEL1 impair telomere maintenance and promote epithelial cell senescence.
• Telomere shortening is present in 25–30% of IPF patients, even in sporadic cases.
• These changes reduce regenerative capacity and increase vulnerability to injury.

Surfactant protein dysfunction

• Mutations in SFTPC and SFTPA2 are linked to familial IPF and may cause earlier disease onset.
• These mutations disrupt surfactant homeostasis, resulting in endoplasmic reticulum stress and type II pneumocyte apoptosis.

MUC5B promoter polymorphism

• The rs35705950 variant in the MUC5B gene promoter is the most robust genetic risk factor for both sporadic and familial IPF.
• It increases mucin 5B expression, alters mucociliary clearance, and impairs epithelial function.
• Despite increasing disease susceptibility, it is associated with slower disease progression and better survival.

Other genetic loci

• Additional variants in TOLLIP (immune regulation), DSP (cell adhesion), and TINF2 (telomere integrity) have been implicated.
• Genes such as FAM13A, DPP9, and AKAP13 also influence disease susceptibility, phenotype, or progression.

Immunological and Inflammatory Contributions

• Both innate and adaptive immune responses are involved in IPF progression.
• Neutrophils and monocytes release fibrogenic mediators, including proteases and reactive oxygen species.
• Fibrocytes recruited from the bone marrow differentiate into fibroblasts within the lung.
• Th2 cytokines, such as IL-4, IL-9, and IL-13, promote fibroblast activation and collagen deposition.
• Transforming growth factor-beta (TGF-β) is the central profibrotic cytokine, inducing fibroblast proliferation and epithelial–mesenchymal transition.
• Dendritic cells contribute to immune activation and perpetuation of fibrosis.

Viral and Microbial Triggers

• Respiratory viruses are frequently detected in lung tissue and are postulated to initiate or exacerbate fibrosis.
• Epstein–Barr virus (EBV), cytomegalovirus (CMV), and hepatitis C virus have all been identified in IPF lungs.
• Torque teno virus (TTV) has been found in patients during acute exacerbations of IPF, though its role remains unclear.
• Chronic viral infections may induce epithelial apoptosis and immune dysregulation.

Gastro-oesophageal reflux disease (GORD)

• Chronic microaspiration of gastric contents may cause lower lobe–predominant epithelial injury.
• GORD is highly prevalent in patients with IPF, even in the absence of typical symptoms.
• Some observational studies suggest a potential protective role of antacid therapy, though this remains unproven in randomised trials.

Diabetes mellitus

• Diabetes is associated with increased oxidative stress, systemic inflammation, and impaired tissue repair.
• Restrictive pulmonary physiology has been observed more frequently in diabetic populations.
• The direct contribution of diabetes to IPF remains unclear due to heterogeneity in available evidence.

Thyroid dysfunction

• Hypothyroidism is more common in patients with IPF than in the general population.
• Potential mechanisms include autoimmune activation, hormonal modulation of fibrogenesis, and impaired repair.
• Low thyroid hormone levels have been associated with worse clinical outcomes and increased mortality in IPF.

Mechanisms of Fibrotic Progression

• Following epithelial injury, type II alveolar cells release profibrotic mediators such as TGF-β, PDGF, and endothelin-1.
• Myofibroblasts accumulate from epithelial–mesenchymal transition, resident fibroblast activation, and fibrocyte recruitment.
• These cells produce excess collagen and ECM components, disrupting alveolar architecture.
• Histopathological features include fibroblastic foci, honeycombing, and temporal-spatial heterogeneity.
• The cycle of injury and dysregulated repair results in progressive decline in lung function.

Current Understanding of Disease Mechanism

• IPF is no longer viewed as a primary inflammatory disorder; rather, it is now considered an epithelial-fibroblastic disease.
• The process begins with repetitive epithelial injury in genetically predisposed individuals, triggered by environmental exposures such as cigarette smoke, airborne pollutants, chronic aspiration, or respiratory infections.
• Injury to the alveolar epithelium leads to abnormal repair and persistent activation of fibroblasts and myofibroblasts.
• These activated mesenchymal cells produce excessive extracellular matrix (ECM), progressively distorting normal lung architecture.
• Fibroblastic foci, clusters of activated fibroblasts and myofibroblasts, are the histopathological hallmark of IPF and represent sites of ongoing fibrogenesis.

Epithelial and Mesenchymal Cell Dysfunction

• Alveolar epithelial cells in IPF are aberrantly activated and release profibrotic mediators including:
  • Transforming growth factor-β (TGF-β)
  • Tumour necrosis factor-α (TNF-α)
  • Platelet-derived growth factor (PDGF)
  • Insulin-like growth factor-1 (IGF-1)
  • Endothelin-1 (ET-1)
• These factors stimulate fibroblast proliferation and their transition into myofibroblasts, which produce ECM proteins like collagen.
• Myofibroblasts should normally undergo apoptosis during the resolution of wound healing, but in IPF, they become resistant to apoptosis, promoting persistent fibrosis.
• Conversely, alveolar epithelial cells undergo excessive apoptosis, impairing re-epithelialisation and contributing to defective repair.

Apoptotic Imbalance

• The imbalance between epithelial cell death and fibroblast survival promotes chronic fibrogenesis.
• Studies have shown that deficiency of prostaglandin E2 in fibrotic lungs increases alveolar epithelial cell sensitivity to apoptosis while making fibroblasts resistant to death signals.
• TGF-β is implicated in this apoptotic resistance by promoting a pro-survival phenotype in fibroblasts.

Genetic Influences on Pathogenesis

• Up to 20% of IPF cases are familial, and several genetic variants have been linked to disease development.
• Mutations in telomerase-related genes (TERT, TERC, RTEL1) impair telomere maintenance and promote epithelial cell senescence and vulnerability to injury.
• Telomere shortening, seen with age or inherited mutations, leads to impaired epithelial regeneration and abnormal repair.
• The MUC5B promoter polymorphism (rs35705950) is strongly associated with both familial and sporadic IPF.
  • This variant results in mucin 5B overexpression in distal airways, impairing clearance and increasing susceptibility to injury.
• Caveolin-1, a regulatory protein that normally inhibits TGF-β signalling and supports alveolar repair, is downregulated in IPF, especially in fibroblasts.
  • Loss of caveolin-1 contributes to unopposed fibrogenic signalling.

Histopathological Features

• The typical histological pattern is that of usual interstitial pneumonia (UIP), which is defined by:
  • Patchy fibrosis alternating with normal lung parenchyma.
  • Dense fibrosis with architectural distortion and honeycomb change.
  • Fibroblastic foci in areas adjacent to preserved lung tissue.
• Fibrosis typically begins in the subpleural and basilar regions and extends to the peribronchial parenchyma.
• Bronchoscopic biopsies often miss the diagnosis due to sampling error; surgical lung biopsy remains the gold standard if histology is needed.
• Features such as granulomas or multinucleated giant cells suggest alternative diagnoses and should be absent in IPF.

Acute Exacerbations

• A subset of patients experience acute exacerbations (AE-IPF) characterised by sudden worsening of respiratory symptoms and new diffuse alveolar damage superimposed on background UIP.
• These exacerbations may occur without a clear trigger and are associated with abrupt, often irreversible, declines in pulmonary function.
• The pathogenesis of AE-IPF is thought to reflect accelerated injury-repair responses rather than a separate disease process.

Functional and Radiographic Correlates

• The progressive fibrotic process leads to:
  • Declining forced vital capacity (FVC)
  • Reduced diffusing capacity for carbon monoxide (DLCO)
  • Restrictive pulmonary physiology
• High-resolution CT imaging reveals:
  • Subpleural reticulation
  • Honeycombing
  • Traction bronchiectasis
  • Ground-glass opacities in areas of acute injury

Comorbid Pathophysiological Manifestations

• Smoking history is common and contributes to concurrent emphysema in ~30% of IPF patients.
  • These patients may show preserved lung volumes with disproportionately reduced DLCO.
• Pulmonary hypertension occurs frequently and worsens prognosis even when mild.
• Coronary artery disease (CAD) is significantly more prevalent in IPF, with studies showing a threefold increased risk of acute coronary syndrome.
• IPF patients have a 3–6 times higher risk of venous thromboembolism, especially in the context of lung cancer, which is five times more common in this population.
• Gastro-oesophageal reflux disease (GORD) is common and may exacerbate IPF through chronic microaspiration.
  • Trials assessing anti-reflux therapy in IPF have been inconclusive.
• Hiatal hernia is frequent and has been successfully treated in transplant candidates with IPF.
• Osteoporosis is prevalent and correlates with lower FVC and DLCO, even in steroid-naïve patients.
• Hypothyroidism is more common in IPF and has been linked to increased mortality.
• Anxiety and depression are frequent, often correlating with hypoxaemia and impaired quality of life.

Global Incidence and Prevalence

• IPF is a rare but increasingly recognised interstitial lung disease with variable incidence across regions.
• In Europe and North America, incidence ranges from 2.8 to 19 per 100,000 persons per year.
• In Asian populations, incidence is generally lower, estimated between 1.2 and 4.6 per 100,000 persons per year.
• A global estimate suggests incidence is approximately 10.7 cases per 100,000 person-years in men and 7.4 in women.
• Prevalence estimates globally range from 3.3 to 45 per 100,000 persons, but higher values are reported in older populations.
• IPF incidence and prevalence continue to rise worldwide, possibly due to increased disease awareness, better access to high-resolution CT imaging, and ageing populations.

Epidemiology in the United States

• Among US adults aged ≥65 years, Medicare data report a prevalence of 494.5 cases and an incidence of 93.7 cases per 100,000 persons per year.
• In adults aged 18–64 years, prevalence increased from 13.4 per 100,000 in 2005 to 18.2 per 100,000 in 2010.
• In a Minnesota-based cohort aged ≥50 years, incidence ranged from 8.8 (narrow-case criteria) to 17.4 (broad-case criteria) per 100,000 person-years.
• Corresponding prevalence estimates ranged from 27.9 to 63 per 100,000 persons depending on diagnostic stringency.

Age Distribution

• IPF primarily affects individuals over 50 years of age.
• Approximately two-thirds of patients are aged ≥60 years at diagnosis.
• Mean age at diagnosis is generally between 60 and 70 years.
• In individuals aged 75 years or older, incidence increases sharply, ranging from 27.1 to 76.4 per 100,000 person-years.
• IPF is extremely rare in those under 50 and virtually absent in children.

Sex Distribution

• IPF is more common in males than females, particularly in those over the age of 55.
• This male predominance has been consistently observed across US and international datasets.

Race and Ethnicity

• No definitive racial or ethnic predisposition has been established due to limited data from large, diverse population studies.
• Available evidence suggests that geographic, cultural, or racial factors do not significantly influence overall disease risk.

Temporal Trends

• The incidence of IPF appears to be rising, even after adjusting for improved diagnostic tools and population ageing.
• This increase may be attributed to heightened clinical awareness among primary care physicians and pulmonologists, as well as greater use of high-resolution imaging in elderly patients.

Familial Pulmonary Fibrosis

• Familial pulmonary fibrosis, typically defined as IPF in two or more first-degree relatives, accounts for 10–20% of cases.
• While clinically indistinguishable from sporadic IPF, familial cases tend to occur earlier, with mean age at diagnosis between 55 and 60 years.
• Family history of interstitial lung disease should prompt genetic counselling and possibly earlier screening in relatives.

Acute Exacerbations

• Acute exacerbations of IPF, defined as sudden worsening without identifiable cause, occur in 4–20 cases per 100 patient-years.
• They are more frequent in patients with advanced physiological and radiographic disease.
• A retrospective review found that 35% of patients experienced at least one rapid deterioration event, with 55% of these classified as acute exacerbations.

Dyspnoea on Exertion

• The most common and earliest symptom reported in IPF.
• Usually progressive, insidious in onset, and not episodic.
• Often present for 6 months or more before diagnosis.
• May initially be attributed to cardiac disease, and many patients are first referred to cardiology.
• In rare cases (approximately 5%), patients may be asymptomatic at the time of diagnosis, with radiographic abnormalities found incidentally.

Cough

• Typically dry, non-productive, and persistent.
• Can be severe and refractory to antitussive treatments.
• May significantly impair quality of life.

Constitutional Symptoms

• Less common but may include fatigue, malaise, weight loss, low-grade fever, arthralgia, or myalgia.
• These symptoms are non-specific and may lead to diagnostic delays.

Delay in Diagnosis

• The median delay from symptom onset to confirmed diagnosis is 12 to 24 months.
• Due to the non-specific nature of initial symptoms, IPF is often misattributed to more common pulmonary or cardiac conditions.

Family History

• A history of familial pulmonary fibrosis (FPF) should be explored, especially in younger patients.
• Familial disease often presents a decade earlier (mean age 55–60 years) and follows an autosomal dominant inheritance with incomplete penetrance.
• Ask about premature greying of hair or signs of premature ageing which may signal underlying telomere disorders.

Environmental and Occupational Exposures

• History should include exposure to:
  • Metal dusts (e.g. steel, aluminium)
  • Wood dusts (especially pine)
  • Silica
  • Asbestos
  • Livestock farming
  • Mouldy foliage
  • Bird droppings
• 44% of patients with IPF report occupational exposure to vapours, gas, dust, or fumes (VGDF).
• These exposures are associated with increased risk of IPF and are important in distinguishing from other interstitial lung diseases.

Smoking History

• A major independent risk factor for IPF.
• Present in up to 70–80% of patients at the time of diagnosis.
• Cigarette smoke may cause oxidative injury to alveolar epithelial cells and promote fibrotic pathways.
• A genetic predisposition to smoking-related damage may interact with environmental exposures to trigger disease onset.

Medication and Drug History

• Important to exclude drug-induced pulmonary fibrosis.
• Offending agents may include:
  • Amiodarone
  • Bleomycin
  • Nitrofurantoin
  • Methotrexate
• Ask specifically about past and present use of these agents.

Review of Systems for Autoimmune Disease

• Aim to identify symptoms suggesting connective tissue disease (CTD)–associated ILD, such as:
  • Arthralgias or arthritis
  • Photosensitivity
  • Dry eyes or mouth
  • Raynaud phenomenon
  • Sclerodactyly
  • Muscle weakness or tenderness
• Important to rule out autoimmune causes before making a diagnosis of IPF.

Gastro-oesophageal Reflux Disease (GORD)

• A common comorbidity in IPF; may be clinically silent.
• Chronic microaspiration is thought to contribute to ongoing alveolar injury.
• Although therapy for GORD is not currently recommended to improve respiratory outcomes, history of reflux should still be assessed.

Infectious Triggers

• Past viral infections may contribute to pathogenesis.
• Viruses implicated include EBV, CMV, HHV-7, HHV-8, and hepatitis C.
• Co-infection with bacteria and viruses may lead to worse respiratory outcomes.
• Bacterial colonisation may also promote inflammation and fibrosis.

Metabolic Risk Factors

• Diabetes mellitus may be associated with restrictive lung physiology, although evidence is inconsistent.
• A full metabolic history should be taken, including screening for prediabetes or long-standing diabetes.

Sleep Disorders

• Obstructive sleep apnoea (OSA) is highly prevalent in patients with IPF.
• In one study, 88% of stable IPF patients had mild to severe OSA based on polysomnographic criteria.
• History should include snoring, witnessed apnoeas, nocturnal awakenings, and daytime somnolence.

Psychosocial and Mental Health

• Anxiety and depression are common and may correlate with the severity of dyspnoea or chronic hypoxia.
• Psychological evaluation and support should be considered part of routine care in symptomatic individuals.

Bibasilar Inspiratory Crackles

• Fine, end-inspiratory crackles are the most consistent physical finding.
• Described as “Velcro-like” and predominantly heard over the posterior lung bases.
• Usually bilateral and symmetrical.
• Present even in early or asymptomatic stages of disease.
• Not associated with wheezing, distinguishing IPF from obstructive airway diseases.
• In advanced stages, additional inspiratory “squeaks” may be heard due to traction bronchiectasis.

Digital Clubbing

• Present in 25–50% of patients with IPF.
• More common in advanced disease and may be absent in early stages.
• Reflects chronic hypoxaemia and fibrotic progression.
• Should prompt exclusion of differential diagnoses such as bronchogenic carcinoma or other chronic suppurative lung diseases if asymmetrical.

Signs of Pulmonary Hypertension (PH)

• Affects up to 40% of IPF patients undergoing transplant evaluation.
• Clinical findings may suggest underlying PH and right heart strain:
  • Loud P2 component of the second heart sound.
  • Fixed split of S2.
  • Holosystolic murmur of tricuspid regurgitation at the lower left sternal edge.
  • Right ventricular heave on palpation.
  • Jugular venous distension reflecting elevated right atrial pressure.
  • Peripheral oedema or hepatomegaly in more advanced cases.

Resting or Exertional Hypoxaemia

• Seen in moderate to advanced disease.
• Peripheral cyanosis may be noted in hypoxaemic individuals.
• Desaturation may be more prominent on exertion and is often assessed through walk tests rather than visual inspection.

Reduced Chest Expansion

• Chest wall expansion is often symmetrically reduced, especially in lower zones.
• Findings are consistent with restrictive ventilatory impairment.

Absence of Extrapulmonary Manifestations

• Unlike connective tissue disease–related ILDs, IPF does not typically present with signs of systemic involvement (e.g., rash, joint swelling, sclerodactyly).
• Physical examination should include careful screening to exclude these features, which would support an alternative diagnosis.

Initial Imaging

Chest X-ray (CXR)

• Frequently abnormal at presentation, though findings may be subtle.
• May incidentally identify early disease in asymptomatic individuals.
• Typical findings include bilateral, basilar-predominant reticular opacities.
• Less sensitive than HRCT but helpful in identifying alternative diagnoses or complications in acute settings.

High-Resolution Computed Tomography (HRCT)

• Essential for all patients suspected of having IPF.
• Can obviate the need for lung biopsy when characteristic features are present.
• Typical findings:
  • Subpleural and basal-predominant reticulation.
  • Honeycombing, with or without traction bronchiectasis or bronchiolectasis.
  • Absence of extensive ground-glass opacities.
• Diagnostic accuracy increases with experienced radiological interpretation; confident UIP diagnosis on HRCT can exceed 90% accuracy.
• HRCT classification:
  • Typical UIP: Honeycombing, reticular opacities, and traction bronchiectasis in subpleural/basal distribution.
  • Probable UIP: Reticulation with traction bronchiectasis but no honeycombing.
  • Indeterminate UIP: Subtle findings not specific to UIP.
  • Alternative diagnosis: Features suggestive of another ILD (e.g., NSIP, hypersensitivity pneumonitis).

Pulmonary Function Tests (PFTs)

• Support diagnosis by identifying a restrictive ventilatory pattern.
• Common findings include reduced total lung capacity (TLC), vital capacity (VC), and forced vital capacity (FVC).
• Diffusing capacity for carbon monoxide (DLCO) is typically reduced and may be the earliest abnormality.
• Serial monitoring of FVC and DLCO is used for prognostication:
  • 10% decline in FVC or >15% decline in DLCO over 6–12 months is associated with increased mortality.

6-Minute Walk Test (6MWT)

• Measures functional capacity and exertional desaturation.
• Desaturation to <88% is linked with increased mortality.
• Declines in walking distance >24–45 metres over time are clinically significant.
• Heart rate recovery (HRR) failure post-exercise also indicates worse prognosis.

Histological Assessment

Surgical Lung Biopsy (SLB)

• Gold standard for histological diagnosis when HRCT is inconclusive (i.e., probable UIP, indeterminate, or alternative pattern).
• Typically performed via video-assisted thoracoscopic surgery (VATS).
• Histological UIP features:
  • Patchy fibrosis with architectural distortion.
  • Subpleural and paraseptal distribution.
  • Fibroblastic foci and honeycomb changes.
  • Minimal inflammation.
• May not be necessary if HRCT shows classic UIP and other causes of ILD are excluded.

Transbronchial Lung Cryobiopsy (TBLC)

• Acceptable alternative to SLB in centres with experience.
• COLDICE study supports comparable diagnostic yield (~79%).
• ATS/ERS guidelines endorse cryobiopsy as conditionally recommended for ILD of indeterminate type.
• Best performed using COLDICE protocol: ≥4 biopsies from ≥2 lobes using a 1.9 mm cryoprobe.

Transbronchial Lung Biopsy (TBLB)

• Limited role due to small sample size and crush artefacts.
• May be useful for excluding alternative diagnoses (e.g., granulomatous disease, neoplasia).

Bronchoalveolar Lavage (BAL)

• Not required if HRCT shows classic UIP pattern.
• May aid in excluding other conditions in indeterminate cases.
• Elevated lymphocytes (>30–40%) suggest chronic hypersensitivity pneumonitis or other non-IPF ILD.
• BAL neutrophilia is common in IPF and correlates with increased early mortality risk.

Laboratory Investigations

Inflammatory Markers (CRP, ESR)

• Frequently normal or mildly elevated.
• Non-specific and not routinely used to guide management.

Autoimmune Serologies

• Mildly positive ANA or rheumatoid factor may be seen in up to 30% of IPF patients.
• High titres (>1:160) or other positive serologies (e.g., anti-CCP, myositis panel) suggest connective tissue disease-associated ILD.
• Important for excluding autoimmune conditions that mimic IPF.

Specialised Biomarkers (Not Recommended)

• Tests such as MMP-7, SPD, CCL-18, and KL-6 are not recommended for diagnostic purposes due to lack of standardisation or clear clinical benefit.

Cardiac Assessment

Transthoracic Echocardiography

• Assesses for pulmonary hypertension, a common comorbidity.
• May show right heart strain, elevated right ventricular systolic pressure, or impaired RV function.
• Diagnostic utility is limited in fibrotic lungs; right heart catheterisation may be necessary for definitive diagnosis.

Diagnostic Approach Summary

• Diagnosis of IPF requires:
  • Exclusion of alternative aetiologies (e.g., environmental, autoimmune, drug-induced).
  • Presence of a UIP pattern on HRCT.
  • Histopathological confirmation when HRCT is non-definitive.
• Multidisciplinary discussion among pulmonologists, radiologists, and pathologists is essential for accurate diagnosis.

Idiopathic Non-Specific Interstitial Pneumonia (NSIP)

• Common in patients with underlying autoimmune conditions such as systemic sclerosis or polymyositis.
• Clinical course is often slower and more variable than IPF.
• HRCT usually shows diffuse or basal ground-glass opacities with minimal or no honeycombing.
• The presence of circulating autoantibodies may aid differentiation.
• Some cases respond well to immunosuppressive therapy.

Desquamative Interstitial Pneumonia (DIP)

• Strongly associated with smoking.
• Presents subacutely with ground-glass opacities and minimal fibrosis.
• Better prognosis; responds to corticosteroids.

Respiratory Bronchiolitis-Associated ILD (RB-ILD)

• Seen almost exclusively in smokers.
• Typically mild symptoms and good response to smoking cessation.
• CT shows centrilobular nodules and patchy ground-glass opacities.
• Pulmonary function tests (PFTs) may show a mixed obstructive-restrictive pattern.

Cryptogenic Organising Pneumonia (COP)

• Often post-infectious or autoimmune-related.
• Subacute onset with systemic symptoms such as fever, malaise, and weight loss.
• HRCT shows patchy alveolar consolidation or nodules.
• Generally steroid-responsive, distinguishing it from IPF.

Acute Interstitial Pneumonia (AIP)

• Rapid-onset ILD in previously healthy individuals.
• Often preceded by flu-like symptoms, leading to acute respiratory failure.
• HRCT demonstrates bilateral ground-glass opacities and consolidations.
• Histology reveals diffuse alveolar damage rather than UIP.
• Poor prognosis despite aggressive therapy.

Connective Tissue Disease–Associated ILD (CTD-ILD)

• Seen in conditions like rheumatoid arthritis, systemic sclerosis, lupus, or dermatomyositis.
• Systemic symptoms include rash, Raynaud’s phenomenon, or arthralgia.
• Autoantibodies (e.g., ANA, anti-CCP) may be positive.
• HRCT patterns may overlap with UIP or NSIP.
• Often responds to immunosuppressive therapy.

Asbestosis

• Occupational exposure history is key.
• HRCT shows lower-lobe fibrosis and pleural plaques.
• Histology reveals ferruginous bodies.
• Differs from IPF by associated pleural involvement and exposure history.

Chronic Hypersensitivity Pneumonitis (CHP)

• Caused by inhaled antigens like mould or bird proteins.
• Symptoms often fluctuate with antigen exposure.
• HRCT may show centrilobular nodules, mosaic attenuation, and upper-lobe fibrosis.
• BAL lymphocytosis and poorly formed granulomas on biopsy support the diagnosis.
• Avoidance of the offending antigen may halt progression.

Drug-Induced Pulmonary Fibrosis

• Caused by drugs such as amiodarone, methotrexate, bleomycin, or nitrofurantoin.
• Clinical and radiological features may mimic IPF.
• Diagnosis depends on exposure history and exclusion of other causes.
• May improve following drug discontinuation.

Sarcoidosis

• Multisystem granulomatous disease affecting younger patients.
• HRCT typically shows upper-lobe predominance and bilateral hilar lymphadenopathy.
• Histology reveals non-caseating granulomas.
• May involve skin, eyes, liver, or lymph nodes.
• Often responsive to corticosteroids.

Lymphoid Interstitial Pneumonia (LIP)

• Associated with Sjögren’s syndrome, HIV, or immune dysregulation.
• Presents with dyspnoea and systemic autoimmune features.
• HRCT shows ground-glass opacities, cysts, and septal thickening.
• Lung biopsy shows polyclonal lymphoid infiltrates.

Langerhans Cell Histiocytosis (LCH)

• Rare; almost exclusively seen in smokers.
• Presents with spontaneous pneumothorax or non-productive cough.
• HRCT reveals upper- and mid-zone cysts and nodules.
• Diagnosis confirmed with biopsy showing CD1a-positive Langerhans cells.

Lymphangioleiomyomatosis (LAM)

• Affects premenopausal women; may present with pneumothorax.
• CT shows diffuse, thin-walled cysts throughout the lungs.
• Obstructive defect seen on PFTs.
• Associated with tuberous sclerosis complex.

Combined Pulmonary Fibrosis and Emphysema (CPFE)

• Seen in smokers, especially men.
• Presents with dyspnoea, exercise-induced hypoxaemia, and preserved lung volumes despite low DLCO.
• HRCT shows upper-lobe emphysema with lower-lobe fibrosis.
• Associated with pulmonary hypertension and poor prognosis.

Pneumocystis jirovecii Pneumonia

• Seen in immunocompromised individuals.
• Presents with fever, dyspnoea, and diffuse bilateral infiltrates.
• HRCT shows ground-glass opacities.
• Diagnosed via sputum or BAL fluid analysis.

Chronic Fungal or Bacterial Infection

• Includes tuberculosis, atypical mycobacteria, and endemic fungal infections.
• May present with chronic infiltrates and fibrosis.
• Diagnosis confirmed by microbiology and histology.

Aspiration Pneumonitis

• Associated with impaired swallowing or reflux.
• Predominantly affects posterior lower lobes.
• Diagnosis supported by history and presence of lipid-laden macrophages on BAL.

Pulmonary Oedema

• Presents acutely with bibasilar crackles and peripheral oedema.
• Reversible with diuresis.
• Echocardiography and BNP help differentiate from IPF.

Lung Cancer

• May mimic or coexist with IPF.
• New or growing nodules on imaging should prompt further investigation.
• CT and PET scan help in differentiation.

Overview

• IPF is a progressive fibrotic lung disease marked by irreversible scarring, characterised histologically and radiologically by a usual interstitial pneumonia (UIP) pattern. 
• Given its variable course, therapeutic strategy hinges on early diagnosis, functional staging, antifibrotic treatment, vigilant monitoring, symptomatic support, and evaluation for lung transplantation. 
• A multidisciplinary, dynamic approach is necessary due to the risk of sudden exacerbations and heterogeneous progression.

Pharmacological Management

Nintedanib

• Nintedanib inhibits multiple tyrosine kinase receptors including VEGF, PDGF, and FGF, disrupting fibroblast proliferation and extracellular matrix deposition.
• Clinical trials demonstrate a significant reduction in the annual rate of FVC decline, with modest delay in first acute exacerbation.
• The standard regimen is 150 mg twice daily, but dose reductions to 100 mg twice daily may be needed for tolerability.
• Adverse effects are predominantly gastrointestinal, particularly diarrhoea, which may necessitate antidiarrhoeal therapy, dose adjustment, or treatment interruption.
• Monitoring of liver function tests is essential, particularly during the first three months.
• Use is contraindicated in patients with moderate-to-severe hepatic impairment.

Pirfenidone

• This pyridone derivative possesses both antifibrotic and anti-inflammatory actions by modulating TGF-β-mediated pathways.
• Administered at a target dose of 2403 mg/day in three divided doses, titrated over two weeks to minimise gastrointestinal side effects.
• It reduces the rate of FVC decline, increases progression-free survival, and has shown a mortality benefit in pooled analyses.
• Side effects include nausea, photosensitivity rash, fatigue, and elevated liver enzymes.
• Liver function tests should be assessed at baseline and regularly thereafter.
• Use is avoided in patients with severe hepatic or renal dysfunction.

Combination Therapy

• Simultaneous administration of pirfenidone and nintedanib is not routinely recommended.
• While small studies show possible feasibility, gastrointestinal toxicity—especially diarrhoea—can be prohibitive.

Acute Exacerbation Management

• Defined as a sudden worsening in respiratory status with new bilateral alveolar infiltrates not explained by other causes.
• Management is supportive: supplemental oxygen, symptom relief, and high-dose corticosteroids may be administered despite limited evidence.
• Cytotoxic agents (e.g., cyclophosphamide) have been associated with harm and are not recommended.
• Mechanical ventilation is typically avoided due to high mortality unless performed for other reversible causes.
• Antifibrotic therapy may reduce future exacerbation risk and is generally continued during exacerbations.

Supportive and Non-Pharmacological Management

Smoking Cessation and Drug Review

• All patients should be advised to quit smoking and avoid lung-toxic medications such as amiodarone, bleomycin, and methotrexate.

Pulmonary Rehabilitation

• Includes aerobic and resistance training, education, and behavioural modification.
• Improves exercise tolerance, dyspnoea, and quality of life.
• Effects are sustained for 6–12 months post-programme in many patients.

Oxygen Therapy

• Indicated for patients with resting or exertional hypoxaemia (PaO₂ ≤55 mmHg or SpO₂ ≤89%).
• Benefits include improved exercise performance and delay in development of pulmonary hypertension or cor pulmonale.
• Selection should be individualised as not all patients respond beneficially.

Vaccination

• Annual influenza, pneumococcal, COVID-19, and RSV vaccination is advised to reduce infectious complications.

Palliative Care

• Initiated early in the disease course, based on individual symptom burden and psychosocial needs.
• Symptoms such as chronic cough, dyspnoea, fatigue, anxiety, and depression are targeted.
• Low-dose opioids (e.g., morphine) may reduce cough frequency and improve breathlessness.
• Palliative referral is warranted for persistent symptoms despite standard care, or when ventilatory support or oxygen therapy is being considered.
• Advance care planning discussions are essential and should be revisited periodically.

Lung Transplantation

Referral and Timing

• Referral should occur at diagnosis in appropriate patients, particularly those with familial disease, to ensure timely evaluation.
• Candidates include those with FVC decline ≥10% in 6 months, DLCO <40%, 6MWT desaturation <88%, or hospitalisation for respiratory decline.

Procedure Considerations

• Bilateral lung transplantation is associated with better long-term outcomes than single-lung procedures.
• Postoperative complications include chronic lung allograft dysfunction, infection, malignancy, and side effects of chronic immunosuppression.
• Pre-transplant assessment should screen for telomerase mutations and marrow dysfunction in familial IPF.
• High-dose glucocorticoid therapy prior to transplant may impair post-operative survival.

Discouraged or Contraindicated Therapies

• Agents such as ambrisentan, bosentan, macitentan, imatinib, and interferon gamma-1b have shown no clinical benefit and may cause harm.
• Warfarin is contraindicated unless indicated for unrelated conditions due to increased mortality risk.
• Triple immunosuppressive therapy (prednisolone, azathioprine, NAC) increases death and hospitalisation risk.
• NAC monotherapy does not improve outcomes and is not advised.
• Sildenafil and other phosphodiesterase-5 inhibitors are not routinely beneficial.
• Empiric antireflux therapy for asymptomatic gastro-oesophageal reflux is not recommended, though symptomatic GERD should be treated per standard guidelines.

Emerging and Investigational Therapies

Nerandomilast

• A selective PDE4B inhibitor showing modest FVC preservation in phase 2 trials, particularly when combined with existing antifibrotics.
• Gastrointestinal side effects, especially diarrhoea, are frequent.

Admilparant

• An antagonist of lysophosphatidic acid receptor 1, with early-phase data suggesting reduced disease progression markers.

Pamrevlumab

• A monoclonal antibody targeting connective tissue growth factor (CTGF); failed to meet endpoints in phase 3 trials despite encouraging phase 2 findings.

Pentraxin 2 (Serum Amyloid P)

• An innate immune modulator. While earlier data were promising, later trials did not confirm benefit and its development has ceased.

Overall

• IPF is a relentlessly progressive interstitial lung disease with a median survival estimated between 2 to 5 years from the time of diagnosis.
• Disease trajectory is highly variable:
  • Some patients exhibit slow progression over several years.
  • Others experience a more rapid functional decline.
  • A subset remain stable for a period and then deteriorate abruptly due to acute exacerbations.

Favourable Prognostic Indicators

• Atypical high-resolution CT (HRCT) features that do not conform to the classic UIP pattern.
• Stable or improved forced vital capacity (FVC) or diffusing capacity for carbon monoxide (DLCO) within the first 6 months after diagnosis.
• Paradoxically, current smoking has been associated with better survival, although this is likely due to confounding by disease severity at presentation.

Adverse Prognostic Indicators

• Advanced age and male sex.
• Lower baseline FVC or DLCO values.
• Decline in FVC or DLCO over 6–12 months following diagnosis.
• Presence of extensive fibroblastic foci on histology.
• Oxygen desaturation during a 6-minute walk test (6MWT).
• Impaired heart rate recovery after exertion.
• Occurrence of acute exacerbations.
• Family history of pulmonary fibrosis, particularly in first-degree relatives, which confers a 4.7-fold increase in mortality risk.

Mortality Statistics

• In one cohort, IPF-related mortality rose by 53% over a decade, with higher rates in men than women.
• Placebo-controlled trial meta-analyses showed:
  • Mortality rate of 78.6 per 1,000 patient-years in mild-to-moderate disease.
  • Mortality rate of 188.6 per 1,000 patient-years in severe disease.
• Acute exacerbations can account for up to 46% of IPF-related deaths.

Prognostic Models

• The Gender-Age-Physiology (GAP) index is a validated staging system that stratifies risk of death based on:
  • Gender (male = 1 point; female = 0).
  • Age (0–2 points based on age brackets).
  • FVC % predicted (0–2 points).
  • DLCO % predicted (0–3 points or “cannot perform” = 3).
• GAP stage correlates with mortality:
  • Stage I (score 0–3): lowest risk.
  • Stage II (score 4–5): intermediate risk.
  • Stage III (score 6–8): highest risk.
• The GAP model was originally validated in untreated patients; its application to treated populations is under ongoing evaluation.

Survival and Quality of Life

• Although the median survival remains poor, around 20–25% of patients may live beyond 10 years post-diagnosis.
• A small proportion survive long-term without pharmacological intervention.
• Dyspnoea, limited exercise tolerance, and fatigue severely impair quality of life.
• Pulmonary hypertension is common in advanced disease and contributes to increased risk of pulmonary embolism and sudden cardiac death.
• Mortality peaks during winter months, even in the absence of overt infection.

Biomarkers

• Numerous blood-based biomarkers have been explored (e.g., KL-6, surfactant proteins A and D, MMP-7).
• Their integration into clinical decision-making is limited due to inconsistent validation across studies.

Impact of Treatment

• Antifibrotic therapies and earlier diagnosis appear to have contributed to a modest improvement in survival trends since 2010.
• Ongoing monitoring of disease progression is essential to guide timely treatment adjustments, palliative support, and consideration for lung transplantation.

Lung Cancer

• IPF significantly increases the risk of bronchogenic carcinoma, with incidence reported between 4% and 48%.
• The exact mechanism linking fibrosis and malignancy remains unclear, but chronic epithelial injury is likely contributory.
• Antifibrotic therapies may reduce the incidence of lung cancer and are associated with improved survival in patients with concurrent disease.

Pulmonary Hypertension (PH)

• Classified under WHO Group 3, PH is a common and serious complication of IPF.
• Prevalence at diagnosis is estimated at 8–15%, rising to 50–60% in advanced and end-stage disease.
• The presence of PH markedly worsens prognosis and survival.
• Systemic vasomodulators are generally not recommended, though treprostinil may offer benefit in select patients with exercise limitation.
• Sildenafil, when combined with antifibrotics, has shown inconsistent clinical benefits despite possible improvements in some endpoints.

Pulmonary Infection

• Bacterial and viral infections contribute to acute worsening of symptoms and disease progression.
• Co-infections are linked to significantly higher mortality and poorer respiratory outcomes.
• Preventive strategies such as vaccination and prompt antibiotic therapy are essential in at-risk patients.

Gastro-Oesophageal Reflux Disease (GORD)

• Highly prevalent in IPF and hypothesised to promote fibrosis via chronic microaspiration.
• Despite its frequency, the 2022 guidelines advise against medical or surgical treatment of asymptomatic reflux purely to improve respiratory outcomes.
• Symptomatic cases should be treated according to standard GORD management protocols.

Pulmonary Embolism (PE)

• PE can cause sudden clinical deterioration in IPF and contributes to up to 7% of disease-related deaths.
• The chronic inflammatory and fibrotic state in IPF increases thrombogenic risk.
• Prompt recognition and treatment are crucial in acutely decompensating patients.

Acute Coronary Syndrome (ACS)

• Patients with IPF are at increased risk of coronary artery disease and myocardial infarction.
• Chronic systemic inflammation and shared risk factors such as smoking may underlie this association.
• Cardiovascular monitoring is important, particularly in patients with exertional dyspnoea disproportionate to lung function decline.

Deep Venous Thrombosis (DVT)

• IPF is associated with a higher incidence of venous thromboembolism, including DVT.
• Factors contributing include physical deconditioning, systemic inflammation, and vascular dysfunction.
• The clinical threshold for DVT investigation should be lower in symptomatic IPF patients.

Pneumothorax

• Although uncommon in IPF, when it occurs, it presents a management challenge due to fibrotic lung stiffness.
• Treatment may be complicated by persistent air leak and poor lung expansion.
• Increased vigilance is warranted in cases with sudden pleuritic chest pain or subcutaneous emphysema.

1. American Thoracic Society; European Respiratory Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. Am J Respir Crit Care Med. 2000;161(2 Pt 1):646–664.
2. Armanios M, Blackburn EH. The telomere syndromes. Nat Rev Genet. 2012;13(10):693–704.
3. Baumgartner KB, Samet JM, Coultas DB, et al. Occupational and environmental risk factors for idiopathic pulmonary fibrosis: a multicenter case–control study. Am J Epidemiol. 2000;152(4):307–315.
4. Beasley MB, Gal AA. Current diagnostic criteria for idiopathic pulmonary fibrosis: what pathologists need to know. Arch Pathol Lab Med. 2010;134(6):837–851.
5. Behr J, Nathan SD, Harari S, et al. Pulmonary hypertension in idiopathic pulmonary fibrosis. Eur Respir J. 2009;34(3):623–628.
6. Behr J, Ryu JH. Pulmonary hypertension in interstitial lung disease. Eur Respir J. 2008;31(6):1357–1367.
7. Bjoraker JA, Ryu JH, Edwin MK, et al. Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998;157(1):199–203.
8. Borie R, Kannengiesser C, Gouya L, et al. Pilot study of blood telomere length in adult patients with idiopathic pulmonary fibrosis. Eur Respir J. 2015;46(5):1710–1712.
9. Cottin V, Cordier JF. Combined pulmonary fibrosis and emphysema. Curr Opin Pulm Med. 2005;11(5):422–426.
10. Cottin V, Hirani NA, Hotchkin DL, et al. Presentation, diagnosis and clinical course of the spectrum of progressive-fibrosing interstitial lung diseases. Eur Respir Rev. 2018;27(150):180076.
11. Collard HR, Chen SY, Yeh WS, et al. Health care utilization and costs in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2015;192(3):392–398.
12. Collard HR, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. 2006;27(1):136–142.
13. Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2007;176(7):636–643.
14. Collard HR, King TE Jr. Demystifying idiopathic interstitial pneumonia. Arch Intern Med. 2003;163(1):17–29.
15. Corte TJ, Wort SJ, Wells AU. Pulmonary hypertension in idiopathic pulmonary fibrosis: a review. Sarcoidosis Vasc Diffuse Lung Dis. 2007;24(2):123–132.
16. du Bois RM, Weycker D, Albera C, et al. Six-minute-walk test in idiopathic pulmonary fibrosis: test validation and minimal clinically important difference. Am J Respir Crit Care Med. 2011;183(9):1231–1237.
17. Egan JJ, Stewart JP, Hasleton PS, et al. Epstein-Barr virus replication within pulmonary epithelial cells in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1995;151(2):758–763.
18. Fernandez Perez ER, Daniels CE, Schroeder DR, et al. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study. Chest. 2010;137(1):129–137.
19. Fingerlin TE, Zhang W, Yang IV, et al. Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. Nat Genet. 2013;45(6):613–620.
20. Flaherty KR, King TE Jr, Raghu G, et al. Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis? Am J Respir Crit Care Med. 2004;170(8):904–910.
21. Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718–1727.
22. Garcia CK. Idiopathic pulmonary fibrosis: update on genetic discoveries. Proc Am Thorac Soc. 2011;8(2):158–162.
23. Glassberg MK. Overview of idiopathic pulmonary fibrosis, evidence-based guidelines, and recent developments in the field. Am J Manag Care. 2011;17(3 Suppl):S118–S124.
    Heukels P, Moor CC, von der Thüsen JH, et al. Inflammation and immunity in IPF pathogenesis and treatment. Respir Med. 2019;147:79–91.
24. Hubbard RB, Smith CJP, Le Jeune I, et al. The association between idiopathic pulmonary fibrosis and vascular disease: a population-based study. Am J Respir Crit Care Med. 2008;178(12):1257–1261.
25. Hutchinson J, Fogarty A, Hubbard R, McKeever T. Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Respir J. 2015;46(3):795–806.
26. Hetzel J, Maldonado F, Ravaglia C, et al. Transbronchial cryobiopsies for the diagnosis of diffuse parenchymal lung diseases: expert statement from the Cryobiopsy Working Group on Safety and Utility and a call for standardisation of the procedure. Respiration. 2018;95(3):188–200.
27. Kinder BW, Brown KK, Schwarz MI, et al. Baseline BAL neutrophilia predicts early mortality in idiopathic pulmonary fibrosis. Chest. 2008;133(1):226–232.
28. King TE Jr, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet. 2011;378(9807):1949–1961.
29. Kolilekas L, Manali ED, Bouros DE, et al. Obstructive sleep apnea and idiopathic pulmonary fibrosis: an under-recognised overlap syndrome. Lung. 2013;191(1):9–14.
30. Kropski JA, Blackwell TS. Progress in understanding and treating idiopathic pulmonary fibrosis. Annu Rev Med. 2019;70:211–224.
31. Kropski JA, Blackwell TS. Endoplasmic reticulum stress in the pathogenesis of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2018;315(4):L684–L695.
32. Lawson WE, Grant SW, Ambrosini V, et al. Genetic mutations in surfactant protein C and lung disease. Am J Respir Cell Mol Biol. 2004;31(5):582–591.
33. Lee JS, Collard HR, Anstrom KJ, et al. Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. Lancet Respir Med. 2013;1(5):369–376.
34. Lee JS, Ryu JH, Elicker BM, et al. Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184(12):1390–1394.
35. Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med. 2018;378(19):1811–1823.
36. Ley B, Ryerson CJ, Vittinghoff E, et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med. 2012;156(10):684–691.
37. Lynch DA, Sverzellati N, Travis WD, et al. Diagnostic criteria for idiopathic pulmonary fibrosis: A Fleischner Society White Paper. Lancet Respir Med. 2018;6(2):138–153.
38. Maher TM. Why study IPF now? Respir Med. 2011;105(Suppl 2):S3–S8.
39. Mermigkis C, Chapman J, Golish JA, et al. Sleep-related breathing disorders in patients with idiopathic pulmonary fibrosis. Lung. 2007;185(3):173–178.
40. Molyneaux PL, Cox MJ, Willis-Owen SA, et al. The role of bacteria in the pathogenesis and progression of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2014;190(8):906–913.
41. Molyneaux PL, Maher TM. The role of infection in the pathogenesis of idiopathic pulmonary fibrosis. Eur Respir Rev. 2013;22(129):376–381.
42. Noble PW, Barkauskas CE, Jiang D. Pulmonary fibrosis: patterns and perpetrators. J Clin Invest. 2012;122(8):2756–2762.
43. Nathan SD, Shlobin OA, Ahmad S, et al. Pulmonary hypertension and pulmonary function testing in idiopathic pulmonary fibrosis. Chest. 2007;131(3):657–663.
44. Nathan SD, Meyer KC. IPF clinical trial design and endpoints: lessons learned and future directions. Eur Respir Rev. 2014;23(132):374–380.
45. Noth I, Zhang Y, Ma SF, et al. Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study. Lancet Respir Med. 2013;1(4):309–317.
46. Olson AL, Swigris JJ, Lezotte DC, Norris JM, Wilson CG, Brown KK. Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003. Am J Respir Crit Care Med. 2007;176(3):277–284.
47. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines. Am J Respir Crit Care Med. 2011;183(6):788–824.
48. Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. 2006;27(1):136–142.
49. Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2018;198(5):e44–e68.
50. Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174(7):810–816.
51. Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of idiopathic pulmonary fibrosis: An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198(5):e44–e68.
52. Seibold MA, Wise AL, Speer MC, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011;364(16):1503–1512.
53. Steele MP, Speer MC, Loyd JE, et al. Clinical and pathologic features of familial interstitial pneumonia. Am J Respir Crit Care Med. 2005;172(9):1146–1152.
54. Stewart JP, Egan JJ, Ross AJ, et al. Infection with Epstein-Barr virus in idiopathic pulmonary fibrosis: a study using polymerase chain reaction. Thorax. 1999;54(4):295–301.
55. Sweet MP, Patti MG, Leard LE, et al. Gastro-oesophageal reflux in patients with idiopathic pulmonary fibrosis referred for lung transplantation. J Thorac Cardiovasc Surg. 2007;133(4):1078–1084.
56. Tzouvelekis A, Karampitsakos T, Kourtidou S, et al. Thyroid dysfunction in idiopathic pulmonary fibrosis: a neglected comorbidity? Respir Res. 2020;21(1):261.
57. Wells AU, Flaherty KR, Brown KK, et al. Nintedanib in patients with progressive fibrosing interstitial lung diseases—subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2020;8(5):453–460.
58. Wootton SC, Kim DS, Kondoh Y, et al. Viral infection in acute exacerbation of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183(12):1698–1702.
59. Zhang Y, Noth I, Garcia JG, Kaminski N. A variant in the promoter of MUC5B and idiopathic pulmonary fibrosis. N Engl J Med. 2011;364(16):1576–1577.