Infectious Diseases

Pleural Effusion and Empyema

OVERVIEW: What every practitioner needs to know

Empyema is a collection of pus between the lung and the chest wall (pleural space). Infections of the pleural space most commonly follow pneumonia, accounting for 40 to 60% of all empyema. Thoracotomy is the next most common cause of empyema, accounting for approximately 20%, and trauma accounts for another 10%. Less commonly empyema can develop following esophageal rupture, subdiaphragmatic spread, or direct extension from head and neck infections.

Overall parapneumonic empyema hospitalization rates in the United States have increased across all age groups.

Despite advances in antimicrobial therapy and improved imaging, empyemas remain an important cause of morbidity and mortality. Delays in diagnosis, failure to start appropriate antimicrobial therapy, and inadequate drainage contribute to increased morbidity, mortality, and costs.

Are you sure your patient has empyema? What should you expect to find?

  • The clinical presentation varies with the underlying disease process, the microbiology, and host factors.

  • Patients with bacterial pneumonia present with fever, shortness of breath, productive cough, and chest pain. Patients with anaerobic pleuropulmonary infection may present with a more insidious course and present with weight loss, fever, and chronic cough. A history of aspiration and poor oral hygiene is often evident. Esophageal rupture or perforation, and subdiaphragmatic rupture of a liver abscess or subphrenic abscess generally present with acute pain, fever, and respiratory distress.

  • The microbiology of empyema has changed significantly over the last 50 years after the introduction of antibiotics. Streptococcus pneumoniaestill accounts for approximately 5 to 10% of cases, but many cases are now mixed, with aerobic and anaerobic organisms. A recent study found aerobic organisms present in 24% of patients, anaerobic bacteria in 35%, and both aerobic and anaerobic bacteria in 41% on the medical service without prior surgery. Factors predisposing to aspiration such as altered mental status, alcoholism, and periodontal disease are common with anaerobic infections of the pleura. Several recent studies have reported S. anginosus (formerly called S. milleri) as the leading bacterial cause in community-acquired empyema, many with underlying coexisting conditions. By contrast, the causes of hospital-acquired empyema or empyema in patients after trauma or surgery include staphylococcal infections (including methicillin-resistant Staphylococcus aureus)and gram-negative organisms. Immunocompromised patients have a higher frequency of empyema caused by gram-negative organisms, Mycobacterium, or fungi. Several studies have linked an increased incidence of S. aureus, S. pneumoniae, and S. pyogenes empyema associated with influenza. Amebic liver abscesses can be associated with pleural involvement in up to 15 to 20% of cases.

  • The physical exam reveals decreased breath sounds, dullness to percussion, and frequently crackles over the affected area. Chronic empyema may erode the chest wall and present with a draining sinus called empyema necessitatis.

How did the patient develop empyema? What was the primary source from which the infection spread?

  • The most common cause of empyema is extension of bacterial infection of the lung into the pleural space. This accounts for 40 to 60% of cases in most publications. Prior thoracic surgery accounts for another 20% of cases, and extension from subdiagphragmatic infections accounts for 5 to 10%.

Which individuals are of greater risk of developing empyema?

  • Since bacterial pneumonia is the most common predisposing factor for empyema, patients at risk for pneumonia are at risk for empyema. However, independent risk factors for empyema include diabetes mellitus, alcoholism, chronic obstructive pulmonary disorder, postinfluenza, gastroesophageal reflux disease, and intravenous drug abuse. Poor oral hygiene and aspiration predispose to infection with anaerobic organisms. Up to one third of cases occur without an obvious predisposing risk factor. The remaining cases are iatrogenic due to surgery or trauma.

  • Most patients with empyema present with a clinical picture of cough, fever, purulent sputum, shortness of breath, and chest pain. The laboratory findings usually demonstrate an increased white blood cell (WBC) count, and a chest X-ray indicates pleural fluid.

  • The common predisposing factors are pneumonia, prior thoracic surgery, trauma, and subdiaphragmatic surgery.

Beware: there are other diseases that can mimic empyema:

  • Several noninfectious causes can present with chest pain and pleural effusions. It is estimated that between 30 and 50% of patients with pulmonary emboli can have an associated pleural effusion. Patients with acute pancreatitis frequently develop a left-sided pleural effusion. Rheumatic conditions such as rheumatoid arthritis and lupus erythematosus can present with pleuritic chest pain and a pleural effusion. Patients who have experienced a pericardiectomy or myocardial infarction can present with pericarditis and/or pleural disease weeks after the event. Lastly, patients with malignancy with pleural involvement can present with chest wall pain and a pleural effusion.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

  • Most patients with acute empyema will have an elevated WBC with a left shift.

Results that confirm the diagnosis

  • Blood cultures may be positive from 10 to 22% in most series.

  • It is recommended that all patients where an empyema is suspected should undergo a diagnostic thoracentesis. After obtaining fluid, the first step is to determine if the effusion is transudative or exudative by applying Light criteria (Table I). Fluid obtained by thoracentesis should be sent for cell count with differential, glucose, protein, lactate dehydrogenase (LDH), and pH. If tuberculous empyema is suspected an adenosine deaminase determination or polymerase chain reaction (PCR) assay for M tuberculosis can be sent. Fluid should be sent to microbiology for Gram stain and aerobic and anaerobic cultures. Detection of pneumococcal antigen in pleural fluid increases the yield over conventional microbiology, particularly if the patient has received prior antibiotics. Cytology studies should be sent if a malignant effusion is suspected.

Table I

  • A predominance of leukocytes usually indicates an acute process. A predominance of lymphocytes usually indicates a more indolent process such as tuberculosis or fungal infection. Empyema usually decreases the pH and the glucose level, and raises the LDH level. A low pleural fluid glucose level (<60mg/dL) is consistent with a complicated parapenumonic effusion or malignancy. The level of LDH is correlated with the degree of pleural inflammation. Empyema fluid generally has a pH of less than 7.2, a glucose level of less than 40mg/dL, and an LDH activity generally over 1,000IU/L. A pleural fluid pH below 7.2 indicates the need for drainage. If the pleural effusion is secondary to pancreatitis (usually on the left) an amylase should be obtained which is usually quite high. See Table I, Features differentiating exudative from transudative pleural effusion.

What imaging studies will be helpful in making or excluding the diagnosis of empyema?

  • The standard plain chest X-ray is still useful in detecting pleural effusions which may represent an empyema. Up to 200 to 500mL of pleural fluid is necessary to be visible on a plain X-ray. A lateral decubitus film can detect as little as 5mL of free pleural fluid. Most studies recommend a thoracentesis if on a lateral decubitus film the fluid is more than 10mm. Ultrasound is widely available and costs much less than computed tomography (CT) or magnetic resonance imaging (MRI). Ultrasound is useful for detecting small amounts of pleural fluid and can be useful for guiding diagnostic thoracentesis or for pleural drainage. CT has emerged as the imaging study of choice. It is more accurate in distinguishing lung abscess from empyema than traditional chest films. Chest CT with contrast may also help differentiate transudates from exudates. Pleural thickening and enhancement is usually only seen with exudative effusions. The role of MRI in the evaluation of empyema is more limited. It may be useful when intravenous contrasts cannot be given with CT imaging. MRI can detect pleural effusions, pleural tumors, and chest wall invasion. In some cases MRI can distinguish hemorrhagic causes from other etiologies. MRI may be able to differentiate transdates from exudates with the use of triple echo pulse sequence or the use of gadolinium.

  • The average costs: chest X-ray, $; ultrasound, $$; limited CT scan, $$$; MRI scan, $$$$ ($ = 60–125, $$ 125–500, $$$ 500–1,000, $$$$ >1,000).

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

Consultation with pulmonary and/or thoracic surgery and infectious diseases specialists may be helpful. Interventional radiology may be consulted for initial localization and diagnostic thoracentesis.

If you decide the patient has empyema, what therapies should you initiate immediately?

Therapeutic options for a pleural effusion depend on the type and stage of the effusion. The American College of Chest Physicians has published evidenced-based consensus guidelines for the medical and surgical treatment of parapneumonic effusions (Table II). The three variables are pleural space anatomy, pleural fluid microbiology, and the pleural fluid chemistries which have been used to categorize patients into four risk levels:

Table II

  1. very low risk

  2. low risk

  3. moderate risk

  4. high risk

The panel divided the management of pleural effusions into six categories:

  1. no drainage

  2. therapeutic thoracentesis

  3. tube thoracotomy

  4. fibrinolytic therapy

  5. video-assisted thoracoscopic surgery (VATS)

  6. open surgery

Uncomplicated effusions (category 1 or 2) usually resolve with appropriate antibiotics alone. Drainage is strongly encouraged along with appropriate antibiotics for management of patients in category 3 or 4. The literature supports fibrinolytic drugs, VATS, or surgery for these categories. Thoracentensis and tube thoracotomy are usually insufficient for category 3 or 4. See Table II, Categorizing risk of poor outcome in patients with parapneumonic effusion.

Key principles of therapy:

  • Antimicrobial therapy and appropriate drainage play complementary roles. Most antimicrobial agents can adequately penetrate into the infected pleural space; however aminoglycosides are less capable of entering the pleural space and have decreased activity in an acidic anaerobic environment.

  • Initial empiric antimicrobial therapy should be based on the most likely pathogens, local antimicrobial susceptibility patterns, and all available results such as Gram stains, PCR, or pneumococcal antigen.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Empiric antimicrobial therapy should be based on the most likely pathogens, local susceptibility patterns, and all other available results such as a Gram stain or bacterial antigen tests. In community-acquired infections the most likely organisms include S. anginosus, S. pneumoniae, S. aureus, and mixed aerobic and oral anaerobic flora. In contrast, in hospital-acquired conditions, S. aureus and gram-negative organisms may predominate. There are potentially many choices including combination β-lactam β-lactamase inhibitors, carbapenems, or combination therapy with an advanced generation cephalosporin with either clindamycin or metronidazole. If S. aureus is suspected vancomycin or linezolid should be considered. Treatment options are summarized in Table III.

Table III.

Treatment options for empyema.
Organism Antibiotic Dose Alternative
Streptococcus pneumoniae (PCN MIC <2ug/mL) PenicillinAmpicillin 8–12 million units (divided every 6 hours)4–6g daily (divided every 6 hours) Ceftriaxone 1–2g daily
S. pneumoniae (MIC >2ug/mL) Ceftriaxone 1–2g daily Respiratory fluoroquinolone (levofloxacin, moxifloxacin)
Methicillin-sensitive Staphylococcus aureusMethicillin-resistant S. aureus Nafcillin or oxacillinVancomycin 6–8g daily (divided every 6 hours)2g daily (divided every 12 hours) CefazolinLinezolid
Aspiration pneumonia Clindamycin 1,800mg (divided every 8 hours) Ampicillin/sulbactam
Antibiotic sensitive enteric gram-negative organism (Escherichia coli, Klebsiella, Serratia)Pseudomonas aeruginosa, ESBLGram-negative organisms, multidrug resistant acinetobacter CeftriaxoneCefepimePiperacillin/tazobactam 2g daily4–6g daily (divided every 8–12 hours)18g daily (divided every 6 hours) ErtapenemAnti-Pseudomonas carbapenem (imipenem, meropenem, or doripenem with or without aminoglycoside)

2. Other key therapeutic modalities

  • The key for treatment of patients with an empyema is rapid recognition, appropriate antimicrobial therapy, and adequate drainage.

  • Controversial or evolving therapies: fibrinolytic therapy with drugs like streptokinase and urokinase has been recommended as a therapeutic option for loculated collections of less than 10 to 12 days. However, a recent study has raised the question of whether fibrinolytic therapy should be used on a routine basis. A controlled study showed no benefit with regard to mortality, need for surgery, or length of stay. However, many of the patients enrolled in this trial were older and had a median duration of symptoms of 2 weeks. Overall, the selection of fibrinolysis is best confined to younger patients with short duration of symptoms.

What complications could arise as a consequence of empyema?

  • When the patient is treated late or drainage is inadequate, pleural thickening and encasement of the lung, along with reduced lung function, can result. Chronic empyema can also form draining fistulas or empyema necessitatis.

What should you tell the family about the patient's prognosis?

  • With appropriate treatment most patients fully recover from empyema.

What pathogens are responsible for this disease?

In many parts of the world, tuberculous effusions are common and may be secondary to a primary infection or reactivation. In most cases, tuberculous effusions resolve spontaneously; however, up to 50% of patients not treated will develop active tuberculosis within 5 years.

Fungal infections of the pleural space are uncommon in the normal host and are mostly caused by Candida species. Candida empyema has been reported as a complication of surgery, the results of esophageal rupture, a subdiaphragmatic infection, and rarely hematogenously. Many of these infections are polymicrobial.

Immunocompromised patients have a higher risk for empyemas caused by fungi. Pleural reactivation of fungal infection is more common, but they rarely present with empyema without evidence for disseminated disease. Resection of cavitary coccidioidomycosis or aspergillosis can be complicated by empyema and/or bronchopleural fistula from that organism.

Viral infections are a rare cause of empyema.

The only significant parasite associated with pleural involvement is Entamoeba histolytica (amebiasis). Amebic liver abscess is associated with pleural involvement in up to 15 to 20% of cases by two mechanisms. First, an amebic liver abscess can irritate the diaphragm producing a sympathetic effusion. The second mechanism involves the rupture of the amebic liver abscess through the diaphragm into the pleural space leading to a complex pleural effusion.

How do these pathogens cause empyema?

Pneumonia continues to be the most common predisposing factor in the development of empyema. If the infection and or inflammation spreads beyond the lung a pleural effusion will form. The pleural fluid can be divided into three phases in the progression to empyema. In the exudative stage, proinflammatory cytokines such as interleukin-8 and tumor necrosis factor are released in pleural space leading to fluid accumulation. The effusion at this phase is usually free flowing with a low number of neutrophils, a pH greater than 7.2, a LDH level of less than 1,000IU/L, a glucose level of greater than 60mg/dL, and negative cultures. The fibrinopurulent stage usually develops in response to bacterial invasion which promotes neutrophil migration leading to increasing numbers of neutrophils and fibrin which can lead to loculation. The pleural glucose level and the pH falls and the LDH level increases. The last phase, called the organization stage, is characterized by fibroblast proliferation leading to thickened pleura that can encase the lung.

What other clinical manifestations may help me to diagnose and manage empyema?

In patients with tuberculosis, symptoms of weight loss, night sweats, fever, and hemoptysis may be helpful clues to the diagnosis. In patients with actinomycosis, the development of a draining fistula with sulfa granules is very suggestive.

What other additional laboratory findings may be ordered?

The use of an immunochromatographic test for the detection of S. pneumoniae has been found to be a useful test in the diagnosis of pneumococcal empyema. The sensitivity of this test was higher than that of blood cultures or pleural fluid culture. Prior antibiotics did not influence the antigen detection in pleural fluid.

Pleural tuberculosis can be diagnosed by stains of pleural fluid in only approximately 20% of patients, but cultures of pleural fluid and histologic examination of pleural biopsy specimens permit the diagnosis in up to 95% of cases. Three other diagnostic tests may be useful, including the adenosine deaminase, interferon-γ, and PCR.

How can empyema be prevented?

The use of influenza vaccine can reduce infection due to influenza, which in turn reduces the risk of secondary bacterial pneumonia, particularly S. pneumoniae and S. aureus. Despite an increase in empyema of all causes, the rate of pneumococcal empyema has been stable. It is possible that this may be due to the introduction of conjugated vaccine (PCV7) in children, which started in 2000 and which has resulted in a decrease in pneumonia hospitalization in both children and adults. However, recent studies observed an increase in pneumococcal pneumonia and empyema in children aged less than 5 years. Most of this has been with serotypes not covered in the PCV7 formulation. The recent introduction of a 13-valent pneumocococal conjugated vaccine should provide protection against serotypes 1, 3, 7F, and 19A, which are associated with empyema.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Rahman, NM, Chapman, SJ, Davies, RR. "The approach to the patient with a parapneumonic effusion". Clin Chest Med. vol. 27. 2006. pp. 253-66.

(This is a very nice review on pathogenesis, definitions, diagnosis, and treatment.)

Grijalva, CG, Zhu, Y, Nuorti, J, Griffin, M. "Emergence of parapneumonic empyema in the USA". Thorax. vol. 66. 2011. pp. 663-8.

(This article provides the most recent trends in the incidence and pathogens associated with parapneumonic empyema in the United States.)

Colis, GL, Curtis, A, Deslauriers, J. "Medical and surgical treatment of parapneumonic effusions: an evidence-based guideline". Chest. vol. 118. 2000. pp. 1158-71.

(This is the American College of Chest Physicians evidence-based consensus guideline. They use three variables—pleural space anatomy, microbiology, and pleural fluid chemistries—and characterize patients into four levels for outcome. The panel grouped management of pleural effusions into six categories: no drainage, therapeutic thoracentesis, tube thoracostomy, fibrinolytic therapy, VATS, and open surgery.)

Maskell, NA, Davies, CWH, Nunn, AJ. "U.K. controlled trial of intrapleural streptokinase for pleural infection". N Eng J Med. vol. 352. 2005. pp. 865-74.

(This study questioned the use of fibrinolytic therapy on a routine basis. The study did not find benefit in terms of mortality, surgery avoided, or length of stay. However, the patients tended to be older and had a median duration of symptoms of 2 weeks. Other studies in younger patients with shorter duration of symptoms did conclude that intrapleural streptokinase reduced the need for surgery and improved clinical treatment success.)

Kearney, SE, Davies, CW, Davies, RJ. "Computed tomography and ultrasound in parapneumonic effusions and empyema". Clin Radiol. vol. 55. 2000. pp. 542-7.

(This is a nice review of the use of CT in differentiating pulmonary abscess from empyema, particularly the enhancement of visceral and parietal pleura.)
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