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Setting
This case is taken from a health care facility situation in the highlands of Papua Province, Indonesia. The facility has an outpatient clinic without ward capacity, and has access to basic diagnostic facilities with a laboratory; no X-ray capacity is available. Currently the medical staff consists of a local doctor, four nurses and two consultants. A Dutch medical doctor in tropical medicine assists in the clinic on consultant basis, mostly by advising on difficult cases. The nearby hospital has 4 wards and staff consists of several specialists, including an internist. Common conditions include HIV, tuberculosis, asthma, bronchitis and pregnancy-related issues.
Case
A 20-year old woman presented with right thoracic pain, fever and nocturnal sweating, which had started five weeks earlier. A week before, she had also developed dyspnoea and a non-productive cough. She had been suffering intermittent chest pains with fever over the course of a few years and had been treated with antibiotics several times with satisfactory results. Recently, she had been treated with cefixime and metronidazole, followed by amoxicillin, salbutamol and prednisone in another clinic.
On physical examination, the patient did not appear ill but was tachypnoeic and dyspnoeic. On pulmonary auscultation, normal breath sounds were heard over the left hemithorax. On the right side however, there were absent breath sounds over the right middle and lower zones. There was no fever or lymphadenopathy. A chest X-ray showed a right-sided pleural effusion in the basal regions of the lung without infiltrates, miliary opacities, cavities or mediastinal lymphadenopathy.
The differential diagnosis included tuberculous pleural effusion, bacterial pneumonia with pleural effusion and pulmonary embolism.
Specialist advice
Internists were consulted to ask for advice on this case. Particularly, the tropical doctor requested advice on differential diagnosis and therapy. Would it be wise to perform a therapeutic thoracocentesis (pleural tap) and to start the patient on empirical anti-tuberculous medication?
The advice was to perform a diagnostic pleural tap to examine the appearance of the pleural fluid. A cloudy fluid sample would suggest an exudate and bacterial empyema, in which case drainage would be indicated. Alternatively, repeated pleural taps combined with antibiotic therapy (amoxicillin and clavulanic acid or clindamycin) could be considered. In the case of a clear exudate, tuberculosis would be more likely, warranting anti-tuberculous therapy. Furthermore, it was advised to test the patient for HIV.
Follow-up
The patient was referred to a local hospital, where she tested negative on HIV. A pleural tap was not done, because the local internist was afraid of complications and quite convinced that this would be a case of TB. She was started on standard anti-tuberculous medication, after which she gradually improved with reduced dyspnoea and pain. After six months of treatment, an X-ray still showed some pleural effusion, which made the internist decide to continue the anti-tuberculous medication for three more months.
Background
Pathophysiology of pleural effusion
Physiologic pleural fluid is a transudate. [1] Fluid formation is balanced with drainage capacity, maintaining an estimated volume of 0.1 to 0.2 mL/kg. In case of excess formation or decreased drainage, a pleural effusion can occur.
Pleural effusions can be transudates or exudates. In transudates, high hydrostatic pressure or low oncotic pressure lead to fluid extravasation in the pleural cavity. Examples are heart failure, liver cirrhosis, nephrotic syndrome and hypoalbuminemia. In exudates, vascular hyperpermeability due to an underlying malignancy or inflammation gives rise to plasma leak and fluid accumulation; the most common conditions are infection (tuberculosis, bacterial infection), amoebic liver abscess (by spread though diaphragm) and malignancy.
Diagnostic approach to pleural effusion
In a resource-limited setting, a diagnostic tap may be done for appearance of the fluid, total white cell count and differential, protein level and Gram and ZN staining. [2]
The appearance of the fluid can provide useful information: red-brown in amoebic abscess; bloody or chylous in malignancy; straw-coloured in pneumonia or TB; pus in empyema. Raised white blood cell count suggests an exudate; predominantly neutrophils in bacterial infection and lymphocytes in TB, lymphoma and malignancy.
Transudates and exudates can be distinguished from one another using Light’s criteria. [1] An exudative pleural effusion fulfils at least one of the following criteria (none in transudate):
- Pleural fluid / serum protein ratio > 0.5
- Pleural LDH / serum LDH ratio > 0.6
- Pleural fluid LDH > two-thirds of the normal upper limit for serum LDH
These criteria have a sensitivity of 98% and a specificity of 74%. [1] There is a relatively large chance of misclassifying a transudate as an exudate, particularly when the patient is using diuretics or when the criteria are only minimally met (ratios just exceeding the limit). [3] Pleural effusions can correctly be classified as transudates if the difference between protein levels in serum and pleural fluid is greater than 3.1 g/dL. A transudate can be ruled out if the protein level is more than 4.0 g/L.
Gram stain should be done as well as ZN stain, although the latter has low sensitivity.
Depending on the facilities available, a culture may be obtained. Other parameters include pH, glucose, adenosine deaminase (ADA), amylase, triglycerides, procalcitonin, NT-proBNP and tumour markers. [4] Further diagnostic methods in high-resource settings include serum analysis and urinalysis, pleural biopsy, radiology (chest radiograph and CT-scan), thoracoscopy and bronchoscopy. [3,4]
Treatment of pleural effusion
In most cases of pleural effusion, the underlying cause should be treated. In cases of empyema or severe dyspnea due to large effusions, thoracocentesis should be performed. Pleurodesis (artificial obliteration of the pleural space f.e. chemically) can be beneficial for refractory symptomatic effusion. [1]
Pleural effusion in tuberculosis
Background
Pleural effusion is among the most common extrapulmonary manifestations of TB. Pleuritis occurs in 25% of patients with TB. It was once thought to develop after a subpleural caseous focus in the lung ruptures into the pleural space, followed by a delayed hypersensitivity reaction. [1,5] However, more recently it has been described to be the consequence of direct infection of the pleural space. [6] It can arise after primary infection or reactivation of latent tuberculosis. [5]
Clinical features
Presenting features are an acute febrile illness, pleuritic chest pain and cough. [1,5] Less acute symptoms include dyspnoea, weight loss, night sweating and malaise. [1] The pleural effusion is often unilateral, is characterised by a high protein level (>5 g/dL) and predominantly contains lymphocytes. [5] Compared to serum, it has a similar or reduced glucose level and a high lactic acid dehydrogenase (LDH) level. [5] Pleural fluid pH is >7.30, but can also be reduced. [5]
Diagnostic criteria
Evidence of mycobacterium in pleural fluid can provide the diagnosis. However, as extrapulmonary TB is paucibacillary, pleural fluid smears and cultures are usually negative in immunocompetent patients. [5] Alternatively, tubercle bacilli can be demonstrated in sputum or pleural biopsy, or granulomas in pleura can lead to the diagnosis. Adenosine deaminase (ADA) and gamma-interferon levels in pleural fluid can be helpful, making TB unlikely in case of ADA <40 IU/l and gamma-interferon <140 pg/mL. [3] In endemic regions, a predominant lymphocytic exudate with a high ADA level can justify treatment initiation. [6]
Therapeutic options
Tuberculous effusions are self-limiting, resolving within 6-12 weeks. [5] Anti-tuberculous therapy should always be initiated, as more than 50% of patients will develop active TB over the course of 5 years. [1,3] A standard 6-month anti-tuberculosis regimen should be followed. [5,7] In some patients, paradoxical worsening of the pleural effusion is seen. [1,5] In severely dyspnoeic patients with large effusions, therapeutical thoracocentesis can be performed. If severe systemic symptoms (fever, malaise, chest pains) continue, administration of 80 mg prednisone every other day is recommended; when the symptoms subside, corticosteroids can be tapered. [5] In co-infection with HIV, co-trimoxazole prophylactic therapy should be started, followed by HAART after two weeks of tuberculostatic medication. [2]
References
- Thomas R, Gary Lee YC. Causes and management of common benign pleural effusions. Thorac Surg Clin. 2013;23(1):25-42.
- Zijlstra EE. The practice of internal medicine in the tropics. 100 cases. Rotterdam: Rotterdam Centre for Tropical Medicine; 2016. P. 144-46.
- Light RW. The undiagnosed pleural effusion. Clin Chest Med. 2006;27(2):309-19.
- Na MJ. Diagnostic Tools of Pleural Effusion. Tuberc Respir Dis. 2014;76(5):199-210.
- Light RW. Update on tuberculous pleural effusion. Respiratology. 2010;15(3):451-58.
- Vorster MJ, Allwood BW, Diacon AH, Koegelenberg FN. Tuberculous pleural effusions: advances and controversies. J Thorac Dis. 2015;7(6):981-91.
- Kim CH, Lim JK, Lee DH, Yoo SS, Lee SY, Cha SI et al. Outcomes of standard and tailored anti-tuberculosis regimens in patients with tuberculous pleural effusion. Int J Tuberc Lung Dis. 2016;20(11):1516-21.
