JAMA Diagnostic Test Interpretation June 14, 2019
Adenosine Deaminase Diagnostic Testing in Pericardial Fluid
Edward Chau, Minoo Sarkarati,Brad Spellberg
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.
一名65岁越南裔男性既往患有高血压、2型糖尿病及慢性乙型肝炎伴肝硬化。患者因静息状态下呼吸困难、端坐呼吸及下肢水肿2周就诊。患者还主诉干咳4个月，体重下降5 kg，且有明显乏力。患者成年后移民至美国，至就诊时在美国生活已超过20年。患者体温37°C，心率78 bpm，呼吸频率17 bpm，血压158/95 mmHg。胸片提示心脏扩大，CT显示中到大量心包积液。遂置入心包引流管并将心包积液送检。心包积液的化验结果见下表。开始经验性抗结合治疗。3天后，心包积液腺苷脱氨酶(ADA)结果回报，为118.1 U/L（正常范围，0.0-11.3 U/L）
讨论
Q: What Would You Do Next? 下一步应该做什么？
A: Stop further nontubercular diagnostic testing and continue antitubercular therapy 停止针对非结核的进一步诊断检查，继续抗结核治疗
Test Characteristics 检查特点
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
ADA是淋巴细胞和髓样细胞中的一种酶，参与毒性嘌呤途径代谢产物的再循环，后者对于DNA代谢和细胞活性非常重要。细菌感染、肉芽肿性炎症（如结核，结节病）、恶性肿瘤及自身免疫病（如狼疮，血管炎）引起的炎性积液（包括胸腔、心包和关节积液）情况下ADA水平升高。以中性粒细胞为主的积液ADA升高，此时ADA的诊断价值不高。然而，在以淋巴细胞为主的积液中，结核(TB)患者的ADA水平通常高于其他病因。
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).
在淋巴细胞为主的积液中，提示为TB的ADA临界值通常为40 U/L。ADA > 40 U/L诊断TB的敏感性87% to 93%，特异性 89% to 97%。临界值为35 U/L时，敏感性更高(93%-95%)，但特异性较低(74%-90%)。对于一名来自流行国家的患者，心包积液以淋巴细胞为主，诊断TB的验前概率为70%时，若ADA > 40 U/L，则验后概率为96%，若ADA <= 40 U/L，则验后概率为 19%。Medicare 与 Medicaid 服务中心对ADA检测的报销价格为 $8.10（当前操作名词编码84311）。
Application to This Patient 在此例患者的应用
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.
对于此例患者，心包积液ADA检查确诊了心包TB的初始诊断。对于这名来自TB流行国家的长期咳嗽、体重下降且心包积液以淋巴细胞为主的患者，由于TB的验前概率很高，因此开始了RIPE（利福平，异烟肼，吡嗪酰胺，乙胺丁醇）治疗。患者ADA水平118.1 U/L明确了诊断，可以停止进一步检查，并支持继续抗结核治疗。
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.
另一种策略是等待TB培养结果阳性后再开始治疗。然而，TB培养需要数周才能得到结果，在此期间感染可能进展。对于验前概率很高的患者，ADA > 40 U/L能够确保足够高的验后概率，可以进行抗结核治疗。而且，即使验前概率很高的患者ADA <= 40 U/L，验后概率仍接近20%，此时仍可进行经验性治疗。但是，如果ADA水平较低，在进行抗结核治疗的同时，需要进一步诊断检查，包括心包活检和血清学检查，以排除其他病因（如结节病，恶性肿瘤和血管炎）。在这种情况下，如果确定其他诊断，则应当停止经验性抗结核治疗。
What Are Alternative Diagnostic Testing Approaches? 是否有其他的诊断方法？
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.
积液中γ干扰素水平升高对于活动性TB具有很高的敏感性(95.7%)和特异性(96.3%)，但由于费用及检查普及性限制了临床应用。还可以对全血通过IGRA方法测定γ干扰素。然而，IGRA及相似的纯化蛋白衍生物(PPD)皮试仅用于诊断潜伏期TB。实验室检查提示ADA > 40 U/L，并不能鉴别潜伏期和活动期TB（缺乏特异性），肺TB患者IGRA/PPD假阴性率可达30%，播散性TB患者假阴性率50% ，这是由于活动期TB可引起T细胞抗原特异性无反应。
Patient Outcomes 患者结局
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.
患者痰涂片抗酸杆菌阴性，TB的PCR检测也为阴性。心包积液细胞学检查显示为炎性细胞，未见肿瘤细胞、抗酸杆菌，TB的PCR检测阴性。但是，3周后心包积液培养分离到TB，5周后痰培养分离到TB。开始治疗后7个月，患者因肺炎和感染性休克住院并死亡（与TB无关）。
Clinical Bottom Line 临床概要
- ADA levels are typically elevated, and not diagnostically helpful, in neutrophil-predominant effusions. 以中性粒细胞为主的积液中ADA通常升高，没有诊断价值
- In lymphocyte-predominant effusions, ADA levels are elevated in effusions caused by tuberculosis, but typically not in effusions due to other diseases. 以淋巴细胞为主的积液中，ADA升高可因结核而非其他疾病引起
- 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. 对于TB感染验前概率较低的患者，以淋巴细胞为主的积液中ADA < 40 U/L时，基本可以排除TB诊断
- 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. 对于心包TB感染验前概率较高的患者，以淋巴细胞为主的积液中ADA > 40 U/L，高度提示TB，可以不再进行其他诊断检查
