|Year : 2014 | Volume
| Issue : 2 | Page : 215-217
A case of recurrent pleural effusion: Can we think beyond tuberculosis and malignancy?
Department of Medicine, Padmashree Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India
|Date of Web Publication||4-Feb-2014|
D-303, Ganeesham Phase-II, Opposite SBI, Nashik Phata Road, Pimple Saudagar, Pune - 411 027, Maharashtra
Source of Support: None, Conflict of Interest: None
Pleural effusion can occur due to a variety of causes such as infectious, neoplastic, inflammatory, autoimmune, traumatic, etc. Recurrent pleural effusions have always been a diagnostic challenge. Here, we present a case of recurrent exudative pleural effusion in a male patient, which was the first clinical manifestation of rheumatoid arthritis. Of note was the absence of articular involvement at the onset of the disease. The low glucose concentration, low pH and low C4 level in the pleural fluid were the most valuable findings to distinguish it from tuberculous and malignant pleural effusions. Pleural biopsy also helped in making such a distinction. Thus, in a patient with recurrent pleural effusion, rheumatoid etiology should also be kept in mind as a differential diagnosis.
Keywords: Anticyclic citrullinated polypeptide antibody, extraarticular disease, pleural effusion, rheumatoid arthritis
|How to cite this article:|
Vaishnav B. A case of recurrent pleural effusion: Can we think beyond tuberculosis and malignancy?. Med J DY Patil Univ 2014;7:215-7
| Introduction|| |
Rheumatoid arthritis (RA) is a common inflammatory disease with multisystem involvement, affecting about 0.8% of the population.  Usually, the extraarticular manifestations of RA occur after joint and articular involvement. Very rarely do non-articular features appear as the first clinical manifestation of RA. Pleural effusion in RA occurs in only 2-3% patients,  and even that is after articular involvement. Thus, if the pleuro-pulmonary involvement precedes onset of RA, then it is difficult to differentiate it from other etiologies like tuberculosis and malignancy. However, recurrence and presence of laboratory data such as RA factor, anticyclic citrullinated polypeptide antibody (ACPA), pleural fluid analysis and histopathological picture of pleural biopsy can collectively indicate underlying rheumatoid etiology.
| Case Report|| |
A 54-year-old male, non-smoker and non-alcoholic, presented with complaints of dry cough, left-sided continuous chest pain that aggravated on coughing and deep breathing and intermittent fever since 7 days. There was no complaint of breathlessness, hemoptysis or any other cardiac symptom. There was no joint pain, swelling or stiffness. Before 1 year, the patient was diagnosed with right-sided tuberculous pleural effusion and had completed a full course of anti-tubercular drugs (category 1 - Directly Observed Treatment Strategy [DOTS]).
On examination, the patient was febrile. Respiratory system examination revealed diminished chest movements on the left side, a dull note on percussion and diminished breath sounds and vocal resonance from the fifth to the seventh left intercostal space in the mid-clavicular line, left infra-axillary region and left infrascapular region. The rest of the systemic examination was normal.
Routine investigations that were carried out included hemoglobin (12.5 g/dL), total leukocyte count (9800/cumm), normal differential count and peripheral smear and erythrocyte sedimentation rate (ESR) (48 mm in the first hour by Westergren's method in an automated analyzer). Renal function tests (RFTs) and liver function tests (LFTs), plasma glucose and serum electrolytes were normal. Chest X-ray revealed a left-sided pleural effusion [Figure 1]. The right lung and pleural cavity were normal.
Sputum culture by BACTEC method was negative for acid fast bacilli. Thoracocentesis was performed, which showed a pH of 7.25 and a white blood cell (WBC) count of 4320 cells per cubic mm, predominantly lymphocytes, sugar 40 mg/dL and protein 5.4 g/dL. Pleural fluid adenosine deaminase (ADA) was 36 IU/L. Malignant cells were not seen. Pleural fluid culture was sent for tuberculosis. The patient was put on anti-tubercular drugs (category 2 - DOTS).
After 15 days of treatment, his symptoms persisted, fever increased and the repeat chest X-ray and thoracic ultrasound showed increased left-sided pleural effusion. Complete hemogram, Renal Function Tests (RFTs) viz. Serum creatinine and blood urea, and Liver Function Tests (LFTs) viz. Serum bilirubin, Serum aspartate Serum transaminase (AST), Serum alanine transaminase (ALT), and Serum alkaline phosphatase, were normal. ESR was 86 mm. C-reactive protein (CRP) was high. A computerized tomography scan of the thorax showed left-sided pleural effusion with underlying lung collapse, no consolidation, no pericardial effusion and no mediastinal lymphadenopathy [Figure 2].
|Figure 2: Computerized tomography of the thorax showing left-sided pleural effusion|
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Bronchoscopy was normal and bronchoalveolar lavage fluid was negative for malignant cells. The patient was asked to continue anti-tubercular drugs. Oral levofloxacin was added for antibacterial coverage of atypical mycobacteria and taking into consideration a possibility of multidrug-resistant tuberculosis. However, symptoms persisted even after 6 weeks of this treatment. An ultrasound of the thorax revealed persistent pleural effusion. Pleural fluid for Mycobacterium tuberculosis was negative after 8 weeks of culture. A repeat pleural fluid examination showed exudative fluid with pH 7.1 and sugar 22 mg/dL (both were low) with lymphocytic cell predominance. Pleural fluid lactate dehydrogenase (LDH) level was 506 U/L (normal 140-280 U/L). Pleural fluid had low C3 and C4 complement levels. Pleural biopsy was performed and the histopathological examination revealed patchy, moderately dense chronic inflammatory exudates with fibrinoid necrotic material. The predominant cells were histiocytes, lymphocytes, plasma cells and a few macrophages in the background of granular debris. Pleural biopsy was suggestive of a possibility of underlying rheumatoid etiology. No evidence of any malignant cells or granuloma was seen [Figure 3].
|Figure 3: Histopathological picture of the pleura showing fibrinoid necrosis with histiocytes suggestive of a rheumatoid nodule formation|
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The patient was worked up for rheumatoid and autoimmune diseases. Rheumatoid factor (RA factor) was positive - 56.7 (normal <14). ACPA was 16.2 (normal < 15). Anti-nuclear antibody (ANA) profile, anti-neutrophil cytoplasmic antibody tests (perinuclear and cytoplasmic staining, i.e. p-ANCA and c-ANCA) were negative.
Taking into consideration the positive RA factor assay, ACPA, high ESR and CRP level in blood as well as low pH, low glucose,  high LDH  and low complement levels , in pleural fluid, a provisional diagnosis of recurrent pleural effusion due to underlying rheumatoid etiology was made.  Anti-tubercular drugs and other antibiotics were stopped. Oral prednisolone at the dose of 1 mg/kg was started and continued for 2 months. The patient improved symptomatically after 2 weeks of steroid therapy. Fever and chest pain disappeared. Repeat chest X-ray and ultrasound of the thorax revealed minimal pleural effusion.
The patient came for regular follow-up visits and, after 4 months of disappearance of pleural effusion, he developed polyarthritis involving both wrist joints and proximal interphalangeal joints of the fingers of the right hand. Classical symptoms of morning stiffness, arthralgia and signs of arthritis were present on examination. Laboratory evaluation and X-rays of the hand re-confirmed the diagnosis of RA. The patient was given non-specific anti-inflammatory drugs to be taken as and when necessary for pain relief. Low-dose glucocorticoids (prednisolone 10 mg to be taken every alternate day) and oral methotrexate (7.5 mg to be taken once a week) were given for long-term control of symptoms of RA. The patient is doing well at present on these drugs.
| Discussion|| |
Pleuro-pulmonary involvement in a case of RA is known,  pleuritis being the most common intrathoracic manifestation. But, an isolated pleural involvement in the form of recurrent pleural effusion without lung involvement and that too prior to development of classical articular symptoms of RA is very rare. 
Differential diagnosis of a recurrent exudative type of pleural effusion includes tuberculosis, malignancy, bacterial and viral infections, systemic lupus erythematosus, RA, vasculitis, etc. 
Although there is a female preponderance for RA (M:F is 1:3), pleural effusions are more commonly seen in middle-aged males. Both genetic and environmental factors like smoking play a role in pathogenesis and severity of RA and extraarticular disease.  Propagation of RA is an immunologically mediated event; hence, multiple systems are involved apart from the joints. Extraarticular disease is present in about 40% of RA patients, and high titers of RA factor and ACPA are found in them, as a rule. Mortality is also higher in these patients. ,
In the present case, a presumptive diagnosis of RA as a cause for recurrent pleural effusion was made on the basis of biochemical analysis of pleural fluid, presence of rheumatoid histology on pleural biopsy and positive RA factor and ACPA.  But, the diagnosis could only be confirmed later when the patient developed classical arthritis involving multiple joints.
The goal of management of extraarticular disease such as pleural effusions in RA is reduction of inflammation and control of symptoms with maintenance of functional life. Oral glucocorticoid therapy not only suppresses the inflammatory process but also retards the progression of disease. Here, the patient responded to it and the pleural effusion disappeared. Pleurodesis is indicated if the pleural effusion is recurrent and unresponsive to drug management. Other agents that can be used in treating RA are disease-modifying anti-rheumatic drugs like methotrexate, biological agents like etanercept, infliximab, adalimunab, anakinra, rituximab and abatacept and immunosuppressive drugs like leflunomide, azathioprine, cyclophosphamide and cyclosporine.
In summary, diagnosing a case of recurrent exudative pleural effusion is a challenge. Tuberculous and malignant etiologies are most often thought of as the cause. But, it is time to think beyond the obvious and keep unusual causes like RA in the differential diagnosis. Extraarticular disease and non-articular complications are part of the clinical spectrum of RA and can precede the articular disease. Relevant and detailed investigations can help in early diagnosis and prevent morbidity caused by it.
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[Figure 1], [Figure 2], [Figure 3]