|
 
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| THE EXTRAPULMONARY DISEASE - THE STRATEGIC PLAN |
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| Year : 2017 | Volume
: 4
| Issue : 2 | Page : 87-93 |
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Current approaches to tuberculous pleural effusion
Neha Mandovra, Preyas J Vaidya, Prashant N Chhajed
Institute of Pulmonology, Medical Research and Development, Mumbai; Fortis Hospitals, Mumbai and Navi Mumbai, India
| Date of Web Publication | 30-Nov-2017 |
Correspondence Address:
Prashant N Chhajed
Institute of Pulmonology, Medical Research and Development, Mumbai, Maharashtra
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/astrocyte.astrocyte_59_17
A common expression of pleural pathologies, most pleural effusions can be diagnosed correctly by the use of simple laboratory investigations, but 15–20% of them fail the test and remain undiagnosed. This paper highlights the advances made in the field of diagnosing a tubercular pleural effusion. In a highly endemic country like India, drug resistant (DR) tuberculosis (TB) is a major public health problem and a low bacillary load in the pleural fluid often results in a negative acid fast bacilli (AFB) culture. Image-guided and pleuroscopic-guided pleural biopsies can increase the yield rates of AFB culture and molecular diagnostic tests like GeneXpert. These tools hold a dual use: they can make a diagnosis of TB and can also detect the DR strains of TB. In the clinical arena, malignant pleural effusions are not uncommonly misdiagnosed initially and treated with antitubercular drugs. The use of newer diagnostic modalities can help limit the risk of such an erroneous diagnosis and unproductive management.
Keywords: Pleural biopsy, pleural effusion, pleuroscopy, tuberculosis
How to cite this article:
Mandovra N, Vaidya PJ, Chhajed PN. Current approaches to tuberculous pleural effusion. Astrocyte 2017;4:87-93 |
| Introduction | |  |
Pleural effusion is defined as the abnormal collection of fluid in the pleural space. It can result from excess fluid production or decreased absorption or both.[1] Pleural effusions are the most common manifestations of diseases involving the pleura. They are major causes of morbidity in India as well as in other parts of the world.
Pleural effusions are commonly classified as exudates and transudates on the basis of Light's criteria.[2] Exudative effusions are formed due to increase in vascular permeability due to insult to the pleura due to infection, infarction, or infiltration while transudative effusions occur due to increase in the pulmonary hydrostatic pressure, decrease in plasma oncotic pressure or both. The common causes of exudative pleural effusions include infective causes like tubercular effusion, parapneumonic effusion, malignancy (both primary and metastatic), collagen vascular diseases like rheumatoid arthritis, systemic lupus erythematosis, and pulmonary embolism. The common causes of transudative pleural effusion include congestive heart failure, cirrhosis of liver, nephrotic syndrome, and hypoalbuminemia.
In the recent years, there has been increased application of current and newer technologies in the diagnosis of pleural effusions, particularly those pleural effusions which remain undiagnosed with routine methods. The current article describes the current approach in the diagnosis of tubercular pleural effusions including newer diagnostic imaging and pleural interventions.
| Initial Evaluation | | |
The initial evaluation of pleural effusion includes detailed history and clinical examination. Dyspnea, cough, and pleuritic chest pain are the common symptoms in patients of pleural effusion. Patients with tubercular pleural effusion can have low grade fever, anorexia, and weight loss in addition. The physical examination of patients with pleural effusion reveals diminished chest movements on the affected side, dullness on percussion, and decreased breath sounds with decreased vocal fremitus. Thorough history and clinical examination can also guide in deciding distinction between transudates and exudates which can narrow down the differential diagnosis and directs further investigations.
| Imaging | | |
Conventional chest radiograph
It remains the initial investigation of choice in patients suspected of having pleural effusion. The posteroanterior (PA) chest radiograph shows blunting of costophrenic angle in the presence of about 200 mL of pleural fluid. On a lateral chest X-ray, 50 mL of fluid can cause blunting of posterior costophrenic angle.[3]
If the lung underlying the effusion is diseased, fluid accumulates where the elastic recoil is greatest, resulting in atypical effusions. Loculated pleural effusion can occur when the fluid is encapsulated by adhesions, which can occur in tubercular pleural effusion and also in empyema and hemothorax. A definitive diagnosis of loculated pleural effusion is best made by ultrasound.
Subpulmonic or infrapulmonary effusions occur when collection occurs between the diaphragmatic surface of the lung and the diaphragm. These are difficult to diagnose on PA view, ultrasound is often required for their diagnosis.
The anteroposterior (AP) view shows increase in hemithorax opacity with preserved bronchovascular markings. This view is common in very ill or ICU patients. Increased homogenous densities, blunted costophrenic angles, and loss of diaphragm silhouette are the most accurate signs in diagnosing pleural effusion.[4]
The lateral decubitus radiographs are used for semiquantitating the fluid by measuring the distance between the inner border of the chest wall and the outer border of the lung, greater the distance, more is the free fluid. It has been found that if this distance is less than 10 mm, diagnostic thoracocentesis is difficult.
Ultrasound
Ultrasound remains the most important imaging investigation in diagnosing the pleural effusion. Its advantages include its low cost, ease to use, portability, lack of ionizing radiation, and can be done bedside in critically ill patients in ICU. Ultrasound can be helpful in following situations:
- Determining presence of pleural fluid
- Identifying appropriate location for thoracocentesis, pleural biopsy or chest tube insertion, and ascertaining the appropriate depth for aspiration
- Indentifying loculated pleural effusion
- Distinguishing pleural effusion from pleural thickening
- Semiquantifying amount of pleural fluid
- Determining site for medical thoracoscopy
Several studies have shown that USG guided thoracocentesis have reduced the incidence of iatrogenic pneumothorax and this does not depend on the size of pleural effusion.[5],[6] Ultrasound can also help in aspiration of septated pleural effusions—commonly seen in tubercular effusions.[7]
Computed tomography
The availability of computed tomography (CT) has markedly improved the ability to assess pleural abnormalities radiologically. CT helps in detecting pleural abnormalities from parenchymal and extrapleural disease more accurately than by standard radiographs.
The free flowing fluid produces a sickle-shaped opacity posteriorly in most dependent part of lung while loculated pleural effusions are seen as lenticular opacities of fixed position. It is also helpful in differentiating empyema from air fluid levels of lung abscess. CT is particularly useful in diagnosis of empyema when the pleura intensely enhances around the fluid, called as “split pleura sign”.
The contrast-enhanced CT can also help distinguishing between tubercular and malignant pleural effusions. In a study by Leung et al., 39 out of 74 patients who had malignant disease showed the presence of pleural nodularity, mediastinal pleural thickening, pleural thickening greater than 1cm, and circumferential pleural thickening with specificities of 94%, 94%, 88%, and 100%, and sensitivities of 51%, 36%, 56%, and 41%, respectively.[8],[9]
Magnetic resonance imaging
Magnetic resonance imaging (MRI) is not routinely used in assessment of pleural effusion. It may help to accurately assess the status of pleural disease in which contrast is contraindicated. MRI accurately distinguishes between tubercular and malignant pleural effusion due to differences in signal intensity on T2-weighted images.[10] It has been compared to CT in distinction of morphological features while superior to CT in assessment of diaphragmatic and chest wall involvement.[11]
Positron emission tomography-computed tomography imaging
The role of positron emission tomography-computed tomography (PET-CT) imaging in differentiating tubercular from malignant pleural effusions is limited as there are false positives results in cases of tubercular pleural inflammation and in patients who have undergone talc pleurodesis.[12],[13],[14]
| Pleural Fluid Aspiration | | |
Pleural fluid aspiration remains the mainstay in the diagnosis of its etiology. Thoracocentesis should preferably be done under ultrasound guidance, thus increasing the chances of successful aspiration, minimizing the need of repeated attempts, and decreasing complications like pneumothorax.[15]
For biochemistry of fluid-like lactate dehydrogenase (LDH), protein, microscopy, acid fast bacilli, tuberculosis (TB) culture, and cytology, fluid should be sent in plain container while for pH, fluid should be sent in a heparinized syringe, avoiding exposure to air.[16]
Pleural fluid analysis
Generally the fluid can be serous, blood tinged, purulent, or frankly bloody (hemorrhagic). The appearance and odor of pleural fluid can give us the idea about some specific etiologies. For example, putrid odor is suggestive of anaerobic empyema, presence of food particles is seen in esophageal rupture, and milky fluid is seen in chylothorax or pseudochylothorax.[16] The tubercular pleural effusion is usually serous but sometimes can be hemorrhagic. Grossly hemorrhagic effusions can occur in conditions like pulmonary embolism with infarction, malignancy, trauma, benign asbestos pleural effusions, or post-cardiac injury syndrome.[17],[18]
A hemothorax can be differentiated from blood stained effusions by evaluating hematocrit. A pleural fluid hematocrit >50% of the patient's peripheral blood hematocrit is diagnostic of a hemothorax.[19]
The pleural effusions have been classified into transudates and exudates. The application of Light's criteria is recommended for their differentiation.[2]
Light's criteria [2]
Pleural fluid is an exudate if one or more of the following criteria are met:
- Pleural fluid protein divided by serum protein is >0.5
- Pleural fluid LDH divided by serum LDH is >0.6
- Pleural fluid LDH >2/3 the upper limits of serum LDH
Light's criteria has a diagnostic accuracy of 93–96%,[20],[21] but its limitation is that it can misclassify around 25% of transudates as exudates. This mislabeling occurs more commonly in congestive cardiac failure where diuretic therapy increases the pleural fluid concentration of protein, LDH, and lipids which misclassify the effusion as exudates.[22],[23] So, when there is strong suspicion of transudate and Light's criteria classifies it as exudate, protein and albumin gradient between serum and pleural fluid should be used. If protein gradient is more than 3.1 g/dL and albumin gradient is equal to or greater than 1.2 g/dL, fluid should be relabeled as transudate.[22],[24]
Pleural fluid differential cell counts
Differential cell counts are helpful in narrowing the differential diagnosis of pleural effusions but are not disease specific. Predominantly lymphocytic pleural effusions (>50% lymphocytes) are due to chronic illness. TB, malignancy, and cardiac failure constitute the common causes throughout the world.[25] Lymphocytosis of more than 80% can occur in TB, lymphoma, chronic rheumatoid pleurisy, sarcoidosis, and late post-coronary artery bypass graft surgery (CABG) effusions.[26]
The neutrophilic effusions are associated with acute causes like parapneumonic effusions, pulmonary embolism, acute TB, and benign asbestos pleural effusions.[27],[28]
The eosinophilic effusions (≥10% eosinophils) are usually not seen in TB and can be found in conditions like parapneumonic effusions, drug-induced pleurisy, benign asbestos pleural effusions, Churg Strauss syndrome, lymphoma, pulmonary infarction, and parasitic disease.[29],[30]
pH
TB pleural effusions have pleural fluid acidosis and the pH is less than 7.30 in tubercular pleural effusions. pH less than 7.3 can also occur in conditions like complicated pleural infections, malignant effusions, connective tissue disorders particularly rheumatoid pleuritis, and esophageal rupture.[31]
Glucose
A pleural fluid glucose level is less than 60 mg/dL in tubercular pleural effusions. A pleural glucose less than 60 mg/dL can also be found in conditions like complicated parapneumonic effusions, empyema, rheumatoid and malignant effusions, and esophageal rupture.[32] Very low glucose concentration (<30 mg/dL) is found in rheumatoid pleural effusions and empyema.[33],[34]
Protein and albumin
TB pleural effusions are exudative effusions as per Light's criteria with higher protein levels and pleural fluid protein to serum protein ratio is 0.5 or more. Sometime when Light's criteria label the fluid as exudates but clinical picture is more suggestive of transudates, protein and albumin gradient should be applied for correct classification.
Lactate dehydrogenase
The pleural fluid LDH is increased in TB pleural effusions and is used in Light's criteria to classify transudates and exudates. The pleural fluid LDH is a reliable indicator of pleural inflammation.
Tests for diagnosing pleural malignancy
Often, patients with malignant pleural effusion get misdiagnosed as TB and therefore pleural fluid cytology should be done on pleural fluid to rule out malignancy.
Pleural fluid cytology
Malignant effusions can be diagnosed by pleural fluid cytology in about 60% (range 40–87%) of the cases.[35],[36],[37],[38] The diagnostic yield for malignancy depends on sample preparation, experience of cytologist, and on tumor type. The diagnostic rate is higher for adenocarcinoma than for mesothelioma, squamous cell carcinoma, lymphoma, and sarcoma.
The yield for malignancy increases if both cell blocks and smears are prepared from pleural fluid sample.[39] Once malignancy is confirmed morphologically, differentiation between the different malignant cell types should be done by immunohistochemistry.
Several ratios have been developed recently involving serum LDH, pleural fluid adenosine deaminase (ADA), and pleural fluid lymphocyte count to differentiate between malignant and tubercular pleural effusions. “Cancer ratio” (ratio of serum LDH and pleural fluid ADA), ratio of serum LDH and pleural fluid lymphocyte count and “cancer ratio plus” (ratio of cancer ratio and pleural fluid lymphocyte count) at the cut-off level of >20, >800, and >30 showed sensitivity and specificity of 95% and 85%, 63% and 85%, and 97.6% and 94.1%, respectively. Thus, without adding any additional cost to the patient and any invasive interventions, cancer ratio and cancer ratio plus can help in diagnosing malignant pleural effusions at an early stage.[40],[41]
| Tests for Diagnosing Pleural Tuberculosis | | |
Diagnosis of pleural TB remains difficult. In about two-thirds of the cases the diagnosis is reliant upon clinical suspicion along with consistent fluid biochemistries (i.e., lymphocytic predominant exudates and pleural protein concentrations greater than 5 g/dL).[42] The pleural fluid microscopy for demonstration of acid fast bacilli has a sensitivity of <5% and pleural fluid TB culture has a sensitivity of 10–20%.[43] There are certain surrogate markers which can be useful in diagnosing pleural TB.
Adenosine deaminase
ADA is an enzyme present in lymphocytes, and its level in pleural fluid is significantly raised in most tuberculous pleural effusions. A meta-analysis of 63 studies concluded that ADA has a sensitivity of 92% and specificity of 90% for ADA threshold values varying between 38.1 and 44.0 IU/L.[44] An ADA level of <40 IU/L has a high negative predictive value and a level of >70 IU/L has a high positive predictive value [45],[46] in high endemic countries like India. In a recent meta-analysis, a cut off value of 40 IU/L had good diagnostic accuracy in Indian population.[47] Although ADA is relatively an inexpensive test, it can be false positive in conditions like empyema, rheumatoid pleurisy, and malignancy. Treating tuberculous pleural effusion based only on the basis of raised ADA levels needs caution in areas endemic for drug-resistant TB, when pleural fluid TB GeneXpert and TB cultures are negative. Therefore, close monitoring should be advocated in situ ations where anti-TB treatment is initiated based on elevated ADA levels. On longitudinal follow-up if patient does not behave or respond to the treatment as expected then further tests such as pleuroscopic or image guided pleural biopsies should be performed to confirm the diagnosis of TB and collect pleural biopsy samples for TB GeneXpert and TB culture.
The measurement of isoenzyme ADA-2 can reduce the false positives significantly. ADA-2 represents 88% of total ADA activity observed in pleural TB. Thus an elevation of ADA in the pleural fluid with a ratio ADA1/ADA total <0.45 would be more predictive of TB.[48]
Interferon gamma
It has been observed that there is rise in concentrations of pleural interferon (IFN)-gamma in the pleural TB.[45] A meta-analysis of 22 studies of tubercular pleurisies in areas of low and high endemicity showed sensitivity of 89% and specificity of 97%.[49] Thus, the IFN-assay is more specific and a very relevant marker but the high cost remains the major limitation.
Xpert MTB/RIF assay
A new, rapid, fully automated real-time nucleic acid amplification technique, GeneXpert MTB/RIF (Mycobacterium tuberculosis/rifampin) simultaneously detects MTB and rifampicin resistant strains in less than 2 h. This technique has revolutionized the diagnosis of TB. In a study of 67 patients with pleural effusions, of whom half had tuberculous pleuritis, Xpert yielded 15% sensitivity and 100% specificity in the detection of TB.[50] A meta-analysis of 24 studies was done on determining the accuracy of Xpert-MTB-RIF on pleural fluid samples which showed sensitivity and specificity of 51.4% and 98.6%, respectively for detection of TB.[51] Although Xpert-MTB/RIF has poor sensitivity and a limited diagnostic capacity, may be because the organism burden is low in pleural fluid, Xpert's performance is greater with pleural tissue samples (85.5% sensitivity and 97.2% specificity) as demonstrated in a study of 134 patients which used mycobacteria growth indicator tube culture from pleural biopsy specimens as the reference standard.[52]
TB cultures
Liquid culture media increases sensitivity and decreases time to positivity as compared to solid media. The yield of mycobacterial liquid culture BACTEC MGIT 960 Mycobacteria Growth Indicator Tube was found to be 63% for pleural fluid, 48% for sputum, and 79% for both pooled,[53] while fluid culture on liquid media had a sensitivity of 60.3% in another study.[54]
| Invasive Techniques for Sampling | | |
Fifteen to twenty percent of pleural effusions remain undiagnosed despite intensive efforts.[55] When diagnosis is not ascertained by routine investigations, it is often necessary to obtain the tissue for histological analysis and diagnosis. Until recently, only two methods were available for obtaining tissue, surgical pleural biopsy, or closed/blind pleural biopsy. Over the past few years, image guided tru-cut biopsies and medical thoracoscopic/pleuroscopic biopsies have revolutionized the diagnosis of undiagnosed pleural effusions.
Closed/blind pleural biopsy
It remains an important method of investigation where incidence of TB is high. In this technique, Abram's or Cope's needle is usually used to obtain tissue without any direct pleural visualization or real time image guidance, resulting in low yield.[56] However, as TB involves pleura in a diffuse pattern, sensitivity of closed pleural biopsy reaches up to 80% when combined with fluid cultures.[57],[58] Due to low cost, this technique is commonly used in high TB endemic countries. The closed pleural biopsies are associated with high risk of complications which include site pain, pneumothorax, vasovagal reaction, hemothorax, site hematoma, transient fever, and rarely death secondary to hemorrhage.
Ultrasound and CT-guided biopsy
Image-guided biopsy allows the localization of focal pleural thickening or pleural nodules accurately and safely, minimizing the risks associated with the procedures and increasing the yield. The choice between both the techniques is dependent upon expertise, cost, and equipment. Image-guided biopsies were initially performed only by radiologists but now thoracic ultrasound have started to be incorporated into pulmonary training programs and the diagnostic yield is comparable to that obtained by radiologists.[59],[60]
Ultrasound-guided biopsy allows for real time visualization of the biopsy needle with no radiation risk to the patient. It also does not require breath holding maneuvers in potentially dyspneic patients. Ultrasound-guided biopsies are generally performed in lateral decubitus or prone position, using low frequency (2–5 MHz) curvilinear probe using core cutting biopsy needles. There is decreased risk of complications like pneumothorax and intrapleural hemorrhage.[61]
The CT-guided biopsies are advantageous in areas to be biopsied which are not accessible by ultrasound (e.g., behind ribs). One of the disadvantages of CT-guided biopsy is the lack of real time ability to visualize the needle and tissue target.
Both ultrasound and CT-guided biopsies have an advantage over blind pleural biopsy [56],[62],[63] with sensitivities ranging from 70% to 94% and specificity of 100%.[56],[64],[65],[66],[67],[68],[69]
Image-guided biopsies might also preclude the need for subsequent thoracoscopy. They have less than 5% complication rate (pain, bleeding, and pneumothorax).[59]
Medical thoracoscopy/pleuroscopy
Medical thoracoscopy has gained popularity recently as it has the advantage of performing both diagnostic and therapeutic interventions in the same sitting. It is a safe procedure with mortality rate of less than 1%. It is the key diagnostic test for exudative effusions of unknown cause.[16] It is performed by interventional pulmonologists under local anesthesia and sedation.[70] It involves insertion of port under local anesthesia into the pleural space when the patient is in lateral decubitus position. The fluid is removed with the help of a suction catheter and then pleura is visualized. The direct visualization enables us to distinguish between normal and abnormal areas, allowing for targeted biopsy of nodular, thickened, or erythematous areas. In the absence of visual abnormality, thoracoscopy allows for biopsies to be taken safely from the parietal pleura. The major advantage of medical thoracoscopy is that it enables us to do a combined diagnostic and therapeutic procedure in one setting. Pleurodesis can be performed in cases of recurrent malignant pleural effusions.
The disadvantages include risk of development of re-expansion pulmonary edema when large amount of fluid is suctioned as reported by de Campos et al.[71] However, studies have reported the safe drainage of up to 8 L of pleural fluid without complications.[72]
A study of 22 case series showed a diagnostic sensitivity of medical thoracoscopy of 92.6% for the diagnosis of malignant disease.[73] One study directly compared medical thoracoscopy to Abrams needle biopsy and found that thoracoscopy had 100% sensitivity for diagnosing TB.[57]
The major complications include empyema, hemorrhage, port site tumor growth bronchopleural fistula, postoperative pneumothorax or air leak, and pneumonia.
The contraindications to medical thoracoscopy include obliteration of pleural space by underlying disease, uncorrected bleeding disorders, cardiovascular instability, pulmonary hypertension, and untreated hypoxemia.[74] Highly loculated fluid can also prevent thoracoscopy by preventing adequate lung collapse.
Video assisted thoracic surgery
Video-assisted thoracic surgery (VATS) requires a general anesthetic, a fully staffed operating theatre, and an anesthetist. The diagnostic role of VATS has been largely replaced by medical pleuroscopy wherever feasible. The VATS usually has a role in cases of multiloculated effusions where medical pleuroscopy is not feasible and decortication is required. There are emerging data about role of pleuroscopy in selected cases of empyema. The diagnostic yield of VATS is 90–95%, but due to its relative invasiveness is often only employed only in selected cases where medical thoracoscopy is not feasible.[75]
| Conclusions | | |
The canvas of pleural effusion is multihued. A common manifestation of pleural pathologies, it may equally arise as a manifestation of a systemic disease. Easily distinguishable as a transudate or exudate on the basis of Light's criteria, ADA can play a useful adjunct role in the diagnosis of a tubercular pleural effusion when the values are greater than 40 IU/L. More significantly, GeneXpert MTB/RIF can help in the rapid diagnosis of TB and simultaneously detect rifampicin resistance. Though being less sensitive, it is highly specific in detection of TB.
In exudative pleural effusions with low ADA and high protein and high LDH, newer ratios “cancer ratio” and “cancer ratio plus” can help in diagnosing malignant pleural effusions without utilizing invasive techniques of investigation.
Despite development of a vast array of investigative tools, 15–20% of exudative pleural effusions remain undiagnosed. The role of invasive interventions is still a work in progress. Image-guided pleural biopsies have largely replaced closed pleural biopsies, increasing the yield and decreasing the complications. Of recent, medical pleuroscopies are gaining prominence; they can be utilized for both diagnostic and therapeutic interventions; and diminish the need for surgical thoracoscopies.
In areas highly endemic for multi-drug resistant TB, the practice of initiating anti-tubercular treatment singly on ADA levels must be viewed with due caution. If the patient does not demonstrate the desired clinical response, further investigations stand warranted.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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