DIFFERENTIATING TUBERCULOUS FROM NON - TUBERCULOUS PLEURAL EFFUSION”
Dissertation submitted to
THE TAMILNADU Dr. M.G.R MEDICAL UNIVERSITY CHENNAI-600 032
In partial fulfilment of the regulations For the award of the degree of M.D (GENERAL MEDICINE)
BRANCH-1
GOVT. CHENGALPATTU MEDICAL COLLEGE & HOSPITAL, CHENGALPATTU-603001.
MAY-2020
DIFFERENTIATING TUBERCULOUS FROM NON - TUBERCULOUS PLEURAL EFFUSION”
Dissertation submitted to
THE TAMILNADU Dr. M.G.R MEDICAL UNIVERSITY CHENNAI-600 032
In partial fulfilment of the regulations For the award of the degree of
M.D (GENERAL MEDICINE) BRANCH-1
Reg no : 201711257
GOVT. CHENGALPATTU MEDICAL COLLEGE & HOSPITAL, CHENGALPATTU-603001.
MAY-2020
This is to certify that the dissertation titled “ROLE OF ADENOSINE DEAMINASE IN COMBINATION WITH CLINICAL, RADIOLOGICAL, AND PLEURAL FLUID VARIABLES IN DIFFERENTIATING TUBERCULOUS FROM NON – TUBERCULOUS PLEURAL EFFUSION’’ is the bonafide original work of Dr.SIVAPRAKASAM VENKATESAN in partial fulfilment of the requirements for M.D. Branch-1 (General Medicine) Examination of the Tamil Nadu Dr.M.G.R. Medical University to be held in May 2020. The period of study was from October 2018 to September 2019.
Prof. Dr.HARIHARAN M.S.,MCH. Prof.Dr.R.NARMADHALAKSHMI M.D.,
DEAN Professor & Head
Chengalpattu Medical College Department of General Medicine Chengalpattu-603001 Chengalpattu Medical College
Chengalpattu-603001
Place : Date :
This is to certify that dissertation “ROLE OF ADENOSINE DEAMINASE IN COMBINATION WITH CLINICAL, RADIOLOGICAL, AND PLEURAL FLUID VARIABLES IN DIFFERENTIATING TUBERCULOUS FROM NON –
TUBERCULOUS PLEURAL EFFUSION” is a bonafide work performed by Dr.SIVAPRAKASAM VENKATESAN, postgraduate student of General medicine, Chengalpattu medical college, Chengalpattu, under my guidance and supervision in fulfilment of regulations of The Tamil Nadu Dr. M.G.R Medical University for the award of M.D. Degree during the Academic period 2017-2020.
Prof. Dr. R. NARMADHA LAKSHMI, M.D.,
Prof. and HOD,
Department of General Medicine, Chengalpattu Medical College, Chengalpattu.
Place:
Date:
I, Dr. SIVAPRAKASAM VENKATESAN, solemnly declare that dissertation titled “ROLE OF ADENOSINE DEAMINASE IN COMBINATION WITH CLINICAL, RADIOLOGICAL, AND PLEURAL FLUID VARIABLES IN DIFFERENTIATING TUBERCULOUS FROM NON – TUBERCULOUS PLEURAL EFFUSION” is a bonafide record of work done by me in the Department of Internal Medicine, Government Chengalpattu Medical College and Hospital during October 2018 to September 2019 under the guidance of Prof. Dr.R. NARMADHA LAKSHMI, M.D., Professor of General Medicine, Government Chengalpattu Medical College and Hospital, Chengalpattu. This dissertation is submitted to Tamil Nadu Dr. M.G.R. Medical University, in partial fulfilment of the University regulations for the award of M.D. Degree (Branch 1) General Medicine- May 2020.
SIGNATURE OF THE CANDIDATE
Place:
Date:
I would like to thank our beloved Dean, Govt. Chengalpattu Medical College and Hospital, Dr. HARIHARAN, M.s.,Mch., for permitting me to utilize the hospital facilities for this dissertation.
I extend my sincere thanks to Prof. Dr. R. NARMADHA LAKSHMI, M.D., Professor and Head of the Department of Medicine, Govt. Chengalpattu Medical College and Hospital for her guidance during the study.
I also owe my sincere thanks to my co-guide PROF. DR. B.PRABHAKAR, M.D., for his guidance and support throughout the conduct of the study and also during my post graduate course.
I owe my sincere thanks to my Assistant Professors Dr. J.
HARIKRISHNAN M.D., and Dr. J. CHANDRU, M.D., for their valuable advice and appropriate suggestions.
I extend my thanks to my family and my junior and senior postgraduates who stood by me during my times of need. Their help and support have been invaluable to the study. Finally, I thank all the patients for their extreme patience and cooperation.
S. NO CONTENTS PAGE. NO
1. INTRODUCTION 1
2. AIM OF THE STUDY 4
3. REVIEW OF LITERATURE 5
4. MATERIALS AND METHODS 36
5. RESULTS 46
6. DISCUSSION 75
7. CONCLUSION 82
8. BIBILIOGRAPHY 85
9. PROFORMA
10. ABBREVIATIONS
11. MASTER CHART
1
INTRODUCTION
The pleural space situated between the visceral and parietal layers of the pleurae. It normally contains 0.1-0.2 mL/kg body weight of fluid[1]. Pleural effusion is an abnormal collection of fluid in the pleural cavity and it is the most common manifestation of pleural pathology[2].
The average prevalence of all forms of tuberculosis in India is estimated to be around 5.05 per thousand, prevalence of smear-positive cases 2.27 per thousand and average annual incidence 1004 of smear-positive cases at 84 per 1,00,000 annually. Tuberculosis is the most common cause of pleural effusion in India. The fact that tuberculosis being the most common co-morbid condition associated with acquired immuno-deficiency syndrome (AIDS) has highlighted the importance of this disease. Multidrug resistance in tuberculosis has further compounded and complicated this situation. First line delay in diagnosis and initiation of effective treatment has resulted in indifferent and poor prognosis.
Although, a variety of clinical conditions may be the cause of a pleural effusion, the most common etiology seen is tuberculosis. The proportion of patients with tuberculosis who have pleural effusion differs. The proportion ranges from 16-25% and higher percentage are seen in HIV positive patients. The possibility of a malignant involvement of pleural cavity should always be considered in difficult-to-diagnose cases. Since percutaneous access to the pleural space is relatively simple, techniques such as pleural biopsy and
2
thoracoscopy have become very popular. But these facilities are restricted to tertiary and quartenary care centers only. Hence pleural fluid analysis and cytology remain the mainstay for diagnosing the etiology of pleural effusions[3].
Analysis of pleural fluid can have an important contribution for investigation of patients with pleural effusion [4] Cytological examination not only helps for diagnosing cancer but also for staging and prognosis of diseases [5] Levels of adenosine deaminase (ADA) are particularly useful in areas where the prevalence of tuberculosis is high [6]. Closed pleural biopsy provides the highest diagnostic yield in cases of pleural tuberculosis and malignancy, the two most important causes of exudative pleural effusion [7].
All the available methods of diagnosis of tuberculosis currently available were evaluated in many situations and health care systems and all of them were found to have clinical diagnostic and screening utility. Direct evidence of acid fast bacilli (AFB) is available only in a very small percentage of cases.The management and prognosis of pleural effusion depends on the accurate, quick and cost effective assessment of underlying etiology. Thus finding of correct etiopathology will help in effective treatment. So there is a need of simple, fast and accurate diagnostic test to establish the aetiology of pleural effusion that can be used in all types of health settings especially in low resource ones.
The reliability and usefulness of adenosine deaminase (ADA) values in pleural fluid has proven in many situations, especially when there is suspicion of tuberculosis in endemic areas. Research has clearly proven that the ADA level
3
rarely exceeds the cutoff set for tuberculous effusion in non-tuberculous pleural effusions.
This study is therefore aimed to identify the role of ADA estimation in differentiation of tuberculous and non-tuberculous exudative pleural effusions among patients presenting to a tertiary centre. Considering this an analytical hospital based study was designed to estimate the predictive potential of ADA when combined with clinical, radiological and biochemical variables in differentiating tuberculous from non tuberculous pleural effusion .
4
AIM OF THE STUDY
PRIMARY
To evaluate the diagnostic efficacy of Adenosine Deaminase (ADA) levels in tubercular pleural effusion
SECONDARY
1. To assess the clinical presentation and etiological profile of patients presenting with pleural effusion
2. To estimate the clinical utility potential of ADA when combined with clinical, radiological and biochemical variables in differentiating tuberculous from non tuberculous pleural effusion.
5
REVIEW OF LITERTURE DEFINITION
Pleural effusion is the result of collection of fluid in the pleural space, is a common medical problem [1] They can be caused by several mechanisms including increased permeability of the pleural membrane, increased pulmonary capillary pressure, decreased negative intrapleural pressure, decreased oncotic pressure, and obstructed lymphatic flow. Pleural effusion indicates the presence of disease which may be pulmonary, pleural or extra pulmonary.
In the course of embryonic development the pleural membrane is formed from mesenchyme to line the space that will separate the lungs from mediastinum, diaphragm and chest wall [1]
NORMAL COMPOSITION OF PLEURAL FLUID [2]
Volume - 0.1-0.2 ml/Kg
Cells/cmm - 1000-5000
Mesothelial cells - 3 – 70 %
Macrophages - 30 –75%
Lymphocytes - 2 – 30%
Granulocytes - 10 %
Protein - 1 – 2 g/ dL
% Albumin - ~ plasma level
Glucose - ~ plasma level
LDH - < 50% of plasma level
Ph - 7.60-7.64
6
ANATOMY OF THE PLEURA [3,4]
Each Lung is invested by a delicate serous membrane which is arranged in the form of a closed invaginated sac and is termed the pleura. The portion that covers the surface of lung and lines the tissues in-between the lobes is called the visceral pleura.
The rest of the membrane lining the inner half of the chest wall is reflected over the structures occupying the middle part of the thorax is termed the parietal pleura. The visceral and parietal pleura are continuous with each other around and below the root of the lung. In healthy they are in actual contact with each other in all phases of respiration. The potential space between them is called the pleural cavity. The right pleural cavity is wider than the left because the heart extends further to the left than to the right. The pleura cover the apices of the lung one inch above the medial third of the clavicle.The anterior margin found to converge, as they pass behind the sternoclavicular joints and come into apposition at the lower border of the manubrium sterni. It may be noticed that the anterior margin remains in apposition up to the level of the 4th costal cartilage. Right Pleura continues vertically, but the left arches out and descend lateral to the border of the sternum, half way to the apex of the heart. Each turn laterally at the 6th costal cartilage and passes around the chest wall crossing the midclavicular line at 8th rib and the mid axillary line at 10th rib. This lower border forms the costophrenic recess, falls somewhat short of the costal margin. It crosses the 12th rib at the lower border of the sacrospinalis muscle and passes in horizontally to the lower border of the 12th thoracic vertebra.
7
The arterial supply and lymphatic drainage of the parietal pleura are intercostals, internal thoracic and musculophrenic arteries and nodes respectively. The nerve supply is from the intercostals and phrenic nerves. The arterial supply of the visceral pleura is by the branches of Pulmonary arteries and the capillaries drain into both systemic and pulmonary venous system. Its lymphatics join with those of the lung and the nerve supply is derived from the autonomic system. It is insensitive to sensorystimuli
PHYSIOLOGY OF PLEURA[2]
FIG 1. Distribution of Hydrostatic (P) and Oncotic (H) pressure across the parietal and visceral pleura. The numbers in the open arrow indicate the net magnitude of pressure gradient between the hydrostatic and oncotic pressure across the visceral and parietal pleura.
During normal inspiration there is negative pressure in relation to the atmosphere (about -0.66kpa at functional residual capacity) within the pleural space.2,5 This would tend to suck capillary fluid and gas from the surrounding tissue into the space. The pleura transmits the force generated by the respiratory muscles of the lung.
There is a regular transfer of low protein fluid from parietal to pleural space.
8
Protein and particles are turned over much less rapidly, being absorbed by lymphatics opening into the parietal pleura. Pleural surface pressure increased approximately 0.5cms of H2O of vertical distance from the apex to the base of the lung[6]. The pleural fluid is in a dynamic state 30-75% of water being turned over every hour on normal respiration [7,8]
Pleural space is lubricated by a thin film of few milliliters ofserous fluid. For this lubrication surfactant would be more effective, have been identified in the fluid.9,1 PATHOPHYSIOLOGY[11]
Normal interstitial fluid is filtered from the arterial end of the capillary, up to 90%
is absorbed at the venous end of the capillary bed and the rest is removed by the lymphatics. Three main factors involved in the fluid movement are:
1. Capillary permeability 2. Hydrostatic pressure 3. Colloid osmotic pressure
The potential pleural space has very close proximity to both the systemic and pulmonary circulation. Thus, the parietal pleura is supplied by the systemic circulation via the intercostals arteries and its venous drainage is mainly through the azygous system into superior venacava. In contrast, the arterial supply of the visceral pleura is by branches of the pulmonary artery and their capillaries drain into both systemic and pulmonary venous system. The intravascular hydrostatic pressure within the venous end of the visceral pleural capillaries is less than hydrostatic pressure in the capillaries of parietal pleura. Thus considering the pleural surfaces in isolation, the two separate
9
circulatory system could presumably cope with filtrate, however, because of their closer proximity the visceral pleura is able to apply a sucking force to the pleural space which not only keep the later virtually free of fluid but also keeps the visceral and parietal surfaces apposed against the forces of lung elastic recoil inwards and chest wall outwards. The visceral pleural capillary bed has a large capacity to absorb protein-free fluid. Protein removal is by the lymphatic system. Normally, the pleural space contains small amount of fluid in protein content but in pleural effusion the later is increased. However, the capacity of the lymphatic system to deal with protein is small.
The factors affecting the pleural fluid transport system have been reviewed in detail by Brook (1972). When equilibrium between formation and absorption of pleural fluid is altered due to either one of the following reasons, abnormal accumulation of pleural fluid occurs.
MECHANISM THAT LEADS TO ACCUMULATION OF PLEURAL FLUID[11,12]
1. Increased Hydrostatic pressure in the microvascular circulation (CCF) 2. Decreased Oncotic pressure in the microvascular circulation (Hypoalbuminemia)
3. Decreased pressure in the pleural space (complete Lung collapse)
4. Increased permeability of the pleural membrane (Inflammatory process) 5. Decreased Lymphatic drainage from the pleural space (Malignancy) 6. Movement of fluid from the peritoneum (Ascites)
10
Small pleural tumor implants are common findings. Such metastatic deposits can cause capillary and lymphatic obstruction resulting in increased pleural fluid production and decreased resorption. In addition secondary infections associated with the tumor deposits results in further inflammation and increased capillary permeability.
Occasionally erosion of small vessels by tumor implants may cause hemorrhage into pleural space.
Major mediastinal lymph node involvement, which occurs commonly in conditions like lymphoma and small cell carcinoma of the bronchus, may interfere with lymphatic drainage and results in pleural effusion with negative cytology. Protein is unable to enter the vascular space and causes increase in pleural osmotic pressure and secondary accumulation of fluid. Obstruction of the superior venacava occurs with bronchial carcinoma and lymphoma elevates the systemic venous pressure causing a decrease in parietal pleural resorption and lymphatic flow.
CAUSES OF PLEURAL EFFUSION
Pleural effusions are classified into transudates and exudates. A transudative pleural effusion occurs when the balance of hydrostatic forces influencing the formation and resorption of the pleural fluid is altered to favour pleural fluid accumulation. The permeability of the capillaries is normal[14]. In contrast, an exudative pleural effusion develops when the pleural surface and/or the local capillary permeability are altered [15]
11
ETIOLOGY [16]
TRANSUDATE
Increased Hydrostatic pressure:
Left ventricular failure
Decreased Osmotic pressure:
Liver cirrhosis
Hypoalbuminemia
Peritoneal dialysis
Hypothyroidism
Nephrotic syndrome
Mitral stenosis
Pulmonary embolism
Constrictive pericarditis
Urinothorax
Superior venacaval obstruction EXUDATE
INFLAMMATORY CONDITIONS OF THE PLEURA
Tuberculosis
Parapneumonic effusion(bacterial, viral, parasitic, fungus)
Pulmonary infections
12
Pulmonary embolism
COLLAGEN VASCULAR DISEASE a. Rheumatoid arthritis
b. Autoimmune diseases (SLE) c. Immunoblastic lymphadenopathy d. Sjogren’s syndrome
e. Wegener’s granulomatosis f. Churg-Strauss syndrome
DISORDERS OF CONTIGUOUS STRUCTURES
Esophageal rupture
Diaphragmatic hernia
Liver abscess
Subphrenic abscess
Pancreatitis
After Liver Transplant MALIGNANCY
Mesothelioma
Malignancy of lung, breast, ovary. (Primary and metastatic disease) RARE CAUSES
Post Myocardial infarction syndrome
Meig’s Syndrome
13
Yellow nail syndrome
Benign asbestos effusion
Uremia
Post radiation therapy
Sarcoidosis
Trapped Lung
Radiation therapy
Post-coronary artery bypass surgery
Ovarian hyperstimulation syndrome
DRUGS KNOWN TO CAUSE PLEURAL EFFUSION a. Amiodarone
b. Nitrofurantoin c. Methotrexate d. Methysergide e. Dantrolene f. Procarbazine g. Procainamide h. Penicillamine i. GCSF
j. Cyclophosphamide k. Bromocripti
14
PATHOGENESIS OF PLEURAL EFFUSION IN VARIED SETTINGS The fluid accumulates in pleural space in varying conditions by these mechanisms in varying combination,these are as follows
Increased pulmonary capillary pressure
Decreased oncotic pressure
Increased pleural membrane permeability
Obstruction of lymphatic flow MALIGNANT PLEURAL EFFUSION
Malignant cells arrive at pleural space either by direct extension, invasion of pulmonary vasculature and hematogenous metastasis from distant tumours to parietal pleura. Then cells promote fluid accumulation by increasing capillary permeability and obstrucution of lymphatic stomata.
PARA MALIGNANT EFFUSION
It is a result of cancer, only that cancers cells are absent.This could be from mediastinal lymphnode infiltration, bronchial obstruction, SVC syndrome or increased permeability as in pulmonary embolism, radiotherapy /
chemotherapy and decreased oncotic pressure.
Mycobacterium Tuberculosis and Pleural effusion [17]
Character of the fluid
Serous exudates, very rarely Hemorrhagic.
15
PATHOGENESIS
Most of the cases it spreads from underlying pulmonary focus. The effusion is always in the side of pulmonary lesion. Sometimes pleural effusion may be due to rupture of sub pleural focus or pleural involvement in milliary tuberculosis.
Clinical Features
**1/3rd of patients will have acute illness less than one week duration.
**2/3rd seek medical attention within a month, after the onset of symptoms.
**common symptoms are - non productive cough, Pleuritic type of chest pain, fever – in 50% cases. Patients with chronic illness will have loss of weight, appetite, malaise and dyspnoea.
Tuberculous effusion is usually moderate and unilateral. In 1/3rd of patients tuberculous effusion will have co-existing parenchymal disease which is evident radiologically. 30% of patients with tuberculous effusion will have negative tuberculin test. It will become positive after 8 weeks of development of symptoms.
Mycobacterium is demonstrable in pleural fluid only in 10% cases.
Culture will be positive in 25% cases. 50% cells in pleural fluid is mature lymphocytes. Eosinophil count rarely exceeds 10%.
HIV Infection [16]
Pleural effusions are uncommon in such patients. The most common cause is kaposi’s sarcoma, followed by parapneumonic effusion. Other common causes
16
are tuberculosis, cryptococcosis and primary lymphoma. Pleural effusions are very uncommon with Pneumocystis carnii infection. A pleural effusion is seen in 7-27 % of hospitalized patients with HIV infection.
NEOPLASMS
Malignant pleural effusions secondary to metastatic disease are the second most common type of exudative pleural effusion. These are the commonest cause of exudative effusion more than 60 years of age. The three tumors that cause approximately 75% of all malignant pleural effusions are lung carcinoma, breast carcinoma, and lymphoma [16] Others include spread from liver metastasis, rarely an ovarian or a gastric cancer. 7% cases show unknown primary. Mediastinal invasion with lymphatic blockage presenting with effusion is suggestive of Hodgkin’s Lymphoma. Very rarely few cases of Multiple myeloma presenting as bilateral pleural effusion have also been noticed. It is usually a late complication and is associated with a poor prognosis (18) .
Most patients complain of dyspnoea, which is frequently out of proportion to the size of the effusion. The exudates may be serous, serosanguinous or hemorrhagic.
Obstructive pneumonitis with pleural effusion have a very strong presumptive evidence per se for diagnosis. Recovery of cells from pleural fluid or sputum, positive pleural biopsy, bronchoscopy or mediastinal node biopsy, fine needle aspiration cytology (FNAC) of secondary lymph node or from metastatic secondaries is helpful in diagnosis
17
MESOTHELIOMA[16]
Malignant mesotheliomas are primary tumors that arise from the mesothelial cells that line the pleural cavities. Most are related to asbestos exposure. Patients with mesothelioma present with chest pain and shortness of breath. The chest radiograph reveals a pleural effusion, generalized pleural thickening, and a shrunken hemithorax. Thoracoscopy or open pleural biopsy is usually necessary to establish the diagnosis [2]
PARAPNEUMONIC EFFUSION
Parapneumonic effusions are associated with bacterial pneumonia, lung abscess or bronchiectasis. Patients with aerobic bacterial pneumonia and pleural effusion present with an acute febrile illness consisting of chest pain, sputum production, and leukocytosis. Patients with anaerobic infections present with a subacute illness with weight loss, a brisk leukocytosis, mild anemia, and a history of some factor that predisposes them to aspiration. If the free fluid separates the lung from the chest wall by more than 10 mm on radiological examinations, a therapeutic thoracentesis should be performed [16]. The concentration of pleural- fluid myeloperoxidase helps to differentiate between nonpurulent complicated and uncomplicated parapneumonic pleural effusions [19].Pleural fluid IL-8 is also an accurate marker for the identification of non-purulent complicated parapneumonic pleural effusion.20
18
EMPYEMA[2]
Refers to a grossly purulent effusion. Clinically features include – high grade remittent fever with rigors and weight loss. Pleural Pain associated with cough and sputum production.Pleural fluid cytology reveals Polymorphonuclear leucocytosis. Organisms resulting in empyema: (75 % - single organisms) Mycobacterium tuberculosis, Streptococcus milleri, Streptococcus pneumonia, Staphylococcus aureus, E.coli, Klebsiella Proteus, B.melaninogenicus, Fusobacterium, Candida21.25% multiple organisms: Streptococcus milleri and anareobes.
PULMONARY EMBOLIZATION
One of the rare cause of pleural effusion, which is usually exudative but can be transudative. Dyspnea is the most common symptom.The diagnosis is established by spiralCT scan or pulmonary arteriography.16
CLINICAL FEATURES OF PLEURAL EFFUSION
The onset of symptoms depends upon the quantity of the effusion and the mode of onset. Pleuritic pain and dry cough are usually the earliest symptoms but there may be preceding period of fever, loss of appetite and loss of weight.
If the effusion accumulates rapidly dyspnoea, cyanosis and mediastinal flutter may be evident. Pleural effusion may be: generalised in the pleural space, loculated in the pleural space, interlobular, intrapulmonary. Pleural effusion can be diagnosed clinically when the pleural is more than 300 ml and it can be diagnosed radiologically in lateral view when it is 200 ml, in lateral decubitus view <200 ml and in PA view 500 – 600 ml.
19
If the effusion is generalised and is sufficiently large, the physical signs are 1. Restriction of respiratory movements on the affected side
2. Stony dullness on percussion
3. Diminished or absent breath sounds
4. Diminished or absent vocal resonance and fremitus 5. Tracheal displacement to the opposite side >1000 ml
Massive pleural effusion without mediastinal shift suggests fixation Of the mediastinum and the following possibilities should be considered:
a. Carcinoma of the main bronchus with atelectasis of the ipsilateral lung b. Fixed mediastinum due to neoplastic lymph nodes
c. Malignant mesothelioma
At the upper level of the dullness, which sweeps upwards towards axilla, it is said that the air conducted through the relaxed or collapsed lung produces tubular breathing, egophony (E- to- A change) and whispering pectoriloquy.
Sometimes pleural friction rub may also be heard if there is associated pleurisy.
With small effusion the signs are best elicited at the base posteriorly.
Effusion located at the fissures may not be detectable on physical examination.
Intrapulmonary effusion (subpulmonic effusion) may be clinically indistinguishable from fixed elevation of hemi–diaphragm with blunting of posterior costo-phrenic angle on lateral chest radiograph and other hint to diagnosis is widening of the distance between the top of the gastric bubble and the top of the left hemi-diaphragm (2cms). Also, an effusion on the Right side causes the minor fissure to appear close to the diaphragm than usual.
20
PHYSICAL SIGNS OF PLEURAL EFFUSION
Amount of Effusion
Expansion Fremitus Percussio n
Breath sounds
Contralateral mediastinal
shift
Small N N N Vesicular No
300-1000ml Decreased Decreased Stony dull Decreased
Vesicular No
1000- 2000ml
Moderately
Decreased Decreased Stony dull Moderately decreased
+
>2000 ml Severely Decreased
Moderately
Decreased Stony dull Severely Decreased
++
INVESTIGATION OF PLEURAL EFFUSION
The initial step in assessing a pleural effusion is to ascertain whether it is a transudate or a exudate. The detailed clinical assessment alone is often capable of identifying a transudative effusion. Approximately 75% of patients with pulmonary embolism and pleural effusion have a history of pleuritic pain. These effusions tend to occupy less than a third of the hemithorax and the dyspnoea is often out of proportion to its size. The patient drug history is also important.
21
RADIOLOGY
The most sensitive method of detection of pleural fluid is by roentgenogram. PA and Lateral chest radiographs should be taken in suspected pleural effusion. The plain chest radiographic features of pleural effusion are usually characteristic. The PA chest radiograph is abnormal in the presence of about 200 ml of pleural fluid. However only 50 ml of pleural fluid can produce detectable posterior costophrenic angle blunting on a lateral chest radiograph23. Lateral decubitus film is occasionally useful as the free fluid gravitates to the most dependant part of the chest wall differentiating between pleural thickening and free fluid.24
Subpulmonic effusion occurs when pleural fluid accumulates in a subpulmonic location. They occur beneath the lung and are often transudates and can be difficult to diagnose on the PA radiograph and may requires a lateral decubitus view or ultrasonogram. The PA radiograph will often show a lateral peaking of apparently raised hemi- diaphragm which has a steep lateral slope with gradual medial slope. The lateral radiograph may have a flat appearance on the posterior aspect of the hemi- diaphragm with a steep downward at the major fissure [26]
PLEURAL FLUID ASPIRATION (THORACOCENTESIS)
A diagnostic pleural fluid sample should be collected with a large bore (21G) needle and a 50 ml syringe. The sample should be placed in sterile vials and blood culture bottles and analyzed for glucose, protein, LDH, gram stain, AFB stain, cytology, microbiological culture.
22
This is the primary means of evaluating pleural fluid and its findings are used to guide further investigations. Diagnostic taps are often performed in the clinic or by the bed side (if necessary under ultrasound guidance).
Microscopic examination of gram stain pleural fluid sediment is necessary for all fluids and particularly when a parapneumonic effusion is suspected. If some of the microbiological specimen is sent in blood culture bottles the yield is greater, especially for anaerobic organisms [27]
20 ml pleural fluid is adequate for cytological examination and the fresher the sample when it arrives at the laboratory the better is the yield. If the part of the sample is clotted, the cytologist must fix and section this and treat it as a histological section as it will increase the yield. Sending the cytological sample in a citrate bottle will prevent clots and is preferred by some cytologists. If delay is anticipated, the sample can be stored at 4oC for up to 4 days [28]
PLEURAL FLUID ANALYSIS
Key facts when investigating undiagnosed pleural effusion [29]
1. If the pleural protein is between 25 and 35 g/L then Light’s criteria are used to differentiate accurately exudates from transudates.
2. Pleural fluid pH should be performed in all non purulent effusions if an infection is suspected.
3. When sending the pleural fluid specimen for microbiological examination, it should be sent in both a sterile tube (for Gram Stain, AFB stain and TB culture) and in blood culture bottles to increase the diagnostic yield.
4. Only 60% of malignant effusions can be diagnosed by cytological
23
examination. A contrast enhanced CT scan of the thorax is best performed in suspected cases for better visualization of pleura and identifying the best site for pleural biopsy.
5. Grossly bloody pleural fluid is usually due to malignancy, pulmonary embolus with infection, trauma, or Post-cardiac injury syndrome(PCIS).
TYPICAL CHARACTERISTICS OF THE PLEURAL FLUID[30]
After performing pleural aspiration the appearance and odor of the pleural fluid should be noted. The unpleasant aroma of anaerobic infection may guide the antibiotic choice. The appearance can be divided into serous, blood tinged, frank blood, or purulent. If the pleural fluid is turbid or milky it should be centrifuged. If the supernatant is clear, the turbid fluid was due to cell debris and empyema is likely. If it is still turbid, this is because of high lipid content and a Chylothorax or Pseudo- chylothorax is likely [32]
A pleural fluid hematocrit is helpful in the diagnosis of Hemothorax.
APPEARANCE OF PLEURAL FLUID
PLEURAL FLUID SUSPECTED DISEASE
Putrid odour Anaerobic Empyema
Food particles Esophageal rupture
Bile stained Biliary fistula
Milky Chylothorax/Pseudochylothorax
‘ Anchovy’ sauce like fluid Ruptured amoebic abscess
24
DIFFERENTIATING BETWEEN A PLEURAL FLUID EXUDATES AND TRANSUDATES
The pleural fluid protein should be measured to differentiate between a transudative and exudative pleural effusion. This will usually be suffice if the patients serum protein is normal and pleural protein is less than 25 g/L or more than 35 g/L. If not, light’s criteria should be used.
LIGHT’S CRITERIA [31]
The pleural fluid is an exudates if one or more of the following criteria are met:
1. Pleural fluid protein / Serum Protein > 0.5 2. Pleural fluid LDH / Serum LDH > 0.6
3. Pleural fluid LDH more than 2/3rd the upper limits of normal Serum LDH The classical way of separating a trasudate from an exudate is by pleural fluid protein, with exudates having a protein level of > 30 g/L and transudate a protein level of < 30 g/L. A considerable number of other biochemical markers have been compared with Light’s criteria. These include measuring pleural fluid cholesterol albumin gradient and Serum/Pleural fluid Bilirubin ratio [36]. Valdes et al., described the ratio between pleural cholesterol to serum cholesterol is more than 0.3 (sensitivity 92.5%, specificity 87.6%). It is found with 0.4 as the cutoff point the specificity was 100% and sensitivity 86.04% [34]
A cutoff value of LDH levels in pleural fluid of >0.66, the upper limits of the laboratory normal might be a better discriminator (“Modified light’s Criteria”).
The weakness of this criteria is that they occasionally identify an effusion in a patient with left ventricular failure on diuretics as an exudate.
25
DIFFERENTIAL CELL COUNT ON THE PLEURAL FLUID
When polymophonuclear cells predominate, the patient has an acute process affecting the pleura surfaces. If there is concomitant parenchymal shadowing, the most likely diagnoses are parapneumonic effusion and pulmonary embolism with infarction. If there is no parenchymal shadowing, then diagnoses are pulmonary embolism, viral infection, acute tuberculosis, or benign asbestos pleural effusion.
An eosinophilic pleural effusion is defined as the presence of 10% or more eosinophils in pleural fluid. Eosinophilic pleural effusions are not always benign.
The presence of pleural fluid eosinophilia is of little use in the differential diagnosis of pleural effusions. Benign etiologies include parapneumonic effusion, tuberculosis, drug induced pleurisy, benign asbestos pleural effusions, Churg-Strauss syndrome, pulmonary infarction, and parasitic disease. It is often the result of air or blood in the pleural cavity.
If the pleural fluid, differential count shows a predominant lymphocytosis, the most likely diagnoses are tuberculosis and malignancy. Although high lymphocyte counts in pleural fluid raise the possibility of tuberculous pleurisy [30]
as many as 10% of tuberculous pleural effusions are predominantly neutrophilic[35]. Lymphoma, sarcoidosis, rheumatoid disease, chylothorax can cause a lymphocytic pleural effusion 37
26
ADENOSINE DEAMINASE LEVELS
The Adenosine deaminase (ADA) level in pleural fluid tends to be higher with tuberculosis than in other exudates 38-39 However, ADA levels are also raised in empyema, rheumatoid pleurisy, and malignancy which makes the test less useful in countries with a low prevalence of tuberculosis. ADA analysis is a sensitive marker of tuberculous pleuritis even in HIV patients with very low CD4 counts in a high TB endemic region. The ADA assay is inexpensive, rapid, and simple to perform and is of great value for the immediate diagnosis of tuberculous pleuritis while waiting for culture result and this has a positive impact on patient outcome. ADA levels more than 70 IU/L has a sensitivity of 98%, specificity of 96% in tuberculous pleural effusion [38].
The study done by Liang QL et al[40] on diagnostic accuracy of adenosine deaminase in tuberculous pleurisy A metaanalysis did a systematic review of 63 studies and concluded ADA is a more sensitive and specific test for the diagnosis of tuberculous pleurisy. The ADA result assays should be [42] interpreted along with the clinical findings and the results of conventional test .
The study done by Patrizio Morrison, Denise Duprat Neves on evaluation of ADA in the diagnosis of pleural tuberculosis: a Brazilian meta-analysis did a systematic review of twenty five studies dating from 1987 to 2005 based on ADA levels Of pleural fluid. They concluded that the determination of ADA has high accuracy in the diagnosis of pleural tuberculosis and should be used as a routine test in its investigation[40].
27
The study done by Yildiz P B et al on predictive role of adenosine deaminase for differential diagnosis of tuberculous and malignant effusion in Turkey found in an analysis of 196 patients that ADA > 55 had a sensitivity of 86.8 %, specificity of 86.8 %, PPV of 90 %, NPV of 82.6 %. When It was combined with Age < 50 it wes to able to discriminate the TPE group ( tuberculous pleural effusion ) with increased specificity ( 95.7%) and PPV ( 98.8%). They concluded that ADA is a very useful parameter in differential diagnosis of TPE and MPE (Malignant pleural effusion) specifically in younger age group with high incidence of tuberculosis[41].
The study done by Gupta BK et.al., on role of ADA estimation in differentiation of tuberculous and on tuberculous exudatie pleural effusion concluded that ADA levels in non tuberculous exudative pleural effusion rarely exceeded the cut off for tuberculous disease. The pleural fluid ADA levels were significantly higher in tuberculous exudative pleural effusions when compared with non tuberculous exudative pleural effusion [42]
The study done by Valdes L et al., on tuberculous pleurisy: A study of 254 patients found lymphocytic rich exudative pleural effusion occurred on average at a young age with no preference for either right or left side side;
normally affected no more than two thirds Of hemithorax, and were generally unaccompanied by pulmonary infiltrates. High ADA concentration was a highly sensitive diagnostic sign and was caused by a rise in ada 2 concentration.
The most sensitive criterion based on pleural biopsy was the observation of caeseous granuloma and culture of biopsy material further increased overall
28
sensitivity. Negative skin test were no guarantee for the effusion being non tuberculous . This together with the low mean age of the patients and the low frequency of associated pulmonary lesion suggest that TPE is a primary form of tuberculosis in this region [43].
The study by Ibrahim WH et al on does pleural tuberculosis disease pattern differ among developed and developing countries, found pleural TB affected younger age groups (84% below 45 years of age) mostly a primary infection. Fever in 90% and the disease can be acute or subacute.Weight loss occurs before other symptoms. Exudative pleural effusion with predominant lymphocytosis is characteristic. They concluded that pleural TB tend to be a primary disease and younger age groups were particularly affected[44] .
The study by S.K.Sharma et al on sensitivity and specificity of ADA in the diagnosis of tuberculous pleural effusion found that a cut off of 35 IU/L, the sensitivity and specificity of pleural fluid ADA in the diagnosis of TB was computed to be 83.3 % and 66.6% respectively. At a cut off level of 100 IU/L, PF-ADA was found to have a sensitivity 40% and specificity 100%. They concluded that, using 100IU/L as the cutoff, it is possible to avoid pleural biopsy to ascertain the diagnosis of TB in as much as 40 % of the patients [45] .
The study by S.K.Verma et al on adenosine deaminase levels in tuberculous pleural effusion showed pleural fluid ADA was more than 36 IU/L in tuberculous pleural effusion. In case of malignancy ADA was more than 18.5 IU/L. More than 100 IU/L was exclusively seen in tuberculous pleural effusion.
They concluded that ADA 100 IU/L was observed in TB only[46].
29
The study by Porcel JM et al on diagnostic performance of adenosine deaminase activity in pleural fluid. A single center experience with over 2100 consecutive patients concluded that pleural fluid ADA should be routinely used to rule TB in or out in areas with moderate to high or low TB prevalence respectively. A high ADA level is a characteristic not only of lymphocytic, but also of neutrophilic TB effusions. An extremely high ADA activity should raise suspicion of empyema or lymphoma [47] .
The study by Lee Y C, Rogers JT, et al on adenosine deaminase levels in non tuberculous lymphocytic pleural effusions concluded that ADA levels in non tuberculous lymphocytic effusions seldom exceeded the diagnostic cutoff for TB effusion. Effusion ADA levels cannot be predicted from total or differential leucocyte counts. Post CABG pleural fluids had ADA levels similar to other non tuberculous lymphocytic effusions. ADA is stable in effusion fluids and its measurement is reproducible [48].
The study by Denise Duprat Neves et al on efficiency of clinical radiological and laboratory testing in the diagnosis of pleural tuberculosis concluded that in patients with ADA >35 at 95% sensitivity , the specificity can be improved to more than 90% if we consider non purulent effusions or effusion with a predominance of Lymphocytes (> 50%)[49]
The study done by Lesley J Burgess et al on combined use of adenosine deaminase with lymphocytic/neutrophil ratio found that ADA of 50 IU/L with combined with lymphocytic neutrophil ratio of 0.75 or greater the sensitivity,
30
specificity, PPV, NPV and efficiency for the identification of TB were calculated at 88%, 95%, 95%, 88% and 92% respectively.They concluded that ADA especially when combined with differential cell counts and lymphocyte/
neutrophil ratios remains a useful test in the diagnosis of tuberculous pleuritis[50] .
The study done by Garcia-Zamalloa A et. al., in diagnostic accuracy of adenosine deaminase and lymphocyte proportion in pleural fluid for tuberculous pleurisy in different Prevalence scenarios found ADA 40 + LP (50) (lymphocyte percentage). The specificity and PPV increased ( 98.3% and 90%) with hardly any decrease in sensitivity or NPV ( 86.3% and 97.5%).They concluded that ADA remains useful for the diagnosis of TPE even in low to intermediate prevalence scenarios when combined with lymphocytic proportion [51].
The study by Antonangelo L et al., on clinical and laboratory parameters in the differential diagnosis of pleural effusion secondary to tuberculosis or cancer concluded that in lymphocytic pleural exudates obtained from patients with clinical and radiological evidence of tuberculosis, protein and ADA were the parameters that better characterize these effusions. In the same way, when the clinical suspicion is malignancy, serous hemorrhagic lymphocytic fluid be submitted to oncotic cytology once this easy and inexpensive exam reaches a high diagnostic performance (approximately equal 80%) In this context we suggest, thoracocentesis with fluid biochemical and cytological examination as the first diagnostic approach in these patients[52]
31
The study by Jimenez Castro D et. al., on diagnostic value of adenosine deaminase in non tuberculous lymphocytic pleural effusion concluded that ADA
< 40 IU/L virtually excluded a diagnosis of tuberculosis in lymphocytic effusion ADA1/ ADA (p) correctly classified all nontuberculous lymphocytic pleural effusion with high Adenosine deaminase levels[53]
The study done by Tunn Ren Tay et. al., on factor affecting pleural ADA level in tuberculous pleural effusion concluded that older patients and those with low pleural protein and cell count, a low pleural fluid ADA does not exclude TB. More extensive tests should be done to confirm or exclude TB.
More extensive tests should be done to confirm or exclude pleural TB in these patients[54].
The study by Antonangelo L et. al., on differentiating between tuberculous related and lymphoma related lymphocytic pleural effusions by measuring clinical and laboratory similarities among the patient with tuberculosis or lymphoma. Although protein and ADA levels in pleural fluid tended to be higher in the tuberculosis group than in the lymphoma group, even these variables showed an overlap, However, none of the Tuberculosis group patients had pleural fluid ADA levels below the 40 IU/L cut off point [55]
The study done by Sales RK et al proposed 2 models each for TPE and MPE for TPE ( i) ADA, globulins and the absence of malignant cells in the pleural fluid and ( ii ) ADA, globulins and pleural fluid appearance for cancer (i) patient age, fluid appearance, macrophage percentage and presence of atypical
32
cells in the pleural fluid and (ii) same as (i) excluding atypical cells.
Application of the models to 64 pleural effusions showed accuracy higher than 85% for all models. They concluded that the models were effective in suggesting pleural tuberculosis or cancer[56]
The study by Porcel J M et. al., on differentiating tuberculous from malignant pleural effusion a scoring model. They choose 2 models in model 1 : ADA > 40 (1), age < 35 years (2), temperature ≥ 37.8 degree celcius (3) and pleural fluid RBC count < 5 x 10(9)/L and model 2 in addition to last three items of model 1, no history of Malignancy (4), pleural protein ≥ 50 g/L and pleural fluid LDH to Serum LDH Ratio .- 2.2 (5). Summated scores of ≥ 5 in model 1 and ≥ 6 in model 2 yielded measures of sensitivity (95% And 97%) and measures of specificity (94% and 91% ) for discriminating tuberculous and malignant effusions respectively. They concluded that the combination of clinical data and pleural fluid chemistry profile into a score model can facilitate diagnosis between tuberculous and malignant effusion[57]
The study by Jose. M. Porcel et al on a decision tree for differentiating tuberculous from malignant pleural effusion found from discriminant parameters pleural fluid ADA > 38 IU/L, temperature ≥ 37.8 degree celcius, age <35 years and pleural fluid LDH > 320 U/L had a combined sensitivity of 92.2% and specificity 98.3% and are under the ROC curve of 0.976 for diagnosing tuberculosis and concluded that decision tree analysis that contains simple clinical and laboratory data can help in the differential diagnosis of tuberculous and malignant effusion[58]
33
The study by Denise Duprat Neves et. al., on predictive model for the diagnosis of tuberculous pleural effusion. After identification of individual discriminatory power aided by clinical, radiological and laboratory variables the following one were included in a multivariate analysis - ADA, total leucocytes, percentile of lymphocytes, protein, lactate dehydrogenase, duration of disease age and gender.The predicitive model improved the specificity of ADA alone, keeping its sensitivity.This model is helpful when a microbiological or histological diagnosis of pleuralTB could not be established [59]
The study by Rafael lariado laborin on ADA in the diagnosis of tuberculous pleural effusion concluded that ADA assay should not be considered as an alternative to biopsy and culture but rather as a screenin test to guide further diagnostic procedures and management of an exudative pleural effusion of unknown origin[60]
The study by Porcel JM et al on etiology and pleural fluid characteristics of large and massive pleural effusion found the most frequent cause of these effusions were malignancy (55%) followed by complicated parapneumonic or empyema(22%) and tuberculosis (12%). Patients with large or massive malignant pleural effusion were more likely to have pleural fluid with higher RBC counts (18 x 10(9)cells ) and lower ADA activity (11.5). They concluded that the presence of large or massive pleural effusion enables the clinician to narrow the differential diagnosis of pleurisy, since most effusions are secondary to malignancy or infection (either bacterial or mycobacterial). Bloody pleural fluid with low ADA favours a malignant condition[62]
34
OTHER INVESTIGATIONS USED IN THE DIAGNOSIS OF TUBERCULOUS ETIOLOGY
a. Needle biopsy shows 80% cases with demonstration of granuloma.
b. The level of ADA, lysozyme, leukocyte count, lymphocytes in tuberculous effusion is higher than that of carcinomatous effusion.
c. Interferon γ production in tuberculous pleurisy is higher than that of malignant effusions. Levels > 140 pg/ml is more in favor of tuberculosis.16 Interleukin-1, TNF-α also increased in tuberculous pleural effusion.
d. Tuberculous pleural effusion, detected by tuberculous-stearic acid in pleural aspirates has a sensitivity of 71% (Grantham Hospital, Aberdin, Hong-kong).
PCR in the diagnosis of tuberculous pleural effusion is a G-C rich repetitive sequence (G=C RS) of mycobacterium tuberculosis that displayed a high homology with amplification of the proximal 150 bp of G=C RS and its detection by non-radioactive hybridization was developed. The accuracy of G=C RS based PCR assay was evaluated in a clinical setting for the detection of mycobacterial DNA in pleural fluid for the diagnosis of tuberculosis using clinical criteria and pleural biopsy histology as the gold standard test.
In a blind study, a total of 67 pleural fluid samples (38 Tuberculous and 29 non Tuberculous) was analyzed by PCR and the results were compared with pleural biopsy, Zeihl-Neihlson staining and culture. Mycobacteria could not be detected by either smear or culture techniques in any of the pleural fluid samples.
Out of 38 tuberculous pleural effusion, 24 were positive by PCR (63.2%)
35
histology, an increased sensitivity of 73.3% was obtained. Out of the obtained accounting for an overall specificity of 93.1%. G=C RS based PCR assays has a definite role in the diagnosis of tuberculous pleural effusion in contrast to smear/culture techniques.
36
MATERIALS AND METHODS
STUDY PLACE
Department of general medicine, govt.chengalpattu medical college hospital.
STUDY DURATION
Study was done over a period of 1year, from march 2018 to febrauary 2019.
STUDY POPULATION
Patients admitted with exudative pleural effusion according to lights criteria in the department of medicine were included in the study
STUDY DESIGN
Cross-sectional study.
INCLUSION CRITERIA
1. Adult patients more than18 years of age of both sexes with unilateral pleural effusion
2. Exudative pleural effusion according to lights criteria .
3. Bilateral pleural effusion with atypical features (fever, pleurisy, asymmetry) or poor response to diuretics.
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EXCLUSION CRITERIA
Withdrawal of consent or no consent.
Nature of effusion
Patients with empyema was excluded because this tends to cause falsely high ADA levels .
Patients with transudate effusion Contraindication to thoracocentesis
Thrombocytopenia, platelets less than 50,000 and prolonged PT/INR > 1.5.
Mechanically ventilated patients.
HIV sero positive patients .
CRITERIA FOR ESTABILISHING TUBERCULOUS PLEURAL EFFUSION
More than one of the following criteria :
1) Clinical presentation consistent with TB and exclusion of other clinical considerations
2) Radiological findings consistent with tuberculosis 3) Sputum positive for acid fast bacilli
4) CBNAT positive in pleural fluid
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5) Definite clinical and radiological improvement after 2months of administration of ATT non tuberculous group of patients
CRITERIA FOR ESTABILISHING MALIGNANT PLEURAL EFFUSION
Positive for malignant cells by pleural fluid cytology or CT guided pleural biopsy.
Paramalignant – if other causes of effusion excluded histological proven malignancy elsewhere.
1) Criteria for establishing Parapneumonic effusion
Pleural effusion associated with acute febrile illness, cough, pulmonary infiltrates in chest x ray and patient responded to antibiotics.
Pleural effusion with pulmonary thromboembolism established by CT pulmonary angiography.
LIGHTS CRITERIA
Pleural fluid protein /serum protein > 0.5.
Pleural fluid LDH/Serum LDH > 0.6 .
Pleural fluid LDH >2/3rd of the upper limit of normal for serum LDH.
METHODOLGY
Patients were selected according to simple random sampling method.
They were subjected to elicitation of detailed history. History included
39
demographic characteristics of patients and symptoms like cough, dyspnea, pleuritic chest pain, weight loss appetite loss, fever, night sweats, gland swelling for their presence and duration. History of contacts with TB patients, history of ATT, cancer, chronic illness, diabetes mellitus, drug allergy, smoking and alcohol.
PHYSICAL EXAMINATION
Patients were physically examined for pallor, lymphadenopathy weight, location of trachea, tactile vocal fremitus, percussion and auscultatory findings were also recorded.
RADIOLOGICAL EXAMINATION
All patients underwent an X ray chest PA view. X ray was interpreted by a senior physician. The presence and side of effusion was noted size was assessed as follows: Small - if costo phrenic angle was obliterated, medium – if half of hemithorax was involved, large -if more than half of hemithorax was involved any associated consolidation or cavity were also noted.
BLOOD INVESTIGATION
All patients with a diagnosis of pleural effusion underwent a series of test that included complete hemogram, HIV(CLIA Method), serum protein measured in gm/dl range(6-8gm/dl). Serum LDH was measured in units/litre range (180 – 360 U /L)
40
THORACOCENTESIS
After confirming the presence of effusion, patient underwent thoracocentesis as per standard procedure guidelines.
INDICATIONS
1. To determine the etiology of pleural effusion . 2. When hemothorax or empyema is suspected.
3. Prior to more invasive procedures such as needle biopsy or thoracocscopy CONTRAINDICATIONS
a. Uncontrolled coagulopathy
b. Small volume less than 10 mm thick on decubitus X-ray or usg or CT scan c. Infection at entry site
d. Clinically apparent heart failure in the absence of asymmetry, chest pain, fever and poor response to diuretics.
TECHNIQUE
Clean the skin around the puncture site with antiseptic solution. Infiltrate the skin with local anesthetic using a short 25G needle replace the small needle with 21G or 22G and insert into the intercostal space over the superior aspect of the rib. As the needle is advanced follow aspiration with injection of small amounts of anesthetic every 1-2 mm. As soon as the pleural fluid is aspirated withdraw the needle slightly and anesthetize the parietal pleura.
41
Partially withdraw the needle to the intercostals tissues and replace the anesthetic containing syringe with a 20-60 ml syringe. Reintroduce the needle with constant aspiration until pleural fluid is obtained once more and the syringe filled, divide the fluid into three sterile bottles (5 -10ml each) and for Aerobic and anaerobic culture bottles.
Pleural fluid is analyzed for RBC, WBC, neutrophils, lymphocytes, eosinophils, cytology, biochemistry : protein, LDH, cholesterol, pH, glucose, adenosine deaminase, microbiology: culture
Special circumstances: Hematocrit, amylase, triglycerides
COMPLICATIONS OF THORACOCENTESIS
RELATIVELY INFREQUENT
Pnumothorax
Pain at puncture site
Cough
Vasovagal syncope RARE
Bleeding (Hematoma, hemothorax)
Rexpansion pulmonary edema
Soft tissue or pleural tissue infection
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Seeding of the needle track with tumor cells
Adverse reaction to the local anesthetic
Transmission of viral infection (Hepatitis, HIV) after needle track injury SPUTUM ANALYSIS
Sputum for AFB was sent in patients with productive cough PLEURAL FLUID ANALYSIS
Pleural fluid was noted for its appearance and the findings were recorded as bloody or serosanginous or yellow citrine.
BIOCHEMICAL ANALYSIS
Pleural fluid protein was determined in all patients. It was measured by the biuret end point method in g/dl. Pleural fluid LDH was determined in all patients. It was measured by UV Kinetic / lactate to pyruvate method in IU/L.
Pleural fluid glucose was determined in all patients. It was measured by oxidase calorimetric method in mg/dl. Pleural fluid ADA was determined in all patients. It was measured by immunoturbidometry method in IU/L. Reference range ( 0 -26 IU/L). These variables were determined because they have value in discriminating tuberculous from non -tuberculous pleural effusion. They are readily available and easy to collect .
43
MICROBIOLOGICAL ANALYSIS
Pleural fluid was submitted for gram stain and culture sensitivity . CYTOLOGICAL ANALYSIS
Pleural fluid cell count, differential cell count were determined by (electrical impedance automated / microscopically with neubar chamber). Cell count measured in cells / mm3 and percentage .
ADDITIONAL INVESTIGATIONS
Patients with in conclusive diagnosis after clinical examination and Pleural fluid analysis were subjected to contrast enhanced CT Thorax with abdominal screening, ultrasonagraphy.
Wherever indicated investigations like CT guided lung/Pleural biopsy, FNAC and CBNAAT were done.
Patients who were with undiagnosed pleural effusion after the workup were started empirically on ATT and followed up at 2 months. The details of demographics, history, physical findings, radiological findings, pleural fluid findings were recorded in a proforma.
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SAMPLE SIZE
Sample size was determined based on the study “clinical study of diagnostic efficacy of adenosine deaminase levels in tubercular pleural effusion”
authored by Mridul Bhushan et al., published in J Int J Adv Med. 2016 Feb;3(1):92-96
In this study, out of 30 patients with tuberculosis pleural fluid ADA was done in them and 28 (93.33%) of them had a level more than 40IU/L. Using a cut off of greater 40IU/L we got a sensitivity and specificity of 93.3% and 90%
respectively and positive predictive value 93.3% and Negative predictive value 90%.
Estimating the confidence level at 93.33%, with a z value of 1.96, the confidence interval or margin of error estimated at ± 6, power of the study at 80% and assuming that the sample will have the specified attribute p% =93.33 and q%=6.67
Adopting the formula: N = p% x q% x [z/e%] ²
n=93.33x6.67x[1.96/6]²
n= 66.43 –rounded up to 67 per intervention group. Therefore 67 is the minimum sample size required for the study. In our study we have taken 70 as the sample size.
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SAMPLING METHOD
Judgement sampling method was adopted STATISTICAL ANALYSIS
Descriptive statistics was done for all data and were reported in terms of mean values and percentages. Suitable statistical tests of comparison were done.
Continuous variables were analysed with the unpaired t test. Categorical variables were analysed with the Chi-Square test and Fisher exact test.The accuracy analysis was reported as sensitivity, specificity, PPV and NPV.
statistical significance was taken as P < 0.05. The data was analysed using SPSS version 16. Microsoft Excel 2010.was used to generate charts.
Ethical Considerations
The following ethical guidelines were put into place for the research period:
The dignity and well being of patients was protected at all times.
The research data remained confidential throughout the study and the researcher obtained the patients permission to use their real names in the research report.
Research protocol was presented in institutional ethical review board and due permission was obtained to undertake the study
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RESULTS
In this study, an analytical approach was adopted to evaluate the diagnostic efficacy of Adenosine Deaminase (ADA) levels in tubercular pleural effusion.Data collected from 70 selected subjects were internally compared, tabulated, analysed and interpreted by using descriptive and inferential statistics based on the formulated objectives of the study
Distribution of Cases Number Percentage
TB ( TBPE) 45 64.29
Cancer 16 22.86
Parapneumonic 6 8.57
Viral fever 1 1.43
Pulmonary Embolism 2 2.86
Total 70 100.00
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AGE DISTRIBUTION
Age - Groups TBPE % Non-TBPE %
21-30 years 14 31.11 8 32.00
31-40 years 11 24.44 6 24.00
41-50 years 8 17.78 5 20.00
51-60 years 12 26.67 6 24.00
Total 45 100.00 25 100.00
