Differential Diagnosis     Workup

     A pleural effusion is an abnormal collection of fluid in the pleural space.  The effusion may be either an exudate or a transudate, and this distinction is the first step in the work up of an effusion of unknown etiology.  Dyspnea is the usual presenting symptom and occurs secondary to compression of lung tissue with resultant decreased ventilation with preserved perfusion which may lead to hypoxia.

     Chest radiography with posteroanterior, lateral and lateral decubitus films are used to detect the presence of a pleural effusion and may provide clues as to its quantity.  When costophrenic blunting is appreciated, the effusion is usually greater than 150 mL.  Clues to the presence of a subpulmonic effusion include: an elevated hemidiaphragm, lateral displacement of the dome of the diaphragm, and an increase in the distance between the left hemidiaphragm and the gastric air bubble.  Layering on a lateral decubitus film indicates that the effusion is free flowing.  In contrast, an effusion which does not layer on lateral decubitus views may be loculated.  If the layering fluid is greater than or equal to 1 cm then fluid may be collected via thoracentesis.  Once a unilateral effusion is appreciated on radiographs, the effect on the mediastinum should be evaluated next.  Normally, the mediastinum will be shifted to the contralateral side of a large unilateral effusion.  If the mediastinum does not shift as expected, then several conditions should be suspected to include: concomitant bronchial obstruction, infiltration of the lung with tumor, a mesothelioma, or the presence of a nonmobile mediastinum secondary to malignant or fibrotic fixing of the mediastinum.  The radiograph should then be used to search for a possible etiology for the effusion.  Cardiomegaly, pulmonary vasculature cephalization, and the presence of Kerley B lines would be consistent with underlying congestive heart failure.  An infiltrate would be consistent with a pneumonia and a parapneumonic effusion, but may also be seen in cases of a pulmonary embolus.  A mass would indicate bronchogenic carcinoma as the etiology.  Pseudotumors are radiographic densities which occur when pleural fluid becomes loculated in the interlobar fissures in patients with exacerbation of congestive heart failure.  The majority occur in the minor fissure of the right lung but may occur in the oblique fissure of the left lung.  The diagnosis is established when the lesion regresses radiographically with proper treatment of the underlying heart failure.  If any questions are unanswered by radiography or further evaluation is required, CT scanning or ultrasonography may help localize an effusion or further identify its etiology.

     If no etiology is apparent from the initial evaluation, thoracentesis with pleural fluid analysis is the next step in the work up.  Potential complications of a thoracentesis include pneumothorax, chest pain, cough, hypoxemia, vasovagal reactions, intercostal artery laceration, and infection.  The first question to be answered is whether the effusion is an exudate or a transudate.  An exudate is diagnosed if any of the following criteria are fulfilled: pleural fluid LDH > 0.45 the upper limits of the normal serum value, pleural fluid cholesterol > 45 mg/dL, pleural fluid protein > 2.9 g/dL.  Older criteria were based on ratios of pleural to serum values for the LDH and protein and an exudate was diagnosed if any of the following criteria were fulfilled: pleural fluid protein/ serum protein ratio > 0.5, or a pleural fluid LDH/ serum LDH ratio > 0.6.  Determination of pleural fluid pH should also be done on initial analysis as this information is quite helpful in decision making regarding parapneumonic or malignant effusions and also helps to narrow the differential diagnosis of an exudative effusion.  In parapneumonic effusions, a pleural fluid pH< 7.2 is an indication for chest tube placement.  In contrast an uncomplicated  parapneumonic effusion with a pH> 7.3 may be managed more conservatively with antibiotic therapy for the pneumonia.  Initial fluid analysis may also include cell count with differential, Gram stain, culture, and cytologic study depending on the individual case.

     Transudative pleural effusions are usually secondary to distant disease.  That is the pathology is usually not pulmonic.  This is in direct contrast compared to an exudative effusion, which is usually associated with pleural pathology.  The differential for a transudative pleural effusion includes: congestive heart failure, cirrhosis with ascites, nephrotic syndrome, myxedema, constrictive pericarditis, peritoneal dialysis, urinothorax, superior vena cava syndrome or atelectasis.  The majority of transudative effusions occur during an exacerbation of congestive heart failure.  Pleural effusions secondary to congestive heart failure typically occur bilaterally and are of equal volume or occur on the right side only.  Other cardiac causes of effusion include post-myocardial infarction (Dressler’s) syndrome, post cardiac surgery (postpericardiotomy syndrome), Meigs syndrome or secondary to pericardial disease.

     Most exudative effusions are secondary to malignancies, pneumonia, tuberculosis, or are idiopathic.  Other causes of an exudative effusion include: rheumatoid arthritis, systemic lupus erythematosus, yellow nail syndrome, asbestosis, chylothorax, uremia, esophageal rupture, postcardiac injury syndrome, Meig’s syndrome (ovarian tumor, ascites, and hydrothorax), sarcoidosis, medication side effect, pulmonary emboli and others.

     A parapneumonic effusion that is grossly purulent, has a pH less than 7.2, a positive Gram stain or is deemed to be loculated requires immediate drainage.  When the pleural fluid amylase concentration is elevated above 200 U/dL, the differential diagnosis should include esophageal rupture, pancreatic disease, and ruptured ectopic pregnancy.  A pleural fluid adenosine deaminase level greater than 43 U/L is consistent with a tuberculous effusion although a lower level does not definitively exclude the diagnosis.  AFB stains and mycobacterial cultures have low yields for diagnosing a tuberculous effusion.  If TB is strongly suspected prior to thoracentesis, a thoracentesis with a closed-needle pleural biopsy will help increase the diagnostic yield.  Also, a PPD should be placed on these patients.  If malignancy is suspected, pleural fluid analysis should include cytologic examination.  The finding of malignant cells on pleural fluid analysis is consistent with severe disease, which is generally incurable.  If pleural fluid cytology is negative but malignancy is still strongly suspected, then determination of the pleural fluid carcinoembryonic antigen (CEA) level along with closed-needle pleural biopsy may prove helpful.  A pleural fluid CEA greater than 10 ng/mL is consistent with a malignant effusion.  When an effusion is bloody, the pleural fluid should have a spun hematocrit performed and if it is greater than 50% of the serum hematocrit, this is consistent with a hemothorax and requires immediate drainage.  When an effusion appears chylous, a pleural fluid triglyceride level should be determined, and if it is greater than 110 mg/dL, this is consistent with a chylothorax.  In young women of child bearing age with a chylothorax, lymphangiomyomatosis should be suspected.  Pulmonary embolism should always be considered as a possible etiology for an undiagnosed pleural effusion.  When evaluating the pleural fluid cell count differential a lymphocyte predominant cell count indicates tuberculosis or malignancy as possible etiologies.  Also, the pH is helpful in narrowing the differential diagnosis.  A pH less than 7.2 is consistent with malignancy, tuberculosis, pneumonia, empyema, rheumatoid arthritis, systemic lupus erythematosus, and esophageal rupture.  A pH greater than 7.3 is consistent with post cardiac injury, yellow nail syndrome, asbestosis, chylothorax, and uremia.  Of special note, when evaluating the pleural fluid glucose level it is important to remember that this value is extremely low in patients with rheumatoid arthritis, and this depression is not associated with concomitant infection.  However, in SLE patients with a pleural effusion, a low pleural fluid glucose level is suggestive of associated empyema and should prompt an aggressive work up.  Effusions secondary to esophageal rupture will possess an elevated amylase content.

     Cell counts should be determined on thoracentesis samples.  When evaluating the red blood cell (RBC) count it is important to remember that traumatic thoracentesis may be the cause of the elevated RBCs.  To distinguish if there was a traumatic thoracentesis it is important to remember that the blood will clot if secondary to thoracentesis technique but will not clot with old hemorrhagic effusions.  Causes of a greatly elevated pleural effusion RBC count include trauma, neoplasm, pulmonary embolism, asbestos-induced effusion, and postmyocardial infarction syndrome.

     Thoracentesis may be done on a diagnostic or therapeutic basis.  The procedure should be performed with the patient in the seated position if possible, with the patient receiving supplemental oxygen, and under sterile technique by an experienced physician using a 22-gauge needle.  Large effusions should not be drained completely as this may lead to reexpansion pulmonary edema.  Therefore, only 500 ml should be removed at any one time.  If removal of larger volumes is required, thoracentesis should be performed while monitoring pleural fluid pressures and the procedure should be discontinued when the pleural fluid pressure falls below –20cm H2O.  Recurrent effusions may require repeat thoracentesis or pleural sclerosis.  When no etiology for an effusion has been determined after thoracentesis and pleural biopsy, medical thoracoscopy should be performed.  If needed, pleurodesis may be performed during thoracoscopy.