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

Data supporting the likelihood of sarcoidosis

  1. Demographics
    1. U.S. African American
    2. Northern European
  2. 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
  3. 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
  4. 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
  5. Skin lesions
    1. Lupus pernio
    2. Erythema nodosum
    3. Maculopapular lesions
  6. Ocular disease
    1. Uveitis
    2. Optic neuritis
  7. Neurological disease
    1. Seventh cranial nerve palsy
  8. Renal disease
    1. Nephrocalcinosis
    2. Interstitial nephritis[2]

Data weakening the likelihood of sarcoidosis

  1. Demographics
    1. Age< 18 years
  1. Medical history
    1. Exposure to tuberculosis
    2. Exposure to organic bioaerosol
    3. Exposure to beryllium
    4. Intravenous drug abuse
  1. Laboratory data
    1. Positive anti-neutrophil cytoplasm antibody (ANCA)
  1. Radiographic findings
    1. CXR:
      1. Pleural effusion
    2. HRCT:
      1. Subpleural honeycombing
  1. Ocular disease
    1. Episcleritis
  1. 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 CXR CT DLCco
Hypersensitivity Pneumonitis + + - + - + - -
  • Constitutional symptoms
  • 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) - + - - + - - -
  • 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
  • N/A
  • Normal
  • N/A
-
  • Clinical diagnosis
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
  • 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
+ + + -
  • 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
Asbestosis
  • Shipyard workers
  • Pipe fitting
  • Insulators
  • 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
  • Diffuse air-space consolidation
  • Pulmonary fibrosis with honeycombing
  • Peri bronchovascular distribution of nodules
  • Ground-glass attenuations
Sarcoidosis + + + + - - - -
  • Usually normal
  • Occasional crackles
  • Bilateral hilar lymphadenopathy
  • High-resolution CT (HRCT) scanning of the chest may identify
    • Active alveolitis
    • Fibrosis
Pleural Effusion + + +/- +/- Transudate

Exudate

+/- +/- +/- +/-
  • 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.
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
Interstitial (Nonidiopathic) Pulmonary Fibrosis + ++ + - + + + +
  • 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] + + + + - + - -
  • 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] + + - - - - - + -
  • 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 + - + +
  • Increased A-a gradient
  • 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
- - - -
  • In severe scoliosis, the rib cage may press against the lungs making it more difficult to breathe.
  • 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
- - - -
  • N/A
  • N/A
N
ALS - + - -
  • Muscle weakness
  • Neurological deficit
- - - -
  • 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 -
Myasthenia gravis - + - + H/O of difficulty getting up from chair - - - -
  • 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




References

  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.
  2. 2.0 2.1 Judson MA: The diagnosis of sarcoidosis. Clin Chest Med 29(3):415–427, 2008.
  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.
  4. 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.
  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.
  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.
  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.
  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.
  9. 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.