Adenosine Deaminase Diagnostic Testing in Pericardial Fluid,
Edward Chau, MD1; Minoo Sarkarati, MD1; Brad Spellberg, MD1
Author Affiliations Article Information
1Los Angeles County + University of Southern California (LAC+USC) Medical Center, Los Angeles, California
JAMA. 2019;322(2):163-164. doi:10.1001/jama.2019.7535
Case
A 65-year-old Vietnamese man with hypertension, type 2 diabetes mellitus, and chronic hepatitis B with cirrhosis presented with a 2-week history of shortness of breath at rest, orthopnea, and lower extremity edema. He reported a 4-month history of nonproductive cough, 5-kg weight loss, and fatigue. He immigrated to the United States as an adult more than 20 years before presentation. His temperature was 37°C, heart rate was 78/min, respiratory rate was 17/min, and blood pressure was 158/95 mm Hg. A chest radiographic image suggested cardiomegaly and a computed tomographic scan demonstrated a moderate to large pericardial effusion. A pericardial drain was placed and pericardial fluid was sent to the laboratory for evaluation. Initial pericardial fluid study results are presented in the Table. Empirical treatment for tuberculosis was initiated. Three days later, an adenosine deaminase (ADA) level of 118.1 U/L (normal range, 0.0-11.3 U/L) from pericardial fluid was reported from the laboratory.
Table. View LargeDownload
Pericardial Fluid Laboratory Results
Pericardial Fluid Laboratory Results
What Would You Do Next?
Perform additional pericardial effusion cytology and culture testing
Stop further nontubercular diagnostic testing and continue antitubercular therapy
Initiate oral colchicine, nonsteroidal anti-inflammatory drugs, and steroids for systemic inflammation
Perform an interferon-γ release assay (IGRA)
Discussion
Answer
B. Stop further nontubercular diagnostic testing and continue antitubercular therapy
Test Characteristics
ADA is an enzyme in lymphocytes and myeloid cells that recycles toxic purine pathway metabolites, which are essential for DNA metabolism and cell viability.1,2 ADA levels are elevated in inflammatory effusions, including pleural, pericardial, and joint effusion, caused by bacterial infections, granulomatous inflammation (eg, tuberculosis, sarcoidosis), malignancy, and autoimmune diseases (eg, lupus, vasculitis).1,2 ADA is normally elevated in neutrophil-predominant effusions and is not a useful diagnostic test in the setting of neutrophil-predominant effusions.3 However, among lymphocyte-predominant effusions, levels of ADA are typically higher in those caused by tuberculosis (TB) than those caused by other conditions.1,2
In lymphocyte-predominant effusions, the most common threshold for an ADA test result indicating TB is an ADA level greater than 40 U/L. An ADA level greater than 40 U/L has a sensitivity of 87% to 93% and specificity of 89% to 97% for TB.2,4 At a threshold of greater than 35 U/L, sensitivity is higher (93%-95%) but specificity is lower (74%-90%).3,5,6 Given a pretest probability of 70% for TB in a lymphocyte-predominant pericardial effusion in a patient from an endemic country,7 an ADA level greater than 40 U/L results in a posttest probability of 96%, while a level less than or equal to 40 U/L results in a posttest probability of 19%. The Centers for Medicare & Medicaid Services reimbursement rate for ADA testing is $8.10 (Current Procedural Terminology code 84311).
Application to This Patient
In the current patient, the ADA test was ordered from pericardial fluid to confirm the presumptive diagnosis of pericardial TB, for which antitubercular therapy was initiated. RIPE (rifampin, isoniazid, pyrazinamide, ethambutol) therapy was started because of the high pretest probability of TB in a patient from a country with endemic TB with chronic cough, weight loss, and lymphocyte-predominant pericardial effusion. The patient’s ADA level of 118.1 U/L confirmed the diagnosis, enabling cessation of further evaluation and supporting continuation of antitubercular therapy.
An alternative approach is to await a culture positive for TB before starting therapy. However, cultures positive for TB can take weeks to grow, which can allow infection to progress while awaiting confirmation. An ADA level greater than 40 U/L in a patient with a high pretest probability of disease results in a sufficiently high posttest probability to justify a full course of TB therapy. Furthermore, even with an ADA level less than or equal to 40 U/L in a patient with a high pretest probability, the posttest probability of approximately 20% is sufficiently high to warrant empirical therapy. However, the low ADA level would necessitate further diagnostic testing, including invasive pericardial biopsy and serologies, to rule out other causes (eg, sarcoid, malignancy, vasculitis) while treating the patient for TB. In that situation, empirical TB therapy could have been stopped if an alternative diagnosis was established.
What Are Alternative Diagnostic Testing Approaches?
Elevated interferon-γ concentrations in effusions have high sensitivity (95.7%) and specificity (96.3%) for active TB, but their use is limited by cost and availability.1,4 Interferon-γ can also be measured from whole blood via IGRAs. However, IGRAs and the similar purified protein derivative skin test are only useful to diagnose latent TB. Laboratory test results indicating ADA values greater than 40 U/L cannot distinguish between latent and active TB (nonspecific), and IGRAs/purified protein derivatives are associated with false-negative results in up to 30% of patients with pulmonary TB and 50% of patients with disseminated TB,8,9 because active TB causes antigen-specific anergy of T cells.
Patient Outcomes
The patient’s sputum was negative for acid-fast bacilli smears and TB polymerase chain reaction. Pericardial fluid cytology demonstrated inflammatory cells, but was negative for malignant cells, acid-fast bacilli stain, and TB polymerase chain reaction. However, the pericardial fluid cultures grew TB at 3 weeks and the sputa cultures grew TB at 5 weeks. Seven months after the start of treatment, the patient was hospitalized and died of complications of pneumonia and septic shock unrelated to TB.
Clinical Bottom Line
ADA levels are typically elevated, and not diagnostically helpful, in neutrophil-predominant effusions.
In lymphocyte-predominant effusions, ADA levels are elevated in effusions caused by tuberculosis, but typically not in effusions due to other diseases.
In a patient with a low pretest probability of TB, an ADA level less than or equal to 40 U/L in a lymphocyte-predominant effusion essentially rules out TB.
In a patient with a high pretest probability of pericardial TB, an ADA level greater than 40 U/L in a lymphocyte-predominant effusion is highly suggestive of TB, precluding the need for further diagnostic testing.
Back to top Article Information
Corresponding Author: Brad Spellberg, MD, LAC+USC Medical Center, 2051 Marengo St, Los Angeles, CA 90033 (spellber@usc.edu).
Published Online: June 14, 2019. doi:10.1001/jama.2019.7535
Conflict of Interest Disclosures: Dr Spellberg reported receiving personal fees from Alexion, Synthetic Biologics, Paratek, TheoremDx, Acurx, and Merck and equity from Motif, BioAIM, Synthetic Biogogics, Mycomed, and ExBaq. No other disclosures were reported.
Section Editor: Mary McGrae McDermott, MD, Senior Editor.
References
1.
Arroyo M, Soberman JE. Adenosine deaminase in the diagnosis of tuberculous pericardial effusion. Am J Med Sci. 2008;335(3):227-229. doi:10.1097/MAJ.0b013e3180cab71aPubMedGoogle ScholarCrossref
2.
Reuter H, Burgess L, van Vuuren W, Doubell A. Diagnosing tuberculous pericarditis. QJM. 2006;99(12):827-839. doi:10.1093/qjmed/hcl123PubMedGoogle ScholarCrossref
3.
Porcel JM, Esquerda A, Bielsa S. Diagnostic performance of adenosine deaminase activity in pleural fluid: a single-center experience with over 2100 consecutive patients. Eur J Intern Med. 2010;21(5):419-423. doi:10.1016/j.ejim.2010.03.011PubMedGoogle ScholarCrossref
4.
Koh KK, Kim EJ, Cho CH, et al. Adenosine deaminase and carcinoembryonic antigen in pericardial effusion diagnosis, especially in suspected tuberculous pericarditis. Circulation. 1994;89(6):2728-2735. doi:10.1161/01.CIR.89.6.2728PubMedGoogle ScholarCrossref
5.
Pandie S, Peter JG, Kerbelker ZS, et al. Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous pericarditis compared to adenosine deaminase and unstimulated interferon-γ in a high burden setting: a prospective study. BMC Med. 2014;12(1):101. doi:10.1186/1741-7015-12-101PubMedGoogle ScholarCrossref
6.
Mayosi BM, Burgess LJ, Doubell AF. Tuberculous pericarditis. Circulation. 2005;112(23):3608-3616. doi:10.1161/CIRCULATIONAHA.105.543066PubMedGoogle ScholarCrossref
7.
Syed FF, Mayosi BM. A modern approach to tuberculous pericarditis. Prog Cardiovasc Dis. 2007;50(3):218-236. doi:10.1016/j.pcad.2007.03.002PubMedGoogle ScholarCrossref
8.
Lewinsohn DM, Leonard MK, LoBue PA, et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention clinical practice guidelines: diagnosis of tuberculosis in adults and children. Clin Infect Dis. 2017;64(2):e1-e33. doi:10.1093/cid/ciw694PubMedGoogle ScholarCrossref
9.
Talati NJ, Seybold U, Humphrey B, et al. Poor concordance between interferon-γ release assays and tuberculin skin tests in diagnosis of latent tuberculosis infection among HIV-infected individuals. BMC Infect Dis. 2009;9(15):15. doi:10.1186/1471-2334-9-15PubMedGoogle ScholarCrossref
Edward Chau, MD1; Minoo Sarkarati, MD1; Brad Spellberg, MD1
Author Affiliations Article Information
1Los Angeles County + University of Southern California (LAC+USC) Medical Center, Los Angeles, California
JAMA. 2019;322(2):163-164. doi:10.1001/jama.2019.7535
Case
A 65-year-old Vietnamese man with hypertension, type 2 diabetes mellitus, and chronic hepatitis B with cirrhosis presented with a 2-week history of shortness of breath at rest, orthopnea, and lower extremity edema. He reported a 4-month history of nonproductive cough, 5-kg weight loss, and fatigue. He immigrated to the United States as an adult more than 20 years before presentation. His temperature was 37°C, heart rate was 78/min, respiratory rate was 17/min, and blood pressure was 158/95 mm Hg. A chest radiographic image suggested cardiomegaly and a computed tomographic scan demonstrated a moderate to large pericardial effusion. A pericardial drain was placed and pericardial fluid was sent to the laboratory for evaluation. Initial pericardial fluid study results are presented in the Table. Empirical treatment for tuberculosis was initiated. Three days later, an adenosine deaminase (ADA) level of 118.1 U/L (normal range, 0.0-11.3 U/L) from pericardial fluid was reported from the laboratory.
Table. View LargeDownload
Pericardial Fluid Laboratory Results
Pericardial Fluid Laboratory Results
What Would You Do Next?
Perform additional pericardial effusion cytology and culture testing
Stop further nontubercular diagnostic testing and continue antitubercular therapy
Initiate oral colchicine, nonsteroidal anti-inflammatory drugs, and steroids for systemic inflammation
Perform an interferon-γ release assay (IGRA)
Discussion
Answer
B. Stop further nontubercular diagnostic testing and continue antitubercular therapy
Test Characteristics
ADA is an enzyme in lymphocytes and myeloid cells that recycles toxic purine pathway metabolites, which are essential for DNA metabolism and cell viability.1,2 ADA levels are elevated in inflammatory effusions, including pleural, pericardial, and joint effusion, caused by bacterial infections, granulomatous inflammation (eg, tuberculosis, sarcoidosis), malignancy, and autoimmune diseases (eg, lupus, vasculitis).1,2 ADA is normally elevated in neutrophil-predominant effusions and is not a useful diagnostic test in the setting of neutrophil-predominant effusions.3 However, among lymphocyte-predominant effusions, levels of ADA are typically higher in those caused by tuberculosis (TB) than those caused by other conditions.1,2
In lymphocyte-predominant effusions, the most common threshold for an ADA test result indicating TB is an ADA level greater than 40 U/L. An ADA level greater than 40 U/L has a sensitivity of 87% to 93% and specificity of 89% to 97% for TB.2,4 At a threshold of greater than 35 U/L, sensitivity is higher (93%-95%) but specificity is lower (74%-90%).3,5,6 Given a pretest probability of 70% for TB in a lymphocyte-predominant pericardial effusion in a patient from an endemic country,7 an ADA level greater than 40 U/L results in a posttest probability of 96%, while a level less than or equal to 40 U/L results in a posttest probability of 19%. The Centers for Medicare & Medicaid Services reimbursement rate for ADA testing is $8.10 (Current Procedural Terminology code 84311).
Application to This Patient
In the current patient, the ADA test was ordered from pericardial fluid to confirm the presumptive diagnosis of pericardial TB, for which antitubercular therapy was initiated. RIPE (rifampin, isoniazid, pyrazinamide, ethambutol) therapy was started because of the high pretest probability of TB in a patient from a country with endemic TB with chronic cough, weight loss, and lymphocyte-predominant pericardial effusion. The patient’s ADA level of 118.1 U/L confirmed the diagnosis, enabling cessation of further evaluation and supporting continuation of antitubercular therapy.
An alternative approach is to await a culture positive for TB before starting therapy. However, cultures positive for TB can take weeks to grow, which can allow infection to progress while awaiting confirmation. An ADA level greater than 40 U/L in a patient with a high pretest probability of disease results in a sufficiently high posttest probability to justify a full course of TB therapy. Furthermore, even with an ADA level less than or equal to 40 U/L in a patient with a high pretest probability, the posttest probability of approximately 20% is sufficiently high to warrant empirical therapy. However, the low ADA level would necessitate further diagnostic testing, including invasive pericardial biopsy and serologies, to rule out other causes (eg, sarcoid, malignancy, vasculitis) while treating the patient for TB. In that situation, empirical TB therapy could have been stopped if an alternative diagnosis was established.
What Are Alternative Diagnostic Testing Approaches?
Elevated interferon-γ concentrations in effusions have high sensitivity (95.7%) and specificity (96.3%) for active TB, but their use is limited by cost and availability.1,4 Interferon-γ can also be measured from whole blood via IGRAs. However, IGRAs and the similar purified protein derivative skin test are only useful to diagnose latent TB. Laboratory test results indicating ADA values greater than 40 U/L cannot distinguish between latent and active TB (nonspecific), and IGRAs/purified protein derivatives are associated with false-negative results in up to 30% of patients with pulmonary TB and 50% of patients with disseminated TB,8,9 because active TB causes antigen-specific anergy of T cells.
Patient Outcomes
The patient’s sputum was negative for acid-fast bacilli smears and TB polymerase chain reaction. Pericardial fluid cytology demonstrated inflammatory cells, but was negative for malignant cells, acid-fast bacilli stain, and TB polymerase chain reaction. However, the pericardial fluid cultures grew TB at 3 weeks and the sputa cultures grew TB at 5 weeks. Seven months after the start of treatment, the patient was hospitalized and died of complications of pneumonia and septic shock unrelated to TB.
Clinical Bottom Line
ADA levels are typically elevated, and not diagnostically helpful, in neutrophil-predominant effusions.
In lymphocyte-predominant effusions, ADA levels are elevated in effusions caused by tuberculosis, but typically not in effusions due to other diseases.
In a patient with a low pretest probability of TB, an ADA level less than or equal to 40 U/L in a lymphocyte-predominant effusion essentially rules out TB.
In a patient with a high pretest probability of pericardial TB, an ADA level greater than 40 U/L in a lymphocyte-predominant effusion is highly suggestive of TB, precluding the need for further diagnostic testing.
Back to top Article Information
Corresponding Author: Brad Spellberg, MD, LAC+USC Medical Center, 2051 Marengo St, Los Angeles, CA 90033 (spellber@usc.edu).
Published Online: June 14, 2019. doi:10.1001/jama.2019.7535
Conflict of Interest Disclosures: Dr Spellberg reported receiving personal fees from Alexion, Synthetic Biologics, Paratek, TheoremDx, Acurx, and Merck and equity from Motif, BioAIM, Synthetic Biogogics, Mycomed, and ExBaq. No other disclosures were reported.
Section Editor: Mary McGrae McDermott, MD, Senior Editor.
References
1.
Arroyo M, Soberman JE. Adenosine deaminase in the diagnosis of tuberculous pericardial effusion. Am J Med Sci. 2008;335(3):227-229. doi:10.1097/MAJ.0b013e3180cab71aPubMedGoogle ScholarCrossref
2.
Reuter H, Burgess L, van Vuuren W, Doubell A. Diagnosing tuberculous pericarditis. QJM. 2006;99(12):827-839. doi:10.1093/qjmed/hcl123PubMedGoogle ScholarCrossref
3.
Porcel JM, Esquerda A, Bielsa S. Diagnostic performance of adenosine deaminase activity in pleural fluid: a single-center experience with over 2100 consecutive patients. Eur J Intern Med. 2010;21(5):419-423. doi:10.1016/j.ejim.2010.03.011PubMedGoogle ScholarCrossref
4.
Koh KK, Kim EJ, Cho CH, et al. Adenosine deaminase and carcinoembryonic antigen in pericardial effusion diagnosis, especially in suspected tuberculous pericarditis. Circulation. 1994;89(6):2728-2735. doi:10.1161/01.CIR.89.6.2728PubMedGoogle ScholarCrossref
5.
Pandie S, Peter JG, Kerbelker ZS, et al. Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous pericarditis compared to adenosine deaminase and unstimulated interferon-γ in a high burden setting: a prospective study. BMC Med. 2014;12(1):101. doi:10.1186/1741-7015-12-101PubMedGoogle ScholarCrossref
6.
Mayosi BM, Burgess LJ, Doubell AF. Tuberculous pericarditis. Circulation. 2005;112(23):3608-3616. doi:10.1161/CIRCULATIONAHA.105.543066PubMedGoogle ScholarCrossref
7.
Syed FF, Mayosi BM. A modern approach to tuberculous pericarditis. Prog Cardiovasc Dis. 2007;50(3):218-236. doi:10.1016/j.pcad.2007.03.002PubMedGoogle ScholarCrossref
8.
Lewinsohn DM, Leonard MK, LoBue PA, et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention clinical practice guidelines: diagnosis of tuberculosis in adults and children. Clin Infect Dis. 2017;64(2):e1-e33. doi:10.1093/cid/ciw694PubMedGoogle ScholarCrossref
9.
Talati NJ, Seybold U, Humphrey B, et al. Poor concordance between interferon-γ release assays and tuberculin skin tests in diagnosis of latent tuberculosis infection among HIV-infected individuals. BMC Infect Dis. 2009;9(15):15. doi:10.1186/1471-2334-9-15PubMedGoogle ScholarCrossref
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