Idiopathic pulmonary fibrosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing disease of the interstitial lung diseases which leads to irreversible decline in the lung functions for unknown cause. IPF is one of the interstitial lung disease and particularly is a subtype of idiopathic interstitial pneumonia. Pulmonary fibrosis share the pathogenesis process of interstitial lung disease which involve the pulmonary parenchyma. Although the exact pathogenesis is not fully understood, there are many initiating factors which cause the pulmonary tissue injury. The main features of the lung injury includes inflammation, fibrosis, and granulomas development. Common causes of pulmonary fibrosis include autoimmunity, rheumatoid arthritis, scleroderma, tuberculosis, SLE, sarcoidosis, and polymyositis. Other causes of pulmonary fibrosis include environmental factors as cigarette smoking and dust exposure. Idiopathic pulmonary fibrosis must be differentiated from other causes of interstitial lung diseases which may cause fibrosis as well. Prevalence of idiopathic pulmonary fibrosis ranges from a low of 0.5 per 100.000 persons to a high of 27.9 per 100.000. Incidence of idiopathic pulmonary fibrosis ranges from a low of 3 per 100,000 persons to a high of 9 per 100,000 persons. Common risk factors of pulmonary fibrosis include cigarette smoking and genetic mutations which include hTERT, MUC5B, TERT, and RTEL1. Other risk factors include GERD and wood dust. If left untreated, idiopathic pulmonary fibrosis will lead to complete respiratory failure and death. Common complications of idiopathic pulmonary fibrosis include pulmonary hypertension, lung cancer, and cardiovascular comorbidities. The prognosis of idiopathic pulmonary fibrosis is usually poor with a survival rate from 2 to 5 years. Common symptoms of idiopathic pulmonary fibrosis include Dyspnea, cough, Clubbing, Crackles, and arthralgia. Physical examination of patients with occupational lung disease is usually remarkable for bronchial breathing, increased vocal resonance, and fine crepitations. On chest CT scan, Idiopathic pulmonary fibrosis is characterized by honeycombing appearance of the lungs, bronchiectasis, ground glass opacities, and distortion of the lung opacities. The mainstay of the therapy is supportive care measures as mechanical ventilation. Lung transplantation is essential in treatment of patients with idiopathic pulmonary fibrosis. Pulmonary fibrosis is the most common interstitial lung disease requiring lung transplant and it should be performed early in order to increase the survival rate.

Pulmonary fibrosis was first described by Dr. Von Buhl in 1872. Dr. Rindfleish reported a case of a 40 year old patient who presented with worsening cough and dyspnea and he named this case as “Cirrhosis cystica pulmonum” in 1898.

Idiopathic pulmonary fibrosis is a disease among a large group of the interstitial lung diseases and particularly a subtype of the idiopathic interstitial pneumonia. The major group Acute Interstitial Pneumonia (AIP), Cryptogenic Organizing Pneumonia (COP), Respiratory Bronchiolitis–Interstitial Lung Disease (RB-ILD), and Desquamative Interstitial Pneumonia (DIP).

Pulmonary fibrosis share the pathogenesis process of interstitial lung disease which involve the pulmonary parenchyma. Although the exact pathogenesis is not fully understood, there are many initiating factors which cause the pulmonary tissue injury. The main features of the lung injury includes inflammation, fibrosis, and granulomas development.

Common causes of pulmonary fibrosis include autoimmunity, rheumatoid arthritis, scleroderma, tuberculosis, SLE, sarcoidosis, and polymyositis. Other causes of pulmonary fibrosis include environmental factors as cigarette smoking and dust exposure.

Idiopathic pulmonary fibrosis must be differentiated from other causes of interstitial lung diseases which may cause fibrosis as well. Other diseases may include acute interstitial pneumonia, hypersensitivity pneumonia, occupational lung diseases, and pulmonary hemorrhage diseases.

Prevalence of idiopathic pulmonary fibrosis ranges from a low of 0.5 per 100.000 persons to a high of 27.9 per 100.000. Incidence of idiopathic pulmonary fibrosis ranges from a low of 3 per 100,000 persons to a high of 9 per 100,000 persons. The prevalence of idiopathic pulmonary fibrosis increases with age. Idiopathic pulmonary fibrosis is more prevalent in men more than women.

Common risk factors of pulmonary fibrosis include cigarette smoking and genetic mutations which include hTERT, MUC5B, TERT, and RTEL1. Other risk factors include GERD and wood dust. 

There is insufficient evidence to recommend routine screening for idiopathic pulmonary fibrosis.

If left untreated, idiopathic pulmonary fibrosis will lead to complete respiratory failure and death. Common complications of idiopathic pulmonary fibrosis include pulmonary hypertension, lung cancer, and cardiovascular comorbidities. The prognosis of idiopathic pulmonary fibrosis is usually poor with a survival rate from 2 to 5 years.

The diagnostic criteria for IPF includes major criteria and minor criteria. The major criteria must include exclusion of other causes of interstitial lung disease, pulmonary function tests that is evident of lung fibrosis, bibasilar reticular abnormalities in CT lung, and lung biopsy shows fibrosis. The minor criteria should include 3 of 4 criterion as age > 50, duration of illness more than 3 months, bibasilar inspiratory crackles, and insidious onset of exertional dyspnea.

Common symptoms of idiopathic pulmonary fibrosis include Dyspnea, cough, Clubbing, Crackles, and arthralgia. Less common symptoms include Hamman-Rich Syndrome.

Patients with idiopathic pulmonary fibrosis usually appear fatigued and short of breath. Physical examination of patients with idiopathic pulmonary fibrosis is usually remarkable for bronchial breathing, increased vocal resonance, and fine crepitations.

There are no diagnostic laboratory findings associated with pulmonary fibrosis. However, useful laboratory findings consistent with the diagnosis of pulmonary fibrosis include abnormal arterial blood gases, sputum analysis, and blood picture.

X ray imaging does not show specific features for idiopathic pulmonary fibrosis. However, patients with idiopathic pulmonary fibrosis have imaging abnormalities from the beginning of the disease course.

On chest CT scan, Idiopathic pulmonary fibrosis is characterized by honeycombing appearance of the lungs, bronchiectasis, ground glass opacities, and distortion of the lung opacities.

There are no MRI findings associated with idiopathic pulmonary fibrosis.

There are no other imaging findings associated with idiopathic pulmonary fibrosis.

Other diagnsotic findings consistent with diagnosis of idiopathic pulmonary fibrosis include reduced lung volumes and decreased diffusion capacity of carbon monoxide. Both are performed via spirometry.

The mainstay of therapy for idiopathic pulmonary fibrosis is the supportive care measures which include mechanical ventilation, pulmonary rehabilitation, and vaccination against influenza and pneumococcus. Medical treatment as nintedanib and pirfenidone can be administrated to slow the disease progression.

Lung transplantation is essential in treatment of patients with idiopathic pulmonary fibrosis. Pulmonary fibrosis is the most common interstitial lung disease requiring lung transplant and it should be performed early in order to increase the survival rate.

The primary prevention of pulmonary fibrosis or usual interstitial pneumonia includes smoking cessation and vaccination against influenza.

The primary and secondary prevention strategies for idiopathic pulmonary fibrosis are the same.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Pulmonary fibrosis was first dexcribed by Dr. Von Buhl in 1872. Dr. Rindfleish reported a case of a 40 year old patient who presented with worsening cough and dyspnea and he named this case as “Cirrhosis cystica pulmonum” in 1898.

• In 1872, Von Buhl reported pulmonary histologic findings which included infiltration of the lung with fibroblasts and excessive connective tissue. Dr. Von buhl reported this cases as a desquamative pneumonia due to desquamation of the alveolar and bronchiolar epithelium. Dr. Von buhl also used the term chronic interstitial pneumonia for the chronic cases and he assumed the cause to be tuberculosis or syphilis.^[1]
• In 1898, Dr. Rindfleisch reported a case of a 40 year old man who presented with worsening cough and dyspnea which are related to idiopathic pulmonary fibrosis. Dr. Rindfleisch described a a small stiffed lungs and hypertrophied right ventricles. The lungs contained dense fibrous tissues with round cells. Dr. Rindfleisch used the term “Cirrhosis cystica pulmonum” for this case at that time.
• In 1907, Dr. Sandoz reported a case in twin sisters who presented also with worsening cough and dyspnea. Both cases had a hypertrophic right ventricle and small lungs with thickened bronchioli and dense interstitial tissue. Dr. Sandoz named this case as “Fetal bronchiectasis“.
• In 1912, Dr. von Hansemann reported five cases with lung interstitial abnormalities in the histologic examination. Dr. von Hansemann named those cases as “lymphangitis reticularis pulmonum”.
• From 1933 to 1944, Hamman and Rich described some cases of IPF. Dr. Hamman and Rich described the clinical and pathological features of a lung disease at which they named it as “acute diffuse interstitial fibrosis of the lungs”. The clinical features included dyspnea, cyanosis, and cough. The histological features included alveolar edema, erythrocytosis, and hyalinization.^[2]
• In 1945, based on the description of Dr. Hamman and Rich, Dr. Eder described fingers and toes clubbing as another clinical feature of IPF.^[3]
• In 1949, it had been reported that the chronic form of IPF is more common than the acute diseae.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Idiopathic pulmonary fibrosis is a disease among a large group of the interstitial lung diseases and particularly a subtype of the idiopathic interstitial pneumonia. The major group include acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP), respiratory bronchiolitis–interstitial lung disease (RB-ILD), and desquamative interstitial pneumonia (DIP).

• Idiopathic pulmonary fibrosis is a disease among a large group of the interstitial lung diseases and particularly a subtype of the idipathic interstitial pneumonia. The major forms of the idiopathic interstitial pneumonia include:
• The idiopathic interstitial pneumonias are classified by the American Thoracic Society/European Respiratory Society (ATS/ERS) into three main groups:^[1]
  • Major idiopathic interstitial pneumonia
  • Rare idiopathic interstitial pneumonia
  • Unclassifiable idiopathic interstitial pneumonia
• The idiopathic interstitial fibrosis is the chronic form of the idiopathic interstitial pneumonia. Other forms of the idiopathic interstitial pneumonia include the following:
  • Acute or subacute: Acute interstitial pneumonia (AIP) and cryptogenic organizing pneumonia (COP)
  • Chronic: Idiopathic pulmonary fibrosis (IPF)
  • Smoking-related: Respiratory bronchiolitis–interstitial lung disease (RB-ILD) and desquamative interstitial pneumonia (DIP)

Template:WH Template:WS [[Category:Primary Care]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Pulmonary fibrosis share the pathogenesis process of interstitial lung disease which involve the pulmonary parenchyma. Although the exact pathogenesis is not fully understood, there are many initiating factors which cause the pulmonary tissue injury. The primary features of the lung injury includes inflammation, fibrosis, and granulomas development.

• Lungs are composed normally of extracellular collagen which allows the lungs to exert their breathing efforts.
• Different collagen types in the lung include the following:^[1]
  • Type 1 and type 3 compose majority of the lung tissue
  • Type 2 is the primary component of the cartilage of the main bronchi
  • Type 4 forms the basement membrane
  • Type 5 forms the interstitial tissue
• Normally, collagen is degraded and produced regularly to preserve the normal lung tissue.^[2]
• Collagen is produced by fibroblasts which also can degrade some of the collagen produced.
• Metalloproteinases produced by fibroblasts, neutrophils, and macrophages plays a primary role in degradation of collagen.

• Interstitial lung disease is a group of disorders that involve pulmonary parenchyma.
• The exact pathogenesis of these disorders is not fully understood.
• There are multiple initiating factors that cause pulmonary injury. However, immunopathogenic responses of lung tissue are quite similar.
• There are two major histopathologic patterns in response to lung injury which include:
  • Inflammation and fibrosis pattern
  • Granulomatous pattern

Tissue injury in lungs

Parenchymal injury

Vascular injury

Mast cells in lungs in response to tissue injury

LPA6, LPA2, and LPA4 receptors[4]

Decreased sFRP-1 (secreted frizzled-related protein 1) in fibroblasts[5]

Secretes tryptase

Transforming growth factor-β (TGF-β)[6]

Insulin-like growth factor (IGF) signalling[5]

Reduced expression of angiogenic factors, vascular endothelial growth factor (VEGF)[7]

Elevation of angiostatic factors, pigment epithelium-derived factor[8]

Wnt/β-catenin signalling pathway[9][10]

PAR-2/protein kinase (PK)C-α/Raf-1/p44/42 signaling pathway[11]

Upregulation of Egr-1 (early growth response protein 1)[12]

IGF-binding protein 5 (IGFBP-5)[13]

IGF-binding protein 3 (IGFBP-3)

Loss of endothelial barrier function

Dysregulation of repair in lung tissue and activation of fibroblasts[14]

Regulates transforming growth factor-β (TGF-β)

Induction of syndecan-2 (SDC2)[15]

Activation,proliferation, and migration of fibroblast to the site of injury

Fibroblasts

Altered PTEN (phosphatase and tensin homologue)/Akt axis

Acquire contractile stress fibres

Inactivates Fox (forkhead box) O3a[16]

Protomyofibroblast, composed of cytoplasmic actins

Pleural mesothelial cells (PMCs)[17][18]

Downregulation of caveolin-1 (cav-1) and Fas expression[19]

De novo expression of α-smooth muscle actin (α-SMA)

TGF-β1-dependent mesothelial–mesenchymal transition

Fibroblast resistant to apoptosis[20]

Myofibroblasts[21]

Different ranges of contractions mediated by RhoA/Rho-associated kinase

Changes in intracellular calcium concentrations

Recruitement of fibrocytes in lungs

Lock step mechanism of cyclic and contractile events[22]

T-helper cell type 2 on site of injury[23][24]

Upregulation of C-X-C chemokine receptor type 4 (CXCR4) on fibrocytes and its ligand CXCL12 (stromal cell-derived factor 1)[25]

Excess extracellular matrix production

Exerting traction force

Interleukin-13

Migration of fibrocytes to the site of injury[26]

Tissue remodelling[27]

Alternate pathway activation of macrophages[28]

Lung Fibrosis

• The most important characteristics of idiopathic pulmonary fibrosis on gross pathology include:^[29]
  • Inferior lobes fibrosis
  • Cobblestone appearance of the pleura
  • Honeycomb appearance of the lung
  • Air-spaces enlargement
  • Fibrotic retraction of the airways

• The microscopic feature associated with idiopathic pulmonary fibrosis is named as “usual interstitial pneumonia (UIP)”.^[30]
• The histologic findings in UIP include the following:
  • Proliferation of mesenchymal cells
  • Areas of different fibrosis degree
  • Dense deposition of collagen fibers
  • Overproduction of extracellular matrix
  • Poor differentiated pulmonary architecture
  • Honeycomb cysts (sub-pleural cysts)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Common causes of pulmonary fibrosis include autoimmunity, rheumatoid arthritis, scleroderma, tuberculosis, SLE, sarocoidosis, and polymyoisitis. Other causes of pulmonary fibrosis include environmental factors as cigarette smoking and dust exposure.

The most common causes of pulmonary fibrosis are:^[1][2]

• Autoimmune diseases:
• Rheumatoid arthritis
• Scleroderma (systemic sclerosis)
• Tuberculosis
• Pneumonia
• Systemic lupus erythematosus
• Sarcoidosis
• Polymyositis
• Dermatomyositis
• Anti-synthetase syndrome
• Gastroesophageal reflux disease

• Cigarette smoke
• Asbestos exposure
• Silica exposure
• Coal dust exposure
• Beryllium exposure
• Hard metal dusts exposure
• Animal protein exposure
• Bacteria, mold exposure
• Radiation

• lomustine
• Panitumumab
• Penicillamine
• Rifapentin
• Methotrexate (Trexall)
• Cyclophosphamide (Cytoxan)
• Amiodarone (Cordarone)
• Nexterone (Pacerone)
• Propranolol (Inderol, Innopran)
• Nitrofurantoin (Macrobid, Macrodantin)
• Sulfasalazine (Azulfidine)

Genetic and Inherited Diseases also make up 10-15% of idiopathic pulmonary fibrosis diagnosis.

Cardiovascular	No underlying causes
Chemical / poisoning	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	Methotrexate, Trexall, Cyclophosphamide, Cytoxan, Amiodarone, Cordarone, Nexterone, Pacerone, propranolol, Inderol, Innopran, Nitrofurantoin, Macrobid, Macrodantin, Sulfasalazine, Azulfidine
Ear Nose Throat	No underlying causes
Endocrine	No underlying causes
Environmental	Cigarette Smoke, Asbestos, silica, Coal dust, Beryllium, heavy metal dusts, Animal proteins, Bacteria, Molds, Radiation
Gastroenterologic	Gastroesophageal reflux disease
Genetic	No underlying causes
Hematologic	No underlying causes
Iatrogenic	No underlying causes
Infectious Disease	Dermatomyositis, Polymyositis
Musculoskeletal / Ortho	Rheumatoid arthritis
Neurologic	No underlying causes
Nutritional / Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	No underlying causes
Opthalmologic	No underlying causes
Overdose / Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	Tuberculosis, Pneumonia, Anti-synthetase syndrome
Renal / Electrolyte	No underlying causes
Rheum / Immune / Allergy	Sarcoidosis, Systemic lupus erythematosus, Rheumatoid arthritis, Lupus pleuritis
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Dental	No underlying causes
Miscellaneous	No underlying causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Idiopathic pulmonary fibrosis must be differentiated from other causes of interstitial lung diseases which may cause fibrosis as well. Other diseases may include acute interstitial pneumonia, hypersensitivity pneumonia, occupational lung diseases, and pulmonary hemorrhage diseases.

To review the complete differential diagnosis of dyspnea, click here.

To review the complete differential diagnosis of hemoptysis, click here.

To review the complete differential diagnosis of restrictive lung disease, click here.

Abbreviations: ABG: Arterial blood gas, BAL: Bronchoalveolar lavage, ESR: Erythrocyte sedimentation rate, CRP: C–reactive protein, FVC: Forced vital capacity, RV: Residual volume, FEV1: Forced expiratory volume during the 1st second, DLCO: Diffusing capacity of the lungs for carbon monoxide, O2: Oxygen, TLC: Total lung capacity, PaO2: Arterial partial pressure of oxygen, FiO2: Fraction of inspired oxygen, LDH: Lactate dehydrogenase, CEA: Carcinoembryonic antigen, Anti-GBM antibody: Anti-glomerular basement membrane antibody, A−a gradient: Alveolar-arterial gradient, PAS: Periodic acid-Schiff stain, LAM: Lymphangiomyomatosis, IgE: Immunoglobulin E, ANCA: Anti-neutrophil cytoplasmic antibody, RBC: Red blood cell, ACE: Angiotensin-converting enzyme

Disease		Clinical manifestation															Investigations
		History							Symptoms				Physical examination				Lab findings	Imaging	Pulmonary function test		Bronchoscopy and BAL	Gold standard
		Duration	Age	Gender	Family history	Smoking history	Environmental exposure	HIV	Dyspnea	Cough	Wheezing	Chest pain	Tachypnea	Auscultation	Cyanosis	Clubbing			Spirometry	ABG
Idiopathic pulmonary fibrosis[1]		Chronic	60−70 years old	Men	+	+	±	−	+	Dry	+	+	+	Inspiratory high−pitched rhonchi Bibasilar inspiratory crackles	−	+	Antinuclear antibody + Rheumatoid factor + Elevated ESR Elevated CRP Polycythemia	Bibasilar, peripheral reticular abnormalities Focal honeycomb cyst formation Traction bronchiectasis	↓ FVC ↑ RV Normal FEV1/FVC ↓ DLCO	↓ O2	Not required ↑ Neutrophils  ↑ Eosinophils	Diagnosis of exclusion  Lung biopsy
Idiopathic nonspecific interstitial pneumonia[2]		Acute/Chronic	50−60 years old	Female	+	−	−	+	+	+	+	−	+	Bibasilar crackles	−	±	Normal	Bilateral ground−glass opacities  Fine reticular infiltrates Traction bronchiectasis Consolidation	Normal to ↑ FEV1/FVC ↓ FVC  ↓ TLC	↓ O2	Nonspecific	Lung biopsy and multidisciplinary approach
Cryptogenic organising pneumonia[3]		Acute/subacute	50−60 years old	Both	−	±	−	−	+	Dry	−	−	−	Inspiratory crackles	−	−	Leukocytosis Elevated ESR Elevated CRP	Alveolar filling and air bronchograms Bilateral ground−glass opacities  Bilateral consolidation	↓ FVC Normal FEV1/FVC ↓ DLCO	↓ O2	↑ Lymphocytes ↑ Neutrophils  ↑ Eosinophils	Lung biopsy
Disease		History							Symptoms				Physical examination				Lab findings	Imaging	Pulmonary function test		Bronchoscopy and BAL	Gold standard
		Duration	Age	Gender	Family history	Smoking history	Environmental exposure	HIV	Dyspnea	Cough	Wheezing	Chest pain	Tachypnea	Auscultation	Cyanosis	Clubbing			Spirometry	ABG
Acute interstitial pneumonia (Hamman−Rich syndrome)[4]		Acute	50−60 years old	Both	−	−	−	−	+	+	−	−	+	Diffuse crackles	−	−	Leukocytosis	Bilateral and symmetric, diffuse ground glass Alveolar consolidation opacities Traction bronchiectasis Honeycomb fibrosis	N/A	↓ O2 PaO2/FiO2 <200 mmHg	Nonspecific ↑ Neutrophils  ↑ Atypical epithelial cells	Lung biopsy
Lymphocytic interstitial pneumonia[5]		Subacute	30−40 years old	Female	−	−	−	±	+	+	+	+	−	Diffuse crackles	−	+	Gammopathy	Diffuse ground glass attenuation with fibrosis Centrilobular and subpleural nodules Lung cysts	↓ FVC ↓ TLC ↓ DLCO	↓ O2	Nonspecific ↑ Total BAL cell count BAL lymphocytosis	Lung biopsy
Respiratory bronchiolitis−interstitial lung disease[6]		Subacute	30−40 years old	Both	−	+	−	−	+	Dry	+	−	−	Inspiratory high−pitched rhonchi Fine, bibasilar end−inspiratory crackles	−	−	Nonspecific	Diffuse or patchy ground glass opacities in a mosaic pattern  Fine nodules  Air trapping	↓ FVC ↓ TLC ↓ DLCO	↓ O2	↑ Macrophages	Clinical evaluation and investigations
Desquamative interstitial pneumonia[7][8]		Chronic	40−50 years old	Both	−	+	−	−	+	Dry	+	−	−	Fine, bibasilar end−inspiratory crackles	−	−	Nonspecific	Ground glass opacities without the peripheral reticular and reticulonodular opacities	↓ DLCO	↓ O2	↑ Eosinophils	Lung biopsy
Disease		History							Symptoms				Physical examination				Lab findings	Imaging	Pulmonary function test		Bronchoscopy and BAL	Gold standard
		Duration	Age	Gender	Family history	Smoking history	Environmental exposure	HIV	Dyspnea	Cough	Wheezing	Chest pain	Tachypnea	Auscultation	Cyanosis	Clubbing			Spirometry	ABG
Pulmonary Langerhans cell granulomatosis[9]		Chronic	20−40 years old	Both	+	+	−	−	±	Dry	+	+	−	Unremarkable	−	−	Nonspecific	Mid to upper lung zone cysts and nodules Reticular and nodular opacities Recurrent spontaneous pneumothorax	↓ FEV1/FVC	Normal	>5 percent langerhans cells (CD−1a positive)	Lung biopsy
Pulmonary alveolar proteinosis[10][11]		Acute/chronic	40−50 years old	Male	+	+	+	−	+	+	+	−	−	Inspiratory crackles	+	+	↑ LDH ↑ CEA ↑ Surfactant protein A, B, and D Anti-GBM antibody + Polycythemia Hypergammaglobulinemia	Bbilateral perihilar and basilar alveolar opacities without air−bronchograms “Bat wing” distribution Intralobular thickening Diffuse ground−glass opacities	↑ FEV1/FVC ↑ A−a gradient ↓ DLCO	↓ PaO2 ↓ O2 Respiratory alkalosis	Large foamy macrophages with amorphous PAS−positive material ↑ Lymphocytes	Bronchoscopy and BAL
Pulmonary lymphangioleiomyomatosis[12]		Acute/chronic	30−40 years old	Female	+	+	−	−	+	Bloody	+	+	−	Decreased breath sounds	−	+	↑ Vascular endothelial growth factor−D (VEGF−D)	Pneumothorax Chylothorax Thin−walled round cystic lesions	↓ FEV1/FVC	↓ PaO2 ↓ O2	LAM cells +	Lung biopsy
Eosinophilic pneumonia[13]		Acute/chronic	20−40 years old	Male	−	−	−	−	+	Dry	+	+	+	Decreased breath sounds	−	−	Neutrophilic leukocytosis ↑ Eosinophils Elevated ESR Elevated CRP Elevated IgE level	Bilateral diffuse mixed ground glass and reticular opacities Small bilateral pleural effusions Centrilobular nodules and air−space consolidation	↑ FEV1/FVC ↓ DLCO	↓ PaO2 ↓ O2	Eosinophilia	Clinical evaluation and investigations
Hypersensitivity pneumonitis[14]		Acute/subacute/chronic	40−60 years old	Both	−	±	+	−	+	Dry/productive	+	+	+	Diffuse fine bibasilar crackles	−	+	Neutrophilic leukocytosis	Centrilobular ground−glass or nodular opacities of mid−to−upper zone  Air−trapping	↓ FEV1 ↓ FVC	↓ PaO2 ↓ O2	Lymphocytosis	Lung biopsy
Disease		History							Symptoms				Physical examination				Lab findings	Imaging	Pulmonary function test		Bronchoscopy and BAL	Gold standard
		Duration	Age	Gender	Family history	Smoking history	Environmental exposure	HIV	Dyspnea	Cough	Wheezing	Chest pain	Tachypnea	Auscultation	Cyanosis	Clubbing			Spirometry	ABG
Occupational lung disease[15]		Chronic	Elderly	Male	+	+	+	−	±	+	+	+	+	Fine crackles	Peripheral/central	+	Anemia Neutrophilia Elevated ESR Elevated CRP Elevated immunoglobulin	Pleural thickening and plaques Calcification Nodular or reticular opacities Lobar consolidation Atelectasis Parenchymal bands Enlarged hilar or mediastinal lymph nodes Granulomata	↑ FEV1/FVC	↓ O2 ↑ CO2 Respiratory acidosis	Mineral dust +	History of environmental exposure and imaging Lung biopsy not required
Radiation−induced lung injury[16]		Subacute/chronic	Any age	Both	−	−	+	−	+	Dry	+	+	+	Crackles Pleural rub Dullness to percussion	+	−	Nonspecific	Perivascular haziness to patchy alveolar filling densities Straight line effect Pleural effusion	↓ TLC ↓ FVC ↓ FEV1 ↓ DLCO	↓ PaO2 ↓ O2	Lymphocytosis	History of irradiation and clinical presentation
Pulmonary hemorrhage syndromes	Goodpasture syndrome[17]	Chronic	All ages	Male	+	±	−	−	±	Bloody	±	−	−	Bilateral coarse crepitations	−	−	Anti-GBM antibody + ANCA + Anemia RBC in the urine	Pulmonary infiltrates	↑ DLCO	Normal	NA	Kidney biopsy
	Idiopathic pulmonary hemosiderosis[18]	Acute/subacute/chronic	Children − 10 years old	Both	+	±	−	−	+	Bloody	+	+	−	Crackles	−	−	Iron deficiency anemia ↑ Plasma bilirubin ↑ Urinary excretion of urobilinogen ↑ Reticulocytes Fecal occult blood +	Mid to lower zone alveolar opacities Multiple honeycomb cysts	↓ TLC ↓ FVC ↓ FEV1 ↑ FEV1/FVC ↑ DLCO	↓ O2 ↓ CO2	↑ Hemosiderin−laden macrophages	Clinical evaluation and investigations
	Isolated pulmonary capillaritis[19]	Chronic	40−60 years old	Both	+	−	±	−	+	Bloody	+	+	+	Decreased breath sounds	−	−	Anemia Leukocytosis	Diffuse alveolar haemorrhage	↓ FEV1/FVC	↓ O2	Diffuse alveolar haemorrhage	Diagnosis of exclusion
Disease		History							Symptoms				Physical examination				Lab findings	Imaging	Pulmonary function test		Bronchoscopy and BAL	Gold standard
		Duration	Age	Gender	Family history	Smoking history	Environmental exposure	HIV	Dyspnea	Cough	Wheezing	Chest pain	Tachypnea	Auscultation	Cyanosis	Clubbing			Spirometry	ABG
Sarcoidosis[20]		Acute/subacute/chronic	20−40 years old	Female	+	±	−	−	±	+	+	±	−	Crackles Wheezing Decreased breath sounds	+	−	Hypercalciuria  Hypercalcemia High ACE Hypergammaglobulinemia	Hilar adenopathy Reticular opacities Pneumothorax Pleural thickening Chylothorax Pulmonary hypertension	↓ TLC ↓ FVC ↓ FEV1 ↑ FEV1/FVC ↓ DLCO	↓ O2 ↓ CO2 Respiratory acidosis	Lymphocytosis  Elevated adenosine deaminase D-dimer +	Clinical evaluation and investigations
Granulomatous vasculitides	Granulomatosis with polyangiitis (Wegener)[21]	Chronic	Elderly	Both	+	−	−	−	+	+	+	±	−	Crackles	−	−	ANCA + Anemia Leukocytosis Thrombocytosis Elevated ESR Elevated CRP Elevated creatinine Urine protein + Hematuria	Cavitate nodules Ground−glass opacity Consolidation Pleural effusion Hilar adenopathy	↓ FEV1/FVC	↓ O2	Alveolar hemorrhage	Lung biopsy
	Eosinophilic granulomatosis with polyangiitis (Churg Strauss)[22]	Chronic	40−50 years old	Both	+	−	−	−	−	+	+	−	−	Scattered wheezing	−	−	Eosinophilia Elevated IgE titers ANCA +	Areas of parenchymal opacification Mixed interstitial patchy alveolar opacities	↓ TLC ↑ RV	Normal	Eosinophilia	Lung biopsy
Bronchocentric granulomatosis[23]		Chronic	30−70 years old	Both	−	−	−	−	±	±	+	±	−	Scattered wheezing	−	−	Eosinophilia Elevated IgE titers Elevated circulating IgE antibodies to Aspergillus species	Upper zone single or multiple pulmonary nodules  Consolidation Atelectasis	↓ FEV1/FVC	Normal	Eosinophilia	Lung biopsy
Pulmonary lymphomatoid granulomatosis[24]		Chronic	30−50 years old	Male	−	−	−	−	+	+	+	+	−	Normal	−	−	Epstein-Barr virus (EBV) serology +	Mid to lower zone multiple poorly defined nodules Diffuse reticular abnormalities	Normal	↓ O2 Chronic respiratory alkalosis	Normal	Lung biopsy
Amyloidosis[25][26]		Subacute/chronic	50−70 years old	Male	+	−	−	−	−	Bloody	+	−	−	Crackles	−	−	Congophilia with apple−green birefringence under polarized light	Tracheobronchial infiltration Persistent pleural effusions Parenchymal nodules	↓ FEV1/FVC	↓ O2	Normal	Lung biopsy
Disease		History							Symptoms				Physical examination				Lab findings	Imaging	Pulmonary function test		Bronchoscopy and BAL	Gold standard
		Duration	Age	Gender	Family history	Smoking history	Environmental exposure	HIV	Dyspnea	Cough	Wheezing	Chest pain	Tachypnea	Auscultation	Cyanosis	Clubbing			Spirometry	ABG

References

1. ↑ Poletti, Venerino; Ravaglia, Claudia; Buccioli, Matteo; Tantalocco, Paola; Piciucchi, Sara; Dubini, Alessandra; Carloni, Angelo; Chilosi, Marco; Tomassetti, Sara (2013). “Idiopathic Pulmonary Fibrosis: Diagnosis and Prognostic Evaluation”. Respiration. 86 (1): 5–12. doi:10.1159/000353580. ISSN 1423-0356.
2. ↑ Travis, William D.; Hunninghake, Gary; King, Talmadge E.; Lynch, David A.; Colby, Thomas V.; Galvin, Jeffrey R.; Brown, Kevin K.; Chung, Man Pyo; Cordier, Jean-François; du Bois, Roland M.; Flaherty, Kevin R.; Franks, Teri J.; Hansell, David M.; Hartman, Thomas E.; Kazerooni, Ella A.; Kim, Dong Soon; Kitaichi, Masanori; Koyama, Takashi; Martinez, Fernando J.; Nagai, Sonoko; Midthun, David E.; Müller, Nestor L.; Nicholson, Andrew G.; Raghu, Ganesh; Selman, Moisés; Wells, Athol (2008). “Idiopathic Nonspecific Interstitial Pneumonia”. American Journal of Respiratory and Critical Care Medicine. 177 (12): 1338–1347. doi:10.1164/rccm.200611-1685OC. ISSN 1073-449X.
3. ↑ Mehrian, P.; Doroudinia, A.; Rashti, A.; Aloosh, O.; Dorudinia, A. (2017). “High-resolution computed tomography findings in chronic eosinophilic vs. cryptogenic organising pneumonia”. The International Journal of Tuberculosis and Lung Disease. 21 (11): 1181–1186. doi:10.5588/ijtld.16.0723. ISSN 1027-3719.
4. ↑ Parambil, Joseph; Mukhopadhyay, Sanjay (2012). “Acute Interstitial Pneumonia (AIP): Relationship to Hamman-Rich Syndrome, Diffuse Alveolar Damage (DAD), and Acute Respiratory Distress Syndrome (ARDS)”. Seminars in Respiratory and Critical Care Medicine. 33 (05): 476–485. doi:10.1055/s-0032-1325158. ISSN 1069-3424.
5. ↑ Panchabhai, Tanmay S.; Farver, Carol; Highland, Kristin B. (2016). “Lymphocytic Interstitial Pneumonia”. Clinics in Chest Medicine. 37 (3): 463–474. doi:10.1016/j.ccm.2016.04.009. ISSN 0272-5231.
6. ↑ Sieminska, Alicja; Kuziemski, Krzysztof (2014). “Respiratory bronchiolitis-interstitial lung disease”. Orphanet Journal of Rare Diseases. 9 (1). doi:10.1186/s13023-014-0106-8. ISSN 1750-1172.
7. ↑ Ryu, Jay H.; Myers, Jeffrey L.; Capizzi, Stephen A.; Douglas, William W.; Vassallo, Robert; Decker, Paul A. (2005). “Desquamative Interstitial Pneumonia and Respiratory Bronchiolitis-Associated Interstitial Lung Disease”. Chest. 127 (1): 178–184. doi:10.1378/chest.127.1.178. ISSN 0012-3692.
8. ↑ Craig, P J; Wells, A U; Doffman, S; Rassl, D; Colby, T V; Hansell, D M; du Bois, R M; Nicholson, A G (2004). “Desquamative interstitial pneumonia, respiratory bronchiolitis and their relationship to smoking”. Histopathology. 45 (3): 275–282. doi:10.1111/j.1365-2559.2004.01921.x. ISSN 0309-0167.
9. ↑ Blakley, Matthew P.; Dutcher, Janice P.; Wiernik, Peter H. (2018). “Pulmonary Langerhans cell histiocytosis, acute myeloid leukemia, and myelofibrosis in a large family and review of the literature”. Leukemia Research. 67: 39–44. doi:10.1016/j.leukres.2018.01.011. ISSN 0145-2126.
10. ↑ Carrington JM, Hershberger DM. PMID 29493933. Missing or empty |title= (help)
11. ↑ Kiani, Arda; Parsa, Tahereh; Adimi Naghan, Parisa; Dutau, Hervé; Razavi, Fatemeh; Farzanegan, Behrooz; Pourabdollah Tootkaboni, Mahsa; Abedini, Atefeh (2018). “An eleven-year retrospective cross-sectional study on pulmonary alveolar proteinosis”. Advances in Respiratory Medicine. 86 (1): 7–12. doi:10.5603/ARM.2018.0003. ISSN 2543-6031.
12. ↑ Xu, Kai-Feng; Lo, Bee Hong (2014). “Lymphangioleiomyomatosis: differential diagnosis and optimal management”. Therapeutics and Clinical Risk Management: 691. doi:10.2147/TCRM.S50784. ISSN 1178-203X.
13. ↑ Bernheim, Adam; McLoud, Theresa (2017). “A Review of Clinical and Imaging Findings in Eosinophilic Lung Diseases”. American Journal of Roentgenology. 208 (5): 1002–1010. doi:10.2214/AJR.16.17315. ISSN 0361-803X.
14. ↑ Miller, Ross; Allen, Timothy Craig; Barrios, Roberto J.; Beasley, Mary Beth; Burke, Louise; Cagle, Philip T.; Capelozzi, Vera Luiza; Ge, Yimin; Hariri, Lida P.; Kerr, Keith M.; Khoor, Andras; Larsen, Brandon T.; Mark, Eugene J.; Matsubara, Osamu; Mehrad, Mitra; Mino-Kenudson, Mari; Raparia, Kirtee; Roden, Anja Christiane; Russell, Prudence; Schneider, Frank; Sholl, Lynette M.; Smith, Maxwell Lawrence (2018). “Hypersensitivity Pneumonitis A Perspective From Members of the Pulmonary Pathology Society”. Archives of Pathology & Laboratory Medicine. 142 (1): 120–126. doi:10.5858/arpa.2017-0138-SA. ISSN 0003-9985.
15. ↑ Sirajuddin, Arlene; Kanne, Jeffrey P. (2009). “Occupational Lung Disease”. Journal of Thoracic Imaging. 24 (4): 310–320. doi:10.1097/RTI.0b013e3181c1a9b3. ISSN 0883-5993.
16. ↑ Giridhar P, Mallick S, Rath GK, Julka PK (2015). “Radiation induced lung injury: prediction, assessment and management”. Asian Pac. J. Cancer Prev. 16 (7): 2613–7. PMID 25854336.
17. ↑ DeVrieze BW, Hurley JA. PMID 29083697. Missing or empty |title= (help)
18. ↑ Khorashadi, L.; Wu, C.C.; Betancourt, S.L.; Carter, B.W. (2015). “Idiopathic pulmonary haemosiderosis: spectrum of thoracic imaging findings in the adult patient”. Clinical Radiology. 70 (5): 459–465. doi:10.1016/j.crad.2014.11.007. ISSN 0009-9260.
19. ↑ Thompson, Gwen; Klecka, Mary; Roden, Anja C.; Specks, Ulrich; Cartin-Ceba, Rodrigo (2016). “Biopsy-proven pulmonary capillaritis: A retrospective study of aetiologies including an in-depth look at isolated pulmonary capillaritis”. Respirology. 21 (4): 734–738. doi:10.1111/resp.12738. ISSN 1323-7799.
20. ↑ Li, Cheng-Wei; Tao, Ru-Jia; Zou, Dan-Feng; Li, Man-Hui; Xu, Xin; Cao, Wei-Jun (2018). “Pulmonary sarcoidosis with and without extrapulmonary involvement: a cross-sectional and observational study in China”. BMJ Open. 8 (2): e018865. doi:10.1136/bmjopen-2017-018865. ISSN 2044-6055.
21. ↑ Greco A, Marinelli C, Fusconi M, Macri GF, Gallo A, De Virgilio A, Zambetti G, de Vincentiis M (June 2016). “Clinic manifestations in granulomatosis with polyangiitis”. Int J Immunopathol Pharmacol. 29 (2): 151–9. doi:10.1177/0394632015617063. PMC 5806708. PMID 26684637.
22. ↑ Greco A, Rizzo MI, De Virgilio A, Gallo A, Fusconi M, Ruoppolo G, Altissimi G, De Vincentiis M (April 2015). “Churg-Strauss syndrome”. Autoimmun Rev. 14 (4): 341–8. doi:10.1016/j.autrev.2014.12.004. PMID 25500434.
23. ↑ Myers, Jeffrey L. (1989). “Bronchocentric Granulomatosis”. Chest. 96 (1): 3–4. doi:10.1378/chest.96.1.3. ISSN 0012-3692.
24. ↑ Ankita, Grover; Shashi, Dhawan (2016). “Pulmonary Lymphomatoid Granulomatosis- a Case Report with Review of Literature”. Indian Journal of Surgical Oncology. 7 (4): 484–487. doi:10.1007/s13193-016-0525-1. ISSN 0975-7651.
25. ↑ Khoor, Andras; Colby, Thomas V. (2017). “Amyloidosis of the Lung”. Archives of Pathology & Laboratory Medicine. 141 (2): 247–254. doi:10.5858/arpa.2016-0102-RA. ISSN 0003-9985.
26. ↑ Milani, Paolo; Basset, Marco; Russo, Francesca; Foli, Andrea; Palladini, Giovanni; Merlini, Giampaolo (2017). “The lung in amyloidosis”. European Respiratory Review. 26 (145): 170046. doi:10.1183/16000617.0046-2017. ISSN 0905-9180.

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