Lupus Masquerading as Tuberculosis: High Pleural ADA Levels Can Deceive Doctors

A 78-year-old man with pneumoconiosis developed progressive pleural effusion, fever, and cough in late November and was admitted to hospital for evaluation. Thoracentesis revealed a lymphocyte-predominant exudative effusion with 92 percent lymphocytes and a markedly elevated adenosine deaminase level of 110.9 U/L, a value far above the commonly used diagnostic cutoff of 40 U/L for tuberculous pleuritis. Cytological examination of the pleural fluid was negative for malignancy, and empirical antibiotic therapy with piperacillin/tazobactam was initiated while further investigations proceeded.

Repeated sputum examinations showed no significant bacterial growth, and acid-fast bacilli smears were negative. Chest computed tomography demonstrated well-defined nodular opacities predominantly in both upper lobes, patchy infiltrates predominantly in the lower lobes, and bilateral pleural effusions, without findings suggestive of active pulmonary tuberculosis. Interferon-γ release assays, including QuantiFERON-TB and T-SPOT.TB, were both negative. Both pleural fluid and sputum were negative for acid-fast bacilli on smear and polymerase chain reaction testing.

On Day 13, the patient developed altered consciousness. Blood tests on Day 15 showed thrombocytopenia and evidence of hepatic and renal dysfunction. Persistent fever was noted, with ferritin at 524 ng/mL and fibrinogen at 152 mg/dL. Computed tomography demonstrated worsening pleural effusion, although splenomegaly was absent. Because a skin rash appeared during treatment, drug hypersensitivity syndrome was suspected, and the anti-tuberculosis therapy was discontinued. Given thrombocytopenia and markedly elevated fibrin degradation products of 201 μg/mL, disseminated intravascular coagulation associated with sepsis was suspected, and treatment with meropenem and recombinant thrombomodulin was initiated.

Despite these interventions, the patient’s respiratory condition deteriorated by Day 17, requiring high-flow nasal cannula oxygen therapy at a flow of 30 L/min with FiO2 of 60 percent. Lactate dehydrogenase levels increased further, and renal dysfunction worsened. Although the antinuclear antibody titre remained low at 1:40, well below the entry criterion of the 2019 ACR/EULAR classification criteria for systemic lupus erythematosus, the patient showed hypocomplementemia with C3 at 35 mg/dL and C4 at 3 mg/dL, positive anti-RNP antibodies at 32.8 U/mL, positive anti-SS-A antibodies at 138 U/mL, and markedly elevated anti-double-stranded DNA antibodies at 353 IU/mL. Based on these findings, late-onset systemic lupus erythematosus was clinically diagnosed despite not fulfilling the ANA entry criterion.

Given the rapidly progressive clinical deterioration, transfer to a tertiary care center for advanced supportive therapy, including continuous haemodiafiltration, was considered. However, the patient’s family declined transfer. High-dose corticosteroid pulse therapy was initiated on the same day. Considering the need for further immunosuppressive therapy under specialist care, the patient was transferred to a tertiary care hospital on Day 31. Subsequent cultures later yielded Mycobacterium intracellulare from a sputum specimen, whereas pleural fluid cultures remained negative. The isolate was considered colonization rather than the primary cause of pleuritis. At the tertiary care center, ANA remained low-titre at 1:40, whereas anti-double-stranded DNA antibodies remained positive with persistent hypocomplementemia, supporting the diagnosis of systemic lupus erythematosus. The patient was later transferred to a rehabilitation facility on Day 57, with chest radiograph showing marked resolution of the pleural effusion.

This case highlights several important clinical lessons regarding the differential diagnosis of pleural effusion with elevated ADA levels. First, markedly elevated pleural ADA levels do not necessarily indicate tuberculous pleuritis. ADA is an enzyme involved in purine metabolism and is particularly abundant in activated lymphocytes. Because tuberculous pleuritis is characterized by intense cellular immune responses with lymphocyte predominance, pleural ADA levels are frequently elevated and have been widely used as a diagnostic marker for tuberculosis. However, ADA elevation is not specific to tuberculosis. Increased ADA levels have also been reported in other conditions associated with lymphocyte-rich pleural effusion, including lymphoma, rheumatoid pleuritis, empyema, and autoimmune diseases such as systemic lupus erythematosus. Therefore, although pleural ADA levels exceeding 40 U/L are commonly used as a diagnostic cutoff for tuberculous pleuritis, clinicians should interpret these findings cautiously in the context of the overall clinical picture.

In this case, tuberculous pleuritis was initially suspected because of the markedly elevated ADA level; however, repeated microbiological tests, including acid-fast smear, PCR, and culture of pleural fluid were negative, and the pleural effusion improved rapidly after corticosteroid therapy. These findings supported a non-tuberculous aetiology. The case also illustrates the diagnostic challenges associated with late-onset systemic lupus erythematosus. SLE typically affects young women; however, approximately 10 to 20 percent of patients develop the disease after the age of 50 years and are classified as having late-onset SLE. Compared with younger patients, late-onset SLE often presents with atypical manifestations and less prominent mucocutaneous findings. Serositis, including pleural effusion, may be one of the initial manifestations and may resemble infectious diseases.

Another notable feature was the absence of significant ANA positivity. The 2019 ACR/EULAR classification criteria require ANA positivity as an entry criterion for SLE classification; however, low-titre ANA SLE has been reported in rare cases. In this patient, despite low-titre ANA results, the markedly elevated anti-double-stranded DNA antibodies and hypocomplementemia, together with multi-organ involvement and a dramatic response to corticosteroid therapy, all supported the diagnosis of SLE. Importantly, the patient fulfilled the 2012 Systemic Lupus International Collaborating Clinics classification criteria, with leukopenia, thrombocytopenia, serositis, hypocomplementemia, and anti-double-stranded DNA antibody positivity. These findings further supported the classification of SLE despite the absence of significant ANA positivity. The presence of pneumoconiosis in this patient may also be relevant: exposure to silica dust has been associated with an increased risk of autoimmune diseases, including SLE, rheumatoid arthritis, and systemic sclerosis. Epidemiological studies have also suggested that occupational exposure to crystalline silica increases the risk of developing SLE. Silica particles may activate the innate immune system and promote autoantibody production, potentially contributing to autoimmune disease development.

The broader message for clinicians is that markedly elevated pleural ADA levels are not pathognomonic for tuberculosis and may lead to diagnostic delay if other causes, including autoimmune diseases such as systemic lupus erythematosus, are overlooked. Late-onset SLE in elderly patients often presents with atypical clinical features and may mimic infectious diseases, which can delay diagnosis.

Subject of Research: A case report of late-onset systemic lupus erythematosus with low-titre antinuclear antibodies presenting as pleural effusion with markedly elevated adenosine deaminase mimicking tuberculous pleuritis.

Article Title: Low‐Titre ANA Late‐Onset Systemic Lupus Erythematosus Presenting With Pleural Effusion and Markedly Elevated Pleural Adenosine Deaminase Mimicking Tuberculous Pleuritis

Article References: Inoue, S., Tatsuta, M., Tatsutani, T., Ueda, S., Wakamatsu, K., & Kawasaki, M. (2026). Low‐Titre ANA Late‐Onset Systemic Lupus Erythematosus Presenting With Pleural Effusion and Markedly Elevated Pleural Adenosine Deaminase Mimicking Tuberculous Pleuritis. Respirology Case Reports, 14(11), Article e70785. https://doi.org/10.1002/rcr2.70785

Image Credits: AI Generated

DOI: 10.1002/rcr2.70785

Keywords: systemic lupus erythematosus, pleural effusion, adenosine deaminase, tuberculous pleuritis, late-onset SLE, antinuclear antibody, pneumoconiosis, hypocomplementemia, anti-double-stranded DNA antibodies, corticosteroid therapy, interferon-gamma release assay, autoimmune disease