Sarcoidosis differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]Roshan Dinparasti Saleh M.D.

Overview

Sarcoidosis has many differentials, which can be classified depending on the organ involved, pathologic findings and laboratory findings.

Differential Diagnosis

Sarcoidosis has been defined as a multisystem granulomatous disorder of unknown cause^[1], but granulomatous inflammation alone is not sufficient for the diagnosis of sarcoidosis because alternative etiologies of granulomatous inflammation need to be excluded.

Causes of granulomatous reaction beside sarcoidosis

Mycobacterium tuberculosis
Mycoplasma
Pneumocystis jiroveci
Brucellosis
Cat-scratch fever
Atypical mycobacteria
Toxoplasmosis
Berylliosis
Hard metal
Zirconium
Tattoo
Hypersensitivity pneumonitis
Medications (e.g., methotrexate)
ANCA-associated vasculitis
Necrotizing sarcoid granuloma
Lymphoma
Cancer
Granulomatous lesions of unknown significance
Crohn’s disease
Lymphocytic interstitial pneumonia
Behçet’s disease
Rheumatoid nodules^[1]

Data supporting the likelihood of sarcoidosis

Demographics
1. U.S. African American
2. Northern European
Medical history
1. Non-smoker
2. No symptoms (in patient with bilateral hilar adenopathy on CXR)
3. Family history of sarcoidosis
4. Symptoms involving more than two organs commonly involved by sarcoidosis
Laboratory data
1. Elevated ACE level (especially if > 2× ULN)
2. Elevated calcium level
3. Elevated alkaline phosphatase level
4. Elevated soluble IL-2 receptor
5. Leukopenia
Radiographic findings
1. CXR:
  1. bilateral hilar adenopathy especially if without symptoms
  2. Upper lobe disease
2. HRCT:
  1. Disease along bronchovascular bundle
  2. Subpleural reticulonodular infiltrates
  3. Mediastinal adenopathy
  4. Peribronchial thickening
  5. Traction bronchiectasis of upper lobe
Skin lesions
1. Lupus pernio
2. Erythema nodosum
3. Maculopapular lesions
Ocular disease
1. Uveitis
2. Optic neuritis
Neurological disease
1. Seventh cranial nerve palsy
Renal disease
1. Nephrocalcinosis
2. Interstitial nephritis^[2]

Data weakening the likelihood of sarcoidosis

Demographics
1. Age< 18 years

Medical history
1. Exposure to tuberculosis
2. Exposure to organic bioaerosol
3. Exposure to beryllium
4. Intravenous drug abuse

Laboratory data
1. Positive anti-neutrophil cytoplasm antibody (ANCA)

Radiographic findings
1. CXR:
  1. Pleural effusion
2. HRCT:
  1. Subpleural honeycombing

Ocular disease
1. Episcleritis

Renal disease
1. Glomerulonephritis ^[2]

Spirometry

Low FEV1/FVC ratio

Normal to high FEV1/FVC ratio

Obstructive Lung Disease

Restrictive Lung Disease

Bronchodilator therapy

DLCO

Increased FEV1

No change in FEV1

Normal DLCO

Decreased DLCO

Asthma

COPD

Chest wall disorders

Interstitial Lung Disease

Spirometry Findings in Various Lung Conditions

Spirometry showing Obstructive and Restrictive Lung Disease ([Source:By CNX OpenStax [CC BY 4.0 (http://creativecommons.org/licenses/by/4.0)], via Wikimedia Commons])

Disease		Clinical manifestations											Diagnosis
		Symptoms				Physical exam							Lab findings	Imaging			Gold standard
		Cough	Dyspnea	Hemoptysis	Fever	History/Exposure	Cyanosis	Clubbing	JVD	Peripheral edema	Auscultation	Other prominent findings	Lab findings	CXR	CT	DLCco
Hypersensitivity Pneumonitis		+	+	-	+	History of allergen exposure	-	+	-	-	Diffuse fine bibasilar crackles	Constitutional symptoms Weight loss Anorexia Muscle weakness	Neutrophilia Elevated ESR Elevated CRP Elevated immunoglobulin No peripheral blood eosinophilia	Poorly defined micronodular or diffuse interstitial pattern In chronic form Fibrosis Loss of lung volume Coarse linear opacities	Ground-glass opacities or Diffusely increased radiodensities Diffuse micronodules Focal air trapping Mosaic perfusion Occasionaly thin-walled cysts Mild fibrotic changes	↓	Clinical diagnosis
Acute Respiratory Distress Syndrome (ARDS)		-	+	-	-	Trauma Sepsis Drug overdose Massive transfusion Acute pancreatitis Aspiration	+	-	-	-	Coarse breath sounds Rhonchi crackles Decreased breath sounds	Initially respiratory alkalosis transforming to respiratory acidosis	BNP level of less than 100 pg/mL PaO₂ / FiO₂ <300 Leukopenia Leukocytosis Thrombocytopenia	Bilateral pulmonary infiltrates Initially patchy peripheral Later diffuse bilateral Ground glass Frank alveolar infiltrate	Bronchial dilatation within areas of ground-glass opacification	↓	PaO₂ / FiO₂ <300
Bronchitis	Acute	+	-	+/-	+	-	-	-	-	-	Diffuse wheezes High-pitched continuous sounds The use of accessory muscles Prolonged expiration Rhonchi Rales	Hoarseness	N/A	Normal	N/A	-	Clinical diagnosis
Bronchitis	Chronic	+	+	-	-	A positive history of chronic productive cough Shortness of breath	+	-	+	+	Prolonged expiration; wheezing Diffusely decreased breath sound Coarse crackles with inspiration Coarse rhonchi	N/A	Chronic hypoxemia may lead to polycythemia Increase in Neutrophils count Chronic respiratory acidosis.	Radiolucency Diaphragmatic flattening due to hyperinflation Increased retrosternal airspace on the lateral radiograph	N/A	↓	N/A
Pneumoconiosis^[3]	SIlicosis^[4]^[5]	+	+	+/-	-	Occupational history Sandblasting Bystanders Quartzite miller Tunnel workers Silica flour workers Workers in the scouring powder industry	+	+	+	-	Hyperresonant Fine crackles Rhonchi Bronchial breath sounds Expiratory wheezing Increased tactile fremitus. Loud P2	Increased susceptiblity to tuberculosis.	Respiratory acidosis Abnormal sputum Anemia Neutrophilia Elevated ESR Elevated CRP Elevated immunoglobulin	Small round opacities Symmetrically distributed Upper-zone predominance Diffuse interstitial pattern of fibrosis without the typical nodular opacities in chronic case	Nodular changes in lung parenchyma Progressive massive fibrosis Bullae, emphysema Pleural, mediastinal, and hilar changes	↓	Lung biopsy
	Asbestosis					Shipyard workers Pipe fitting Insulators						Lung cancer Mesothelioma		Predilection to lower lobes Fine and coarse linear, peripheral, reticular opacities	Subpleural linear opacities seen parallel to the pleura Basilar lung fibrosis Peribronchiolar, intralobular, and interlobular septal fibrosis; Honeycombing Pleural plaques.
	Berylliosis					Electronic manufactures						-		Hilar adenopathy Increased interstitial markings.	Ground glass opacification Parenchymal nodules Septal lines
	Byssinosis					Cotton wool workers						Increased susceptibility to Actinomyces and Aspergillus infection.		Diffuse air-space consolidation	Pulmonary fibrosis with honeycombing Peri bronchovascular distribution of nodules Ground-glass attenuations
Sarcoidosis		+	+	+	+	African Americans Autoimmune	-	-	-	-	Usually normal Occasional crackles	Dermatologic manifestations Ocular involvement Osseous involvement Heart failure from cardiomyopathy Lymphocytic meningitis Cranial nerve palsies	Hypercalcemia or hypercalciuria Elevated 1, 25-dihydroxyvitamin D levels Elevated angiotensin-converting enzyme (ACE)	Bilateral hilar lymphadenopathy	High-resolution CT (HRCT) scanning of the chest may identify Active alveolitis Fibrosis	↓	Biopsy
Pleural Effusion		+	+	+/-	+/-	Transudate CHF Cirrhosis Exudate Parapneumonic causes Malignancy	+/-	+/-	+/-	+/-	Decreased tactile fremitus Diminished or inaudible breath sounds Pleural friction rub	Peripheral edema, distended neck veins, and S₃ gallop suggest congestive heart failure. Edema may also be a manifestation of nephrotic syndrome, pericardial disease, or, when combined with yellow nailbeds, the yellow nail syndrome. Cutaneous changes and ascites suggest liver disease. Lymphadenopathy or a palpable mass suggests malignancy.	Thoracentesis Exudate Transudate LDH, glucose, cytology Other specific labs of underlying etiology	Supine Blunting of the costophrenic angle Homogenous increase in density spread over the lower lung fields Lateral decubitus Free flowing effusion as layers	Thickened pleura Mild effusions can aslo be detected	↓	Thoracocentesis
Interstitial (Nonidiopathic) Pulmonary Fibrosis		+	++	+	-	Connective-tissue disorder Pneumoconiosis	+	+	+	+	Wheezing S3 P2 End-inspiratory rales	Increased A-a gradient	Elevated ESR Serologic testing for ANA, RF, ANCA & ASCA may be positive	Reticular and/or nodular opacities Honeycomb appearance (late finding)	Bilateral reticular and nodular interstitial infiltrates	↓	Video-assisted thoracoscopic lung biopsy
Lymphocytic Interstitial Pneumonia^[6]		+	+	+	+	Autoimmune Lymphoproliferative disorders	-	+	-	-	Wheezing Rales	Increased A-a gradient	Polyclonal hypergammaglobulinemia Increased LDH	Bibasilar interstitial or micronodular infiltrates	Determines the degree of fibrosis Cysts (characterstic)	N	Open lung biopsy
Obesity^[7]^[8]		+	+	-	-	Overweight Diabetes mellitus Asthma	-	-	-	+	Wheezing	-	Increased hematocrit	X ray findings are often limited due to body habitus	CT findings are variable and depends upon severity of obesity	N	Clinical
Pulmonary Eosinophilia^[9]		+	+	+	+	Infections Parasitic Fungal Mycobacterial	+	-	+	+	Wheezing Rales	Increased A-a gradient	Leukocytosis with eosinophilia (> 250/µL)	Interstitial or diffuse nodular densities	Determines extent and distribution of the disease Interstitial infiltrates Cysts and nodules	↓	Biopsy of lesion (skin or lung)
Neuromuscular disease	Scoliosis	-	+	-	-	Postural abnormality	-	-	-	-	Decreased breath sounds	In severe scoliosis, the rib cage may press against the lungs making it more difficult to breathe.	R/0 genetic conditions Marfan's syndrome Edward's syndrome Total lymphocyte count (should be >1500/μL) Nutritional status must be assessed	Accurate depiction of the true magnitude of the spinal deformity can be assessed by supine anteroposterior (AP) and lateral spinal radiographs	N/A	N	Clinical Radiographs
	Muscular dystrophy	-	+	-	-	Proximal muscle weakness	-	-	-	-	Decreased breath sounds	Rash	Elevated CPK and aldolase +ANA +Anti-Jo abs Elevated ESR, CRP and RF	N/A	N/A	N	Muscle biopsy
	ALS	-	+	-	-	Muscle weakness Neurological deficit	-	-	-	-	Decreased breath sounds	Symptoms begin with limb involvement diue to muscle weakness and atrophy. Cognitive or behavioral dysfunction Sensory nerves and the autonomic nervous system are generally unaffected	N/A	Not significant/diagnostic	Not significant/diagnostic	-	Clinical diagnosis Nerve conduction studies and needle electromyography (EMG)
	Myasthenia gravis	-	+	-	+	H/O of difficulty getting up from chair Combing Difficulty in swallowing	-	-	-	-	Decreased breath sounds	Extraocular, bulbar, or proximal limb muscles. Breathing as rapid and shallow Respiratory muscle weakness can lead to acute respiratory failure may require immediate intubation.	Anti–acetylcholine receptor (AChR) antibody (Ab) test +	Thymoma as an anterior mediastinal mass.	Thymoma as an anterior mediastinal mass.	N	Electromyography

References

↑ ^1.0 ^1.1 Statement on sarcoidosis: Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med 160:736–755, 1999.
↑ ^2.0 ^2.1 Judson MA: The diagnosis of sarcoidosis. Clin Chest Med 29(3):415–427, 2008.
↑ Gay SE, Kazerooni EA, Toews GB, Lynch JP, Gross BH, Cascade PN, Spizarny DL, Flint A, Schork MA, Whyte RI, Popovich J, Hyzy R, Martinez FJ (1998). "Idiopathic pulmonary fibrosis: predicting response to therapy and survival". Am. J. Respir. Crit. Care Med. 157 (4 Pt 1): 1063–72. doi:10.1164/ajrccm.157.4.9703022. PMID 9563720.
↑ du Bois RM (2006). "Evolving concepts in the early and accurate diagnosis of idiopathic pulmonary fibrosis". Clin. Chest Med. 27 (1 Suppl 1): S17–25, v–vi. doi:10.1016/j.ccm.2005.08.001. PMID 16545629.
↑ Neghab M, Mohraz MH, Hassanzadeh J (2011). "Symptoms of respiratory disease and lung functional impairment associated with occupational inhalation exposure to carbon black dust". J Occup Health. 53 (6): 432–8. PMID 21996929.
↑ Honda O, Johkoh T, Ichikado K, Tomiyama N, Maeda M, Mihara N, Higashi M, Hamada S, Naito H, Yamamoto S, Nakamura H (1999). "Differential diagnosis of lymphocytic interstitial pneumonia and malignant lymphoma on high-resolution CT". AJR Am J Roentgenol. 173 (1): 71–4. doi:10.2214/ajr.173.1.10397102. PMID 10397102.
↑ Zammit C, Liddicoat H, Moonsie I, Makker H (2010). "Obesity and respiratory diseases". Int J Gen Med. 3: 335–43. doi:10.2147/IJGM.S11926. PMC 2990395. PMID 21116339.
↑ O’Neill, Donal (2015). "Measuring obesity in the absence of a gold standard". Economics & Human Biology. 17: 116–128. doi:10.1016/j.ehb.2015.02.002. ISSN 1570-677X.
↑ de Górgolas M, Casado V, Renedo G, Alen JF, Fernández Guerrero ML (2009). "Nodular lung schistosomiais lesions after chemotherapy for dysgerminoma". Am. J. Trop. Med. Hyg. 81 (3): 424–7. PMID 19706907.

[wasog-1] 1.0 ^1.1 Statement on sarcoidosis: Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med 160:736–755, 1999.

[judson-2] 2.0 ^2.1 Judson MA: The diagnosis of sarcoidosis. Clin Chest Med 29(3):415–427, 2008.

[pmid9563720-3] Gay SE, Kazerooni EA, Toews GB, Lynch JP, Gross BH, Cascade PN, Spizarny DL, Flint A, Schork MA, Whyte RI, Popovich J, Hyzy R, Martinez FJ (1998). "Idiopathic pulmonary fibrosis: predicting response to therapy and survival". Am. J. Respir. Crit. Care Med. 157 (4 Pt 1): 1063–72. doi:10.1164/ajrccm.157.4.9703022. PMID 9563720.

[pmid16545629-4] u Bois RM (2006). "Evolving concepts in the early and accurate diagnosis of idiopathic pulmonary fibrosis". Clin. Chest Med. 27 (1 Suppl 1): S17–25, v–vi. doi:10.1016/j.ccm.2005.08.001. PMID 16545629.

[pmid21996929-5] Neghab M, Mohraz MH, Hassanzadeh J (2011). "Symptoms of respiratory disease and lung functional impairment associated with occupational inhalation exposure to carbon black dust". J Occup Health. 53 (6): 432–8. PMID 21996929.

[pmid10397102-6] Honda O, Johkoh T, Ichikado K, Tomiyama N, Maeda M, Mihara N, Higashi M, Hamada S, Naito H, Yamamoto S, Nakamura H (1999). "Differential diagnosis of lymphocytic interstitial pneumonia and malignant lymphoma on high-resolution CT". AJR Am J Roentgenol. 173 (1): 71–4. doi:10.2214/ajr.173.1.10397102. PMID 10397102.

[pmid21116339-7] Zammit C, Liddicoat H, Moonsie I, Makker H (2010). "Obesity and respiratory diseases". Int J Gen Med. 3: 335–43. doi:10.2147/IJGM.S11926. PMC 2990395. PMID 21116339.

[O’Neill2015-8] O’Neill, Donal (2015). "Measuring obesity in the absence of a gold standard". Economics & Human Biology. 17: 116–128. doi:10.1016/j.ehb.2015.02.002. ISSN 1570-677X.

[pmid19706907-9] Górgolas M, Casado V, Renedo G, Alen JF, Fernández Guerrero ML (2009). "Nodular lung schistosomiais lesions after chemotherapy for dysgerminoma". Am. J. Trop. Med. Hyg. 81 (3): 424–7. PMID 19706907.

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