Incidence of microorganism isolation is highly variable and no responsible microorganism is found in over 40% of empyemas. In PPPEs associated with community-acquired pneumonia, the most frequently isolated Gram-positive bacteria are aerobic, such as streptococci (Streptococcus milleri and Streptococcus pneumoniae) and Staphylococcus aureus, followed by anaerobic microorganisms (common in aspiration pneumonia), and a small group of Gram-negative bacteria (Enterobacteriaceae, Escherichia coli and Haemophilus influenzae) in patients with comorbid conditions, especially diabetes or alcoholism.10 In nosocomial pneumonia, the most frequent pathogen is S. aureus, and 60% correspond to methicillin-resistant S. aureus. The next most frequent are gram-negative aerobes (E. coli, Enterobacter spp. and Pseudomonas spp.), along with anaerobes. Fungal infections are rare, and Candida spp. is the most common fungus, especially in immunocompromised patients.

During the evaluation of any pneumonia, the possibility of PPPE should be considered. Radiological studies are important (standard X-ray, CT, ultrasound, and thoracentesis). Contrast-enhanced CT is useful in differentiating lung consolidation, with contrast medium uptake, from a hypodense PE. Interlobular, mediastinal pleural and small-sized paravertebral collections are identified on CT. With CT, a peripheral abscess can be differentiated from complicated PPPE with the split pleura sign (thickened parietal and visceral pleura with displacement of surrounding vessels) that distinguishes it from a lung abscess. Air inside the PPPE, in the absence of previous maneuvers, may be due to the presence of gas-forming bacteria, or empyema progressing with a bronchopleural or pleuroparietal fistula (empyema necessitatis). Pleural thickening or attenuation of subcostal fat on CT suggest infection of the pleural cavity, and may also be useful for detecting malignancy associated with PPPE.11 However, CT has low sensitivity for displaying septa in the pleural cavity.

Thoracic ultrasound helps identify small PE. The presence of septa on ultrasonography suggests complicated PPPE and hyperechogenicity is associated with pus in the pleural cavity.12 Ultrasound provides guidance for the best location for drainage placement, improves its performance, and reduces the risk of complications (B).

Thoracentesis should always be performed when PE is suspected (B), and blood cultures should be extracted (B). Uncomplicated PPPE may become complicated in less than 12h, so close clinical management is required. Presence of microorganisms, turbidity or putrid odor confirms the diagnosis of PPPE, which is considered empyema when it contains pus. Frequently PF cultures are negative or an early therapeutic decision must be made before results are available (24–48h). In this case, pH is the best marker (A),13 but other biochemical parameters such as glucose or LDH levels are also of great diagnostic and prognostic use. It should be remembered that pH may vary in the different loculated PE chambers, and also that it is acid in malignant PE, rheumatoid arthritis, lupus pleuritis and tuberculous PE. Conversely, Proteus spp. causes PF alkalinization.

The objective is to control the infection with the appropriate antibiotic and drain the infected and/or complicated PE.14,15 Good nutrition, particularly in hypoproteic patients, and antithrombotic prophylaxis should not be forgotten.11Fig. 3 shows the algorithm for the treatment of PPPE.

Fig. 3.

Algorithm for the treatment of parapneumonic effusion. (a) early empirical antibiotic treatment should be initiated in all cases, and then adjusted with the culture results; (b) the presence of loculation can also be based on the findings of CT scan or chest X-ray; (c) also if the pleural fluid is turbid or smelly.

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Early, empirical antibiotic treatment with anaerobic cover should be initiated (C), and adjusted after the cultures result are available. Antibiotic selection should take into account the community or nosocomial origin of the PPPE, patient characteristics, geographical and local microbiological peculiarities, and antibiotic activity in the PF (B). A combination of a third generation cephalosporin with clindamycin or metronidazole, or monotherapy with amoxicillin-clavulanate may be used. Patients with penicillin allergies may be treated with clindamycin, usually in combination with a quinolone. If the source is a nosocomial infection, recommended antibiotics include vancomycin or linezolid (for methicillin-resistant S. aureus), antipseudomonal penicillins (piperacillin-tazobactam), carbapenem, or third-generation cephalosporins with metronidazole. Importantly, aminoglycosides have poor pleural penetration and intrapleural antibiotics are not indicated (H). Therapeutic thoracentesis is an effective procedure for moderately sized PEs that do not meet criteria for chest tube drainage (H). Chest tube is indicated in all cases of empyema or complicated PPPE (pH less than 7.20, loculated PPPE or bacteria in the PF) (B). When pH determination is not available, glucose levels below 60mg/dL and LDH levels above 1000U/L are useful for identifying the need for pleural drainage.13 It should be pointed out that pleural drainage may be required if clinical progress is slow, even if pH is greater than 7.20. In loculated PE, chest ultrasound facilitates drainage positioning and placement, especially if more than one tube is needed to drain different cavities. There is no consensus on the most appropriate tube gauge for drainage, but small catheters (10–14 French) are easier to position, less traumatic and more comfortable for the patient. Additionally, if fibrinolytic therapy and lavage are also applied, efficacy is similar to that of tubes of greater gauge.16 Drainage is considered to have failed when sepsis persists despite antibiotic therapy. This may be due to incorrect drainage placement, the presence of multiple loculations, late initiation of antibiotic treatment, or presence of a bronchopleural fistula. Fibrinolytics should be started early in the case of loculations in the pleural cavity and empyema. These agents facilitate drainage of dense fluids and prevent the formation of septa in the pleural cavity. Streptokinase, urokinase or alteplase with DNase17 are most often used, but there is no consensus on the dose.18Table 1 summarizes the most used regimens. Sufficient scientific evidence to recommend a particular agent or regimen is not available.

Treatment with fibrinolytics is safe and with few side effects; it improves radiological progression and decreases the days of drainage and hospital stay.19 The only contraindication is bronchopleural fistula.

Early thoracoscopy is an option for patients with loculated PPPE. It allows pleural debridement with the subsequent lung reexpansion, pus evacuation and drainage placement. Surgical treatment is indicated for control of sepsis when medical treatment and drainage with fibrinolytics fail.

The characteristics of the methods for PTB diagnosis are shown in Table 2. PF analysis shows a predominantly lymphocytic pleural exudate in most cases (90%), occasionally polymorphonuclear in the first days, with high levels of adenosine deaminase (ADA), without eosinophilia and less than 5% of mesothelial cells (A).20 PTB diagnosis is confirmed with the isolation of Mycobacterium tuberculosis in PF or pleural tissue. BACTEC provides a greater yield and faster results (2 weeks), compared to Löwenstein–Jensen (LJ) culture.21 The microscopic observation drug susceptibility (MODS) assay provides faster results (2 weeks) and higher sensitivity than LJ (20% in PF versus 7%; 81% in pleural tissue samples compared to 51%).21 (C) Nucleic acid amplification tests have low sensitivity for the diagnosis of PTB (this is possibly related to inhibitors in pleural fluid or intracellular sequestration of mycobacteria) and high specificity.22

Analysis of pleural tissue obtained by transmural pleural biopsy may show granulomas, providing a presumptive diagnosis. Its sensitivity is higher than 80% and presence of acid-fast bacilli (30%–50%) or M. tuberculosis (40%–71%) in culture increases its yield (90%) and confirms the diagnosis, (A).20 Diagnostic thoracoscopy is indicated only in case of persistent clinical suspicion and negative results in the clinical studies performed (F).

ADA levels are elevated in PF, with a sensitivity of 88–100% and specificity of 81%–97%,23 and the most accepted cutoff level is 35IU (B). Yields are similar in human immunodeficiency virus (HIV) carriers, even those with very low CD4 counts.24 Yield improves in patients under 35 years with a lymphocyte/neutrophil ratio in PF>0.70 (sensitivity 93%–94%, specificity 94%–97%). ADA false positives occur mainly in complicated PPPE (especially empyema) and lymphoma, and include other less frequent entities such as rheumatoid arthritis and some carcinomas. In PTB, increases in ADA are the result of mainly monocyte-derived macrophages ADA2 isoenzyme. Hence, yields superior to those of ADA are described for ADA1/total ADA ratio values<0.42 (total ADA=ADA1+ADA2), with sensitivity 100% and specificity 97%–99%.25 (F)

Levels of IFNγ derived from T-lymphocyte (CD4) activation are also increased in PTB and the diagnostic yield is as high as that of ADA20 (sensitivity 89%–99%, specificity 92%–98%), with a variable cutoff level depending on the method and units (B). False positives have been described in empyema and lymphomas. ADA has been recommended on the basis of its lower price and the greater speed.

The combination of diagnostic tests for lymphocytic PE, including patient age, ADA levels, PF cultures and staining, mycobacteria cultures and histological analysis of pleural transmural biopsy, along with the therapeutic response, constitutes an appropriate diagnostic approach (Fig. 4).

Fig. 4.

Diagnostic algorithm for patients with suspected pleural tuberculosis (PTB). TB, tuberculosis; ADA, adenosine deaminase.

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Treatment of PTB does not differ from that described for pulmonary tuberculosis: 2 months with rifampicin+isoniazid+ethambutol+pyrazinamide, and the next 4 months with isoniazid+rifampicin (A). Concomitant pleural drainage may reduce the symptomatic period, but no evidence of any improvement in mid to long term outcomes is available.26

Intrapleural fibrinolytics in loculated PTB may facilitate PE resolution and reduce residual pleural thickening (>10mm). However, pleural thickening is observed in less than 20% of patients after one year of follow-up and the functional impact is low in most cases (G). Corticosteroids, initiated two weeks after TB treatment, may be clinically useful in severe cases for shortening the symptomatic period, but have not shown long-term usefulness (G).

Tuberculous empyema is rare, but often requires pleural decortication due to functional disability and treatment failure caused by a trapped and often loculated lung, with thickened and even calcified pleura, which may hinder drug penetration (H).

Most MPE begin with exertional dyspnea that progresses as the effusion enlarges and compresses the lung and the diaphragm. If persistent, severe pain is present, mesothelioma should be suspected, especially in subjects with a history of asbestos exposure.

Radiologically, the following should be taken into account:

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  MPE often occupies more than half of the hemithorax.

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  If bilateral (more common in breast and ovary metastases), the apparent size of the heart is not increased (except in the case of very advanced stages of pericardial effusion).

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  If the mediastinum is centered in presence of a massive unilateral PE, proximal bronchial obstruction, mediastinal fixation due to tumor and/or lymphadenopathy, or extensive pleural infiltration (mesothelioma and/or “trapped lung”) should be suspected.

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  CT with contrast is recommended, on which PE may be observed with no other finding in more than 50% of cases. Malignancy should be suspected if pleural nodules, diffuse thickening of the parietal pleura greater than 1cm, “circumferential” thickening of the entire pleura (including the mediastinum; this appears frequently in advanced mesothelioma), or liver metastases associated with the PE are observed.

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  Thoracic ultrasound may exceed 95% specificity for MPE if marked thickening of parietal or visceral pleura, or nodules on the diaphragm surface are observed.27

Several options are available for the management of MPE.

Pleural involvement is the most common intrathoracic manifestation of rheumatoid arthritis (RA) and occurs in 5% of patients. Although RA is more common in women, the majority of rheumatoid PEs occur in middle-aged males (80%), with high titers of rheumatoid factor, rheumatoid nodules, and presence of both HLA-B8 and Dw3. PE in these cases is usually small, unilateral (70%), on the left side, and asymptomatic. It usually occurs years after RA diagnosis and may be transient, recurrent or chronic. The appearance of the fluid can be serous, milky, hemorrhagic and even purulent. The biochemical characteristics of chronic PE (80% of cases) are usually pH <7.20, with a low glucose content (80% below 50mg/dl), pleura/serum glucose ratio <0.5, elevated LDH (>1000U/L), rheumatoid factor titer higher than 1/320 (generally higher in the fluid than in blood), and low levels of total hemolytic complement and complement components. However, pH and glucose levels are usually normal in acute PE. In countries with a low incidence of tuberculosis, chronic rheumatoid effusions are the most common cause of pseudochylothorax, but chylothorax and empyema have also been described. Pleural biopsy is usually not diagnostic. Usually, rheumatoid PEs do not require treatment, but sometimes repeated therapeutic thoracentesis are needed to prevent pleural thickening and trapped lung.44

Pleural involvement may be the disease presentation in 5% of cases, while 30%–50% will develop symptomatic pleural inflammation throughout their illness. PEs tend to be bilateral (50%), small and rarely associated with underlying lung disease. They behave like typical exudates and there are no definitive tests to differentiate them from other effusion types. Low complement levels and high titers of antinuclear antibodies (ANA) (>1/160) in PF are suggestive but not conclusive, because some MPE, especially lymphomas, may also present high titers. A recent study shows that the determination of ANA in PF does not provide additional information compared to ANA measurement in serum. Therefore, PF determination is recommended only in patients with SLE and a PE of uncertain etiology, since the absence of ANAs in the fluid would act against the diagnosis of lupus pleuritis.45 Presence of lupus erythematosus cells is highly specific, although this test is rarely performed due its long preparation time. In pleural biopsy a specific immunofluorescence pattern can be observed, characterized by nuclear staining of pleural cells either with anti-IgM, anti-IgG or anti-C3. In drug-induced lupus, PE can also be present, and usually disappears once the medication is withdrawn. In most cases, effusions by SLE or drug-induced lupus respond well to nonsteroidal antiinflammatory drugs (NSAIDs) or low-doses of oral corticosteroids.46

It is probably the most common cause of PE. On standard X-ray, approximately 60% of these PEs are bilateral, 30% unilateral in the right side and 10% unilateral in the left side.47 The PE occupies only a third (sometimes less) of the hemithorax in more than 80% of cases.47 PF is accumulated in the fissures and may simulate a lung tumor. PF analysis is not necessary in a typical clinical–radiological context. Thoracentesis is only indicated in: (1) unilateral PE, particularly if there is no cardiomegaly; (2) patients with fever or pleuritic pain; and (3) persistent PE despite diuretic therapy.

In most patients with heart failure, PE is solved with diuretics. In the few cases in which cardiac PE is refractory to conventional medical treatment, repeated therapeutic thoracentesis, pleurodesis or intrapleural insertion of a permanent catheter may be used. Unilateral pleurodesis has the risk of potentially increasing PE on the opposite hemithorax. Although experience is limited, permanent intrapleural catheters control dyspnea in all patients, and it can be removed after a couple of months in half of the cases, mainly thanks to the development of a spontaneous pleurodesis.48

In the immediate postoperative period after revascularization by coronary artery bypass surgery, most patients have small PEs that gradually resolve.49 However, the incidence of PEs occupying more than a quarter of the hemithorax is 10%. These PEs of moderate or large size produce dyspnea and are usually located on the left side; if bilateral, they predominate on the left side. Thoracentesis should always be performed, because the differential diagnosis includes heart failure, pulmonary embolism, chylothorax or infectious PE. Symptomatic PEs within the first 30 days after surgery are usually due to surgical trauma and the PF is a frequently bloody and eosinophilic exudate. PEs that reach their maximum size more than one month after surgery are lymphocytic exudates whose pathogenesis is probably of immune origin that may be a limited variation of post-cardiac injury syndrome. Treatment includes therapeutic thoracentesis that needs to be repeated twice or more in 20% of cases.

Post-cardiac injury syndrome is the occurrence of pericarditis (with or without pericardial effusion), days, weeks or months after an acute myocardial infarction (Dressler's syndrome), cardiac surgery with pericardiotomy, pericardial injury or even a minor precipitating factor such as percutaneous coronary intervention, the insertion of a pacemaker or radiofrequency ablation. The incidence of Dressler's syndrome is less than 1% and that of post-pericardiotomy syndrome is 15%. The mechanism is immune-mediated and patients typically present with pleuritic and/or pericardial pain, fever and elevated acute phase reactants, along with small unilateral pleural exudates predominantly in the left side and, occasionally, pulmonary infiltrates. Treatment consists of aspirin (Dressler's syndrome), NSAIDs (other cases) and, in the case of lack of response or relapse, corticosteroids may be administered. Prophylactic use of colchicine in the immediate postoperative period (0.5mg/12h for 1 month) significantly reduces the risk of pleuro-pericardial effusion after cardiac surgery.50

PE is associated with at least a quarter and over a half of acute and constrictive pericarditis cases, respectively. In the first case, PEs are mostly small (≤1/3 of the hemithorax) and unilaterally left, while in the second case, bilateral PEs are predominant. Biochemical analysis reveals exudative nature almost always. Acute pericarditis is treated with NSAIDs, which must be combined with colchicine for 3 months (0.6mg/day if body weight<70kg or 1mg/day if body weight>70kg) to reduce the risk of persistent or recurrent disease.

Chest X-ray reveals PE in a third of patients with pulmonary embolism, although more sensitive techniques, such as ultrasound or CT, reveal PE in half of cases.51 PE occupies less than a third of the hemithorax in 90% of patients, and is unilateral in 85% of cases. In 20% of subjects, particularly if the diagnosis is delayed more than 10 days after the onset of symptoms, PE is loculated.51 Due to the small size of the PEs and the immediate anticoagulant therapy initiated when this entity is clinically suspected, only one third of patients undergo diagnostic thoracentesis. PF is bloody in half of cases, with biochemical characteristics of an exudate, and varying prevalence of neutrophils or lymphocytes. The treatment of embolism is not modified by the presence of PE.

This is based on two basic options to reduce the chyle leak and lower triglycerides. (1) Oral or enteral nutrition avoiding long-chain triglycerides to prevent the formation of chylomicrons, allowing intake of medium chain triglycerides, as these are directly absorbed into the portal system and decrease the flow through the thoracic duct. (2) Absolute bowel rest and parenteral nutrition. Both alternatives have similar results, although the parenteral nutrition options are slightly better.59

Therapeutic thoracentesis may be sufficient in some cases until treatment of the underlying disease takes effect. If insufficient, a chest tube may be placed for decompression and control of daily leak. Chemical pleurodesis is often performed on patients who do not respond to diet and thoracic drainage. This includes talc instillation through the drainage tube or talc insufflation during thoracoscopy; other forms of mechanical pleurodesis can be performed with thoracotomy or thoracoscopy. Pleurodesis is a well-accepted option for malignant and refractory CHT or when thoracic duct ligation cannot be performed.

This involves the use of a somatostatin analog, octreotide, which decreases splanchnic, hepatic and portal blood flow and also the lymph volume.

This is based on thoracic duct ligation, usually performed by video-assisted thoracoscopy or thoracotomy at the level of the aortic hiatus. Ligation is the standard surgery for traumatic and iatrogenic CHT in the case of a persistent large chyle leak, malnutrition or immunosuppression, prolonged hospitalization or failure of conservative treatment. Other less frequent treatments include pleuroperitoneal shunt, fluoroscopy-guided percutaneous embolization and anastomosis of the thoracic duct to the venous system.

Symptoms and signs vary depending on the cause, the volume and pace of accumulation. Among traumatic hemothoraces, those secondary to hemodynamic instability are usually more frequent and they are painful, while non-traumatic hemothoraces present with dyspnea and signs of occupation by pleural fluid. Radiography, ultrasound and chest CT reveal the presence of free or loculated PE, occasionally with images compatible with clots that may also reveal the associated lesions that point toward the cause. Definitive diagnosis is obtained by thoracentesis and PF study.

Acute and residual hemothorax should be differentiated (Fig. 8).

Fig. 8.

Treatment algorithm for hemothorax. aExcludes aortic dissection.

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