Idiopathic pulmonary fibrosis differential diagnosis

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

Overview

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.

Differentiating Interstitial Lung Disease from other 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		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		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		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)		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		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		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		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		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		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		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		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		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		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		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	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	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	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		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)	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)	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		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		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		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

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