Pleural Space Infections/Empyema

What every physician needs to know:

Pleural space infection/empyema is usually seen in association with pneumonia, although primary empyema is occasionally seen (~4%) with no radiographic evidence of pneumonia or other obvious cause.

Reactive versus infected pleural effusions

Up to 57 percent of patients with pneumonia have an associated pleural effusion, which varies in size from a tiny sub-centimeter effusion not visible on chest X-ray to a large effusion that causes ventilatory compromise. The priority for physicians is to distinguish non-infected reactive effusions (“simple” parapneumonic effusions) from pleural infection (“complicated” parapneumonic effusions/empyema) since this distinction is essential in determining appropriate treatment. Simple parapneumonic effusions usually resolve with standard pneumonia antibiotic therapy, whereas an infected pleural space requires prompt chest tube drainage and prolonged broad-spectrum antibiotic therapy.

When to consider pleural infection

Pleural infection should be suspected in any patient who presents with pneumonia and is found to have a pleural effusion. Pleural infection should also be suspected in those with a non-resolving pneumonia despite appropriate antibiotic therapy (i.e., ongoing fevers, poorly resolving C-reactive protein, or high white cell count).

Diagnostic strategies

The gold standard for diagnosis of pleural space infection is a microbiological culture of pathogens in pleural fluid. However, cultures are typically slow, often taking 24-72 hours, and they also frequently produce false negatives, particularly in patients who have received prior antibiotic therapy. Therefore, biochemical surrogates of infection (low pH, low glucose, and high lactate dehydrogenase [LDH]) are used to identify patients who require chest tube drainage.

Other considerations

Tuberculosis is a common cause of pleural effusion worldwide, but it is usually associated with a low mycobacterial load in the pleural cavity, and it normally develops as a type IV hypersensitivity reaction. Unlike standard bacterial pleural infection, acute presentation with TB pleuritis is uncommon, and dyspnea and constitutional symptoms develop insidiously. Chest tube drainage is rarely required, as the effusion usually responds to anti-tuberculous therapy. Parasitic infections, such as amebiasis, echinococcosis, and paragonimiasis, may cause pleural infections in endemic regions.

Classification:

Pleural effusions found in association with pneumonia are classified as simple parapneumonic, complicated parapneumonic, and empyema.

Simple parapneumonic effusions comprise the majority of pneumonia-associated pleural effusions (~60%). These are reactive non-infectious effusions that usually resolve with standard pneumonia treatment.

Complicated parapneumonic effusions are infectious parapneumonic effusions that may be clear or turbid in appearance. About 25 percent of these effusions are culture-positive. Bacterial and host cell metabolism in the pleural space causes a characteristic biochemical pattern with low pH, low glucose, and high LDH, and these criteria are used to define infection when the culture is negative.

Empyema is defined by frank pus in the pleural space. A culture is positive in about 70 percent of cases.

Pleural infection may also be defined as community-acquired or healthcare-associated infection. This distinction is useful given the distinct microbiological profiles associated with each category (which inform antibiotic selection strategies) and the higher mortality found in healthcare-associated infection.

Other sources of pleural infection include esophageal rupture and intra-abdominal sources of infection (e.g., subphrenic abscess), traumatic pleural infection secondary to penetrating or blunt chest trauma, and iatrogenic pleural infection secondary to thoracic surgery or pleural procedures, such as thoracentesis or chest tube insertion.

Pleural infections can also be classified on the basis of the infecting pathogen:

Gram-positive aerobic bacteria are the commonest cause of pleural infection. However, causative bacteria vary, particularly dependent on whether the infection is community-acquired or healthcare-associated.

Community-acquired pleural infection

Streptococci, including Streptococcus pneumoniae (~20%) and the Streptococcus “milleri”/anginosus (constellatus-intermedius-anginosus) group (~25%), are the commonest causes of community-acquired infection. Gram-negative organisms, including Haemophilus influenzae, Escherichia coli, Pseudomonas spp., and Klebsiella spp., occur in about 10 percent of cases, particularly among patients with comorbidities, such as diabetes.

It is estimated that the incidence of anaerobic organisms is 10-35 percent of cases, although some studies suggest a much higher rate. Therefore, empiric antibiotic therapy should include anaerobic coverage. Polymicrobial infection is comparatively common, often involving anaerobes and gram-negative organisms, especially in the elderly and those with comorbidities.

Healthcare-associated pleural infection

Similar to healthcare-associated pneumonia, resistant pathogens, such as gram-negative organisms and MRSA, are more common in healthcare-associated pleural infection than in community-acquired pleural infection. In patients who have positive pleural fluid culture results, Staphylococcus aureus (frequently MRSA) is isolated in about half of cases. Gram-negatives, including Pseudomonas spp., Enterobacter spp., and E. coli, are common and associated with patients who require intensive care. Fungal pleural infection (particularly with Candida spp.), although rare, carries a high mortality rate (>70%) and is usually associated with immunosuppression.

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

Patients typically present with an acute illness associated with fevers/sweats, dyspnea, cough, pleuritic chest pain, malaise, and decreased appetite. Some cases of pleural infection have a more insidious history, dominated by weight loss, decreased appetite, and malaise. These symptoms are non-specific and compatible with myriad other conditions, including pleural malignancy. The average time between symptom onset and hospital presentation is more than two weeks.

Clinical examination usually reveals signs of a pleural effusion–that is, stony, dull percussion note in association with decreased breath sounds and reduced tactile fremitus. Fever, tachycardia, tachypnea, hypotension, and reduced oxygen saturation are frequently seen.

Beware: there are other diseases that can mimic pleural infection

Pleural malignancy

One of the most common mimics of pleural infection is malignant pleural disease. Patients with pleural malignancy often present with a low-grade fever in association with modestly elevated inflammatory markers and a pleural effusion. Biochemical analysis of such effusions may be indistinguishable from pleural infection, particularly in aggressive malignancy with a poor prognosis.

Pleural inflammation

Patients with other inflammatory conditions, such as rheumatoid arthritis, may present with a unilateral pleural effusion and elevated blood inflammatory markers in association with dyspnea, cough, chest pain, and constitutional symptoms. Pleural fluid pH and glucose are characteristically low, although there are often other indications of a rheumatoid arthritis flare.

Chylothorax and pseudo-chylothorax

These conditions produce milky-appearing pleural fluid that may be mistaken for pus as seen in empyema. Usually, the clinical condition of the patient suggests that pleural infection is unlikely, but, diagnostic doubt could be resolved by centrifugation of the pleural fluid demonstrating chyle and pseudochyle to remain cloudy, while pus sediments.

How and/or why did the patient develop pleural infection?

Development of a non-infectious effusion

A simple (non-infectious) parapneumonic effusion is thought to develop secondary to the ingress of pneumonia-associated leucocytes into the pleural space, resulting in an increase in intrapleural inflammatory cytokines (e.g., interleukin-8 and tumor necrosis factor-α), increased vascular permeability and development of a sterile exudative pleural effusion.

Progression to pleural infection

Conventional wisdom is that a complicated parapneumonic effusion develops when bacteria migrate across the visceral pleura. Bacteria create an intrapleural procoagulant state with increased levels of plasminogen activator inhibitor (PAI) and decreased tissue-type plasminogen activator (tPA). This procoagulant milieu stimulates fibrin deposition and septation development (also known as the “fibrinopurulent” stage of pleural infection).

Which individuals are at greatest risk of developing pleural infection?

Epidemiology

Pleural infection is more common in children and the elderly than in other cohorts. Several cohort studies have suggested that overall incidence is increasing, particularly in children. For example, one study demonstrated incidence rates increasing by 12 percent across all age ranges between 1995 and 2003.

In children, Streptococcus pneumoniae is the commonest cause of pleural infection. Since the licensing of the seven-valent pneumococcal conjugate vaccine (PCV7- active against serotypes 4, 6B, 9V, 14, 18C, 19F and 23F) in 2000, there is evidence that the non-vaccine serotype 1 is causing increasing numbers of cases of empyema and other invasive pneumococcal disease.

Recent novel genetic studies suggest that a variant of the protein tyrosine phosphatase (PTPN22 Trp620) is associated with susceptibility to invasive pneumococcal disease and gram-positive empyema.

There are four primary risk factors for pleural infection: diabetes, immunosuppression, alcohol misuse, and intravenous drug abuse. Anerobic pleural infection is particularly found in association with aspiration and poor oral hygiene.

A prospective study found several factors predictive of the development of pleural infection in patients with pneumonia;

Serum albumin less than 30 g/L
C-reactive protein greater than 100 mg/L
Platelet count greater than 400×10⁹/L
Serum sodium less than 130 mmol/L
Intravenous drug use
Alcohol misuse

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Laboratory blood tests

Patients should have standard hematological and biochemical blood tests, including C-reactive protein (CRP), total protein (TP), and lactate dehydrogenase (LDH). All patients should have peripheral blood cultures drawn, which are positive in about 15 percent of patients with pleural infection.

Laboratory pleural fluid tests

A pleural aspiration (thoracentesis) facilitates the analysis of pleural fluid. Various tests are routinely performed on pleural fluid: (Table 1)

Table 1.

Location	Request	Comment
Microbiology	Gram stain, culture and sensitivity analysis	Culture is positive in 40-60 percent of patients with pleural infection. Physicians should have a low threshold for requested specialized mycobacterial culture.
Microbiology	Culture of pleural fluid in “blood culture bottles”	Bedside inoculation of pleural fluid into aerobic and anaerobic blood culture bottles increases microbiological yield by about 20 percent compared with standard culture techniques.
Bedside	pH measurement	pH should be measured using an anticoagulated blood gas syringe and a point-of-care blood gas analysis machine. Intrapleural bacterial metabolism and host cell phagocytic activity utilizes glucose and produces lactic acid, producing the characteristic biochemical profile of pleural infection: low pleural fluid pH less than 7.2* and glucose with elevated lactate dehydrogenase (LDH). Care should be taken to expel excess heparin and to avoid contamination with lidocaine, both of which may give spuriously acidic pH values. Free air in the syringe may increase pH readings.
Biochemistry	Total protein (TP)	When paired with serum values, pleural fluid TP and LDH allow transudates and exudates to be distinguished using Light’s criteria (see below). Pleural infection is associated with exudative pleural effusions that characteristically have LDH greater than 1000U/L.
	LDH
	Glucose	According to the 2010 British Thoracic Society guidelines, pleural fluid glucose less than 40mg/dL (<2.2mmol/L) is associated with pleural infection, while the 2000 American College of Chest Physicians guidelines suggests less than 60mg/dL (<3.3mmol/L).
Cytology	Cytological examination	Given that some cases of pleural malignancy may mimic pleural infection (with low pH and glucose), cytological assessment of pleural fluid is advocated.

* Physicians should exercise caution in rigidly applying pH cut-off values to define pleural infection. Such caution is particularly important, as some organisms, such as the urea-spitting Proteus spp., may create an alkalotic pleural effusion and because different locules within a multi-loculated effusion have been shown to have varying pH values, some of which may lie on either side of the threshold value for drainage. A holistic approach that considers the pre-test probability of pleural infection (based on clinical history, blood tests, and imaging findings) should be used to inform pH values near the 7.2 threshold.

Light’s criteria for distinguishing between transudates and exudates

An exudate is defined as pleural fluid serum TP greater than 0.5, pleural fluid serum LDH greater than 0.6, or pleural fluid LDH greater than 0.67 of the serum LDH upper limit of normal.

Summary of parapneumonic effusion categorization based on laboratory tests

See Table 2.

Table 2.

	Simple parapneumonic effusions	Complicated parapneumonic effusions	Empyema
Appearance	Clear or slightly turbid	Usually cloudy	Pus
pH	≥7.20	<7.20	Not usually measured
Glucose	≥40mg/dL (2.2mmol/L)	<40mg/dL (2.2mmol/L)	Not usually measured
LDH	≤1000U/L	>1000U/L	Not usually measured
Microbiological positivity	No	~25%	~70%

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

Chest X-ray

Parapneumonic effusions are usually detectable on chest x-rays, often with accompanying consolidation. Complicated parapneumonic effusions/empyema are often loculated, sometimes with air-fluid levels. Given an infective presentation, the finding of a new encapsulated effusion in a non-dependent position is suggestive of pleural infection (Figure 1).

Thoracic ultrasound

Pleural ultrasonography can detect low volumes of pleural fluid with greater sensitivity than chest x-ray. Pleural ultrasonography facilitates accurate pleural fluid localization, which is particularly important given that infectious effusions are often loculated. Recent guidelines from the British Thoracic Society Pleural Diseases group, among others, suggest that ultrasound guidance should be utilized when sampling pleural fluid. Such guidance reduces the risk of organ perforation and iatrogenic pneumothorax while improving rates of fluid recovery (Figure 2).

Heavily echogenic fluid on ultrasound. Features demonstrate an exudate and are suggestive of pus (or blood).

The characteristics of sonographic pleural fluid further inform the nature of the effusion: Echogenic pleural fluid is exudative, and densely echogenic fluid suggests frank pus or intrapleural hemorrhage (Figure 3). Septations are associated with exudates and in effusions with a low pleural fluid pH, low glucose and high LDH. Studies have suggested a correlation between significant septations evident on ultrasound and drainage success, although septated effusions may still drain well (Figure 4).

Moderately septated parapneumonic effusion on ultrasound with underlying consolidation

A loculated pleural effusion typical of pleural infection, with a chest tube in situ. Underlying consolidation is sometimes difficult to discern.

Thoracic computed tomography

Pleural-phase contrast-enhanced thoracic CT is helpful in patients with ambiguous chest x-ray or sonographic appearance. The CT often shows that fluid is lenticular in shape with compression of surrounding lung parenchyma, and pleural thickening occurring in 56-100 percent of cases. In addition, increased attenuation is often seen in the extrapleural subcostal fat.

CT is useful in distinguishing between a peripheral pulmonary abscess and pleural infection. The “split pleura” sign found in pleural infection describes visceral and parietal pleural enhancement around infected pleural fluid that is not present in pulmonary abscess. However, unlike ultrasonography, CT is relatively insensitive at detecting pleural septation.

Practice point

While various pleural fluid imaging features may suggest pleural infection, the absence of such findings does not rule out infection, and most clinicians would advocate performing a diagnostic thoracentesis on pleural fluid with depth greater than 1 cm.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of pleural infection?

Chest ultrasonography is the diagnostic study with the most sensitivity in identifying a pleural effusion in association with pneumonia.

What diagnostic procedures will be helpful in making or excluding the diagnosis of pleural infection?

Thoracentesis with pleural fluid analysis is the most important test in detecting pleural space infection.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of pleural infection?

Pleural fluid analysis with fluid culture and gram stain is the most direct way of establishing a diagnosis of pleural infection. Frank plural pus also establishes the presence of infection. Other pleural fluid tests, such as low pleural fluid pH, low glucose, and high LDH, provide presumptive evidence of infection.

If you decide the patient has pleural infection, how should the patient be managed?

Having diagnosed pleural infection, physicians should address several treatment goals;

Initiation of prolonged broad-spectrum antibiotic therapy
Prompt pleural fluid drainage
Early surgical referral when required
Nutritional support
Prophylaxis against venothromboembolism

Antibiotic therapy

Patients should be initially treated with empiric broad-spectrum antibiotic therapy, particularly given that culture techniques may be negative and take several days to yield a result. The duration of antibiotic treatment has not been the subject of formal randomized trials, but it is commonplace to give a total of at least three weeks of antibiotics for pleural infection.

Initial therapy is usually with intravenous antibiotics for about one week, guided by clinical course and laboratory indices (e.g., white cell count and C-reactive protein). Empirical antibiotic therapy should be determined by considering whether the infection is community-acquired or healthcare-associated, the local prevalence of bacteria, and their resistance pattern.

Community-acquired pathogens are often covered by a beta-lactam antibiotic in conjunction with the beta-lactamase inhibitor, such as amoxicillin and clavulanic acid or piperacillin-tazobactam. Metronidazole is often given to increase anaerobic coverage. Healthcare-associated pleural infection is often associated with resistant bacteria, including gram-negative enteric bacteria and MRSA. A reasonable choice of antibiotic is a carbapenem combined with vancomycin.

Given the excellent pleural penetration of most intravenous and oral antibiotics, intrapleural antibiotic administration is not used.

Prompt pleural fluid drainage

Pleural infection (complicated parapneumonic effusions or empyema) requires prompt tube drainage to prevent increased morbidity. Non-infectious simple parapneumonic effusions do not usually require drainage. Traditionally, large-bore chest tubes were used to drain empyema pus, but recent evidence and clinician practice suggest that small-bore tubes (<15 F) have a similar efficacy, and they are associated with less pain.

Chest tubes should be inserted with image guidance (usually ultrasound) because that infected pleural spaces are often loculated. Clinical examination alone predicts the pleural fluid location poorly and causes organ perforation in about 10 percent of cases. Ultrasound-inserted chest drains are associated with fewer complications, particularly iatrogenic pneumothorax.

A chest tube flush regime (such as 20mL 0.9% sodium chloride solution every six hours) is often used with a small-bore chest tube and thoracic suction using a dedicated thoracic suction unit should be considered.

Adjunctive intrapleural medication

Recent research has examined the potential role of intrapleural fibrinolytics in improving the drainage of poorly resolving pleural infection, particularly those that are heavily septated. Small studies had suggested that streptokinase, a bacterially derived fibrinolytic, may improve pleural fluid drainage when instilled into the pleural space. However, a large randomized trial, MIST-1 (multicenter intrapleural sepsis trial), showed that streptokinase did not improve mortality, surgical requirement, hospital stay, lung function, or radiologic outcome.

Despite this first negative study, the scientific hypothesis and supporting evidence from animal models for fibrinolytics was felt to be strong. The subsequent MIST-2 trial examined a different fibrinolytic (tPA -tissue plasminogen activator) in combination with recombinant human DNase (deoxyribonuclease) to decreased fluid viscosity. This combination of intrapleural t-PA–DNase therapy improved fluid drainage and reduced the frequency of surgical referral and the duration of the hospital stay. Treatment with DNase or t-PA alone was ineffective.

Intrapleural t-PA–DNase therapy is now used in some centres for patients who do not respond to initial therapy of intravenous antibiotics with chest tube drainage and where surgical therapy is inappropriate or there is an anticipated delay.

A pilot study investigated the use of irrigating the pleural space with physiological (0.9%) saline to break down septations. The PIT study instilled 250 ml of 0.9% saline into the pleural space via a chest drain three times a day and allowing it to drain out freely. This technique was found to improve pleural fluid drainage and reduce surgical referrals. Future studies are required to support these early encouraging findings.

Early surgical referral when required

Thirty percent of patients have ongoing sepsis and poorly resolving pleural fluid despite optimal medical management. These patients should be considered for an early surgical opinion. There is no evidence concerning the timing or clinical criteria for such referrals, although the patient’s failure to improve clinically and radiologically after seven days of treatment is often used. Conversely, patients who have some residual pleural fluid but are otherwise well and have improving clinical and laboratory parameters normally see gradual resolution of their pleural fluid over time.

Video-assisted thoracoscopic surgery (VATS) enables decortication of pleural thickening, septation division, and pleural fluid removal, thereby allowing lung re-expansion. VATS is usually performed under general anesthesia with single lung ventilation, although some centers prefer regional anesthesia (epidural or paravertebral blocks). Thoracotomy has slightly higher success rates than VATS, although it is more invasive and associated with greater morbidity and mortality, particularly in older patients.

Some patients who are unfit for general anesthesia may be considered for local anesthetic rib resection, allowing chronic open surgical drainage and gradual withdrawal of chest tubes over several months. This strategy is associated with considerable risk, including ventilatory failure (worsened by chronic pneumothorax) and secondary infection.

Several trials have examined the role of primary VATS versus chest tube drainage on initial presentation of pleural infection. Methodological limitations mean that definitive evidence is lacking, although there may be a reduction in length of hospital stay associated with primary VATS.

Thoracoscopic drainage, under conscious sedation and local anaesthetic, has been use for patients who are not fit for a general anaesthetic by both surgeons and respiratory physicians in small studies.

Nutritional support

Weight loss and low serum albumin concentration, the latter of which is associated with a poorer outcome, are commonplace in pleural infection. While specific nutritional therapy has not been subjected to formal trials in this setting, nutritional support, including nasogastric feeding in selected cases, is likely to be important in counteracting the catabolic state associated with parapneumonic effusion.

Prophylaxis against venothromboembolism

Given the sepsis and relative immobility associated with pleural infection, inpatients should receive regular thromboprophylaxis with a low molecular weight heparin unless contraindicated.

What is the prognosis for patients managed in the recommended ways?

Hospital stay

Median duration of inpatient care is fifteen days, with 20 percent of cases requiring inpatient stays longer than one month.

Morbidity and mortality

Pleural infection is associated with significant morbidity and mortality, as about 20 percent of patients die, and about 15 percent of patients require surgery to treat their pleural infection. Healthcare-associated infection has poorer outcomes than community-acquired infection does. Even so, provided that patients survive to one year, long-term outcomes are favorable. Radiographic pleural abnormalities often take many months to resolve, but they are usually not associated with symptomatic impairment. About 10 percent of patients develop variable degrees of pleural thickening, which are usually of no functional significance. The development of significant pleural fibrosis sufficient to cause activity restriction is rare.

A prognostic scoring system, the RAPID score, was formulated and validated with the MIST1 and MIST 2 trials respectively. Age, urea, albumin, hospital-acquired infection, and non-purulence predicted poor outcome. Patients were stratified into a low to high risk score, with a high-risk score associated with increased mortality.

What other considerations exist for patients with pleural infection?

Patients with compromised lung function, as occurs with severe pneumonia, lung cancer, or COPD, require general support to prevent respiratory compromise.

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