Parapneumonic Pleural Effusions and Empyema Thoracis

Background

Pleural effusions are a commonly noted in patients diagnosed with pneumonia. They can be noted in 14-44% of patients admitted for pneumonia, and 40% of these cases could be complicated by parapneumonic effusion or abscess.^[1]  In most patients, treatment with antibiotics leads to resolution; however, some patients may develop a more fibrinous reaction, with the presence of frank pus in the most severe cases (referred to as empyema or empyema thoracis).

Virtually any type of pneumonia (eg, bacterial, viral, or atypical) can be associated with a parapneumonic pleural effusion. However, the relative incidence of parapneumonic pleural effusions varies with the causative organism. Viral pneumonia and mycoplasmal pneumonia cause small pleural effusions in 20% of patients. For thoracic empyema, bacterial pneumonia is the cause in 70%.^[2]

Increasingly, empyema thoracis is a complication of previous surgery, which accounts for 30% of cases. Trauma may also be complicated by infection of the pleural space. In the absence of trauma or surgery, the infecting organism may spread from blood or other organs into the pleural space. These infections can develop into subdiaphragmatic abscesses, a ruptured esophagus, mediastinitis, osteomyelitis, pericarditis, cholangitis, and diverticulitis, among other conditions.

Classification

Parapneumonic pleural effusions are classified into three broad groups on the basis of fluid characteristics, which, in turn, provides a reflection on both the severity and natural history of the pleural effusion.

Uncomplicated parapneumonic effusions

These are usually small to moderate-sized free-flowing, exudative, predominantly neutrophilic effusions, reflecting an early inflammatory phase associated with the pneumonia that leads to increased passage of interstitial fluid and neutrophils. The fluid may be slightly cloudy or even clear, with no organisms noted on Gram stain or culture. This subtype often resolves with appropriate antibiotic treatment of the pneumonia, without the need for drainage.

Complicated parapneumonic effusions

These are usually moderate-sized to large effusions characterized by increasingly turbid fluid, without or without septations and locations. They occur because of bacterial invasion into the pleural space that leads to an increased number of neutrophils, decreased glucose levels (< 60 mg/L), pleural fluid acidosis (pH < 7.2), and an elevated lactic dehydrogenase (LDH) concentration. The effusions often are sterile. This subtype requires drainage in addition to appropriate antibiotics for resolution.

Empyema thoracis

This develops as frank pus accumulates in the pleural space as a consequence of accumulation of bacterial and inflammatory cell debris. The pus is seen after thoracocentesis or any drainage procedure of the pleural space; it is generally characterized as thick, viscous, and opaque, and it is often associated with a putrid odor. This subtype often requires drainage via chest tube, with or without fibrinolytic therapy, in addition to appropriate antibiotics.

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Pathophysiology

The evolution of a parapneumonic pleural effusion (see the image below) can be divided into the following three stages^[2] :

• Exudative
• Fibrinopurulent
• Organization

View Image

Left pleural effusion developed 4 days after antibiotic treatment for pneumococcal pneumonia. Patient developed fever, left-side chest pain, and incre....

During the first (ie, exudative) stage, sterile pleural fluid rapidly accumulates in the pleural space. This fluid originates in the interstitial spaces of the lung and in the capillaries of the visceral pleura as a consequence of increased permeability. The pleural fluid has a low white blood cell (WBC) count and a relatively low LDH level. Its glucose and pH levels are within the reference range. These effusions resolve with antibiotic therapy, and chest tube insertion is not required. This stage takes approximately 2-5 days from the onset of pneumonia.

In the second (ie, fibrinopurulent) stage, bacterial invasion of the pleural space occurs, with accumulation of polymorphonuclear leukocytes, bacteria, and cellular debris. A tendency toward loculation and septation exists, pleural fluid pH (< 7.20) and glucose levels are lower (< 60 mg/dL), and LDH levels increase. At this stage, bacteriologic stains or cultures of the pleural fluid can be positive for microorganisms. This stage takes approximately 5-10 days after pneumonia onset.

In the third (ie, organization) stage, fibroblasts grow into the exudates from both visceral and parietal pleural surfaces, producing an inelastic membrane called a pleural peel. the pleural fluid is thick. In an untreated patient, pleural fluid may drain spontaneously through the chest wall (ie, empyema necessitatis [necessitans]). Empyema thoracis may arise without an associated pneumonic process (eg, from esophageal perforation, trauma, a surgical procedure in the pleural space, or bloodstream infection [BSI]). This final stage may take 2-3 weeks to develop.

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Etiology

Pneumonia is the leading cause of parapneumonic effusions and empyema thoracis. Increasingly, empyema is also a complication of previous cardiothoracic surgery, which accounts for 30% of cases. The usual organisms are Staphylococcus species and gram-negative bacteria. Trauma can also lead to inoculation and superinfection of the pleural space.

In the absence of trauma or surgery, the infecting organism may have spread from blood or other organs into the pleural space. Possible causes include extension of infections from adjacent or distant sites (eg, ruptured esophagus, mediastinitis, osteomyelitis, pericarditis, cholangitis, diverticulitis, or pericarditis) and subdiaphragmatic abscesses.

Microbiology

The microbiologic etiology of culture-positive parapneumonic pleural effusions has changed over time and varies according to the parapneumonic or nonparapneumonic nature of infection.^{[3, 4, 5]} Before the antibiotic era, Streptococcus pneumoniae was the most common isolate. At present, S pneumoniae and Staphylococcus aureus account for approximately 70% of aerobic gram-positive cultures. Aerobic organisms are isolated slightly more frequently than anaerobic organisms. Streptococcus milleri has also become more common.

Klebsiella, Pseudomonas, and Haemophilus species are the most frequently isolated aerobic gram-negative organisms in this setting; Bacteroides and Peptostreptococcus species are the most commonly isolated anaerobic organisms. Currently, empyema thoracis is most often associated with aspiration pneumonia characterized by a mixed bacterial flora containing both aerobes and anaerobes.^[6]  S aureus is the organism usually isolated in hospital-acquired empyema and in cases occurring as complications after surgery.

Tuberculous effusions are relatively uncommon in developed nations but are frequently noted worldwide and should be considered in specific populations (eg, patients from regions where tuberculosis [TB] is endemic and patients with a history of TB at risk for reactivation).^[7]

Fungal infections are relatively rare as well but should be considered in immunocompromised patients.

Risk factors

Risk factors for empyema thoracis include age (children and elderly persons), debilitation, pneumonia requiring hospitalization, and comorbid diseases, such as bronchiectasis, rheumatoid arthritis, alcoholism, diabetes, and gastroesophageal reflux disease.^[2]

A large prospective observational study in the United Kingdom used multivariate regression analysis to identify seven clinical factors predicting the development of complicated parapneumonic pleural effusions or empyema thoracis.^[8] An albumin value lower than 30 g/L, a serum sodium value lower than 130 mmol/L, a platelet count higher than 400 × 10⁹/L, a C-reactive protein (CRP) level higher than 100 mg/L, and a history of alcohol abuse or intravenous (IV) drug use were found to be independently associated with the development of complicated parapneumonic pleural effusions or empyema thoracis, whereas a history of chronic obstructive pulmonary disease (COPD) was associated with a decreased risk.

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Epidemiology

US and international statistics

Hospital discharge data indicate that in the United States, approximately 1.3 million patients are hospitalized with pneumonia every year. The prevalence of parapneumonic effusions is dependent, in part, on the organism involved.

Overall, pleural effusions are seen in about 35-40% of patients with bacterial pneumonia or anaerobic pneumonia, with a prevalence approaching 60% in pneumococcal pneumonia. Complicated pleural effusions are more common with anaerobic pleuropulmonary infections. This results in an estimated 500,000-750,000 patients with parapneumonic effusions annually. No good estimates are available regarding how many of these patients proceed to complicated effusions or empyema, but in small series, approximately 5-10% have been found require drainage or a surgical procedure.

A study of US hospitalization data found that in 1996, the national hospitalization rate for parapneumonic empyema–related diagnoses was 3.04 per 100,000; by 2008, it had increased to 5.98 per 100,000, and by 2016, it had increased to 11.1 per 100,000.^[9]  The empyema hospitalizations had a high cost per case ($38,591) and required a prolonged stay (13.8 d). Over the study period, a downward trend in length of stay and a small reduction in associated mortality were not, possibly due to increasing use of innovative treatments (eg, surgery or intrapleural enzymatic therapy).

No good estimates are available on the international incidence of pneumonia. The World Health Organization (WHO) cited a figure of 4.2 million for cases involving death from lower respiratory tract infections in 2004. From this figure, it is possible to extrapolate the incidence of pleural effusions and empyema using a US estimate, but caution is advised because lack of treatment and delayed treatment in developing countries may skew the international incidence upward.

Age-, sex-, and race-related demographics

In a 2021 report from the American College of Chest Physicians (ACCP), 60% of the hospitalizations related to pleural infections were found to occur in the 18- to 64-year-old age group.^[9] In the United Kingdom and Europe, this age group accounted for 40% of adult pleural infections.^[10]  Advancing age leads to an increase in associated comorbidities, including a higher risk of pneumonia and, subsequently, pleural effusions and empyema.

In the 2021 ACCP report, a male predominance in adult pleural infections was noted.^[9] Plausible hypotheses for this difference include the following^{[10, 9]} :

• Gender differences in health-seeking behaviors, with a delayed presentation in males
• Worse dental hygiene trends
• Greater frequency of preexisting comorbidities in males

No specific ethnic or racial predisposition is recognized for empyema; however, a larger number of ethnic minorities have limited financial resources, less access to healthcare, and more comorbidities, which, in turn, may increase their risk of pneumonia, pleural effusions, and empyema.

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Prognosis

The prognosis for patients with parapneumonic effusion can be defined in terms of four categories derived from the ABC classification published by the ACCP in 2000.^[11] This classification is based on three characteristics of pleural fluid—namely, pleural space anatomy (A), fluid bacteriology (B) and fluid chemistry (C)—as follows: 

• Category 1 (very low risk, with no drainage indicated) - A0 (minimal free-flowing effusion < 10 mm on lateral decubitus), Bx (culture and Gram stain results unknown), and Cx (pH unknown)
• Category 2 (low risk, with no drainage indicated) - A1 (small to moderate-sized free-flowing effusion >10 mm and < one half hemithorax), B0 (negative culture and Gram stain), and C0 (pH ≥7.20)
• Category 3 (moderate risk, with drainage indicated) - A2 (large free-flowing effusion ≥ one half hemithorax, loculated effusion, or effusion with thickened parietal pleura), B1 (positive culture and Gram stain), and C1 (pH < 7.20)
• Category 4 (high risk, with drainage indicated) - Presence of frank pus in pleural space

Additional scoring systems, such as RAPID (renal, age, purulence, infection source, and dietary factors), can help identify patients at risk of poor outcome at presentation).^{[12, 10]}  This clinical risk score, derived from the first Multicenter Intrapleural Sepsis Trial (MIST1), stratified patients into low-risk (0-2), medium-risk (3-4), and high-risk (5-7) groups. A RAPID score of 3-4 was associated with an odds ratio (OR) of 24.4 for death at 3 months, whereas a score higher than 4 was associated with an OR of 192.4. 

Most patients recover in the early stage, but mortality remains approximately 10%. Appropriate antibiotic therapy and early drainage of pleural fluid, when indicated, are crucial for recovery. Approximately 15-25% of patients require surgical intervention, including decortication or an open drainage procedure, especially in categories 3 and 4

Historically, mortality figures for empyema have been reported to range from 11% to 50%. The width of this range is due in part to limited data, with mortality being higher (~50%) at a time when current diagnostic imaging, antibiotics, and drainage options were not readily available. Other complicating factors include cardiac and respiratory comorbidities, immunosuppressive states related to medications or HIV infection, and age. Death rates related to pneumonia are higher in elderly persons and in those with the outlined underlying comorbidities. Reports from the 2000s have estimated mortality from pneumonia and complicated pleural effusions to be in the range of 7-10%.^[13]

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History

Clinical manifestations of parapneumonic effusions and empyema largely depend on whether the patient has an aerobic or anaerobic infection. Aerobic infections are more acute in onset and give rise to acute febrile symptoms, whereas anaerobic infections can be indolent in their time course and give rise to nonspecific symptoms with low-grade fever. If fever persists for more than 48 hours after the initiation of antibiotic treatment, a complicating parapneumonic effusion or empyema is likely.

Aerobic infection

The clinical presentation of patients with aerobic bacterial pleural-space infection is similar to that of patients with bacterial pneumonia. Patients present with an acute febrile illness with chest pain, sputum production, and leukocytosis. A complicated parapneumonic effusion is suggested by the presence of a fever lasting more than 48 hours after the initiation of antibiotic therapy.

Anaerobic infection

Patients with anaerobic bacterial infections involving the pleural space usually present with a subacute illness. Most of these patients have symptoms persisting for more than 7 days. Approximately 60% of patients have lost weight. Anemia is also common. Patients are likely to have poor oral hygiene and dental infections, chronic alcoholism, or other factors that predispose them to recurrent aspiration.

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Physical Examination

Most patients are febrile with tachypnea and tachycardia, often appearing toxic and fulfilling criteria for the systemic inflammatory response syndrome (SIRS). Signs of pleural effusion upon physical examination include the following:

• Decreased or absent breath sounds
• Dullness to percussion
• Decreased tactile fremitus
• Evidence of tension and contralateral tracheal shift possible with large effusions

In areas where pneumonia and lung consolidation are adjacent and more extensive than pleural fluid, findings include rales or crackles, bronchial breath sounds or egophony, or a combination.

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Laboratory Studies

No specific laboratory studies of the serum suggest the presence of a parapneumonic effusion or empyema. The typical features of infection may be present, such as leukocytosis, elevated markers of infection such as C-reactive protein (CRP), or bacteremia. However, the possibility of a parapneumonic effusion and empyema should be a consideration for every patient with pneumonia. The presence of pleural fluid may be suggested on the basis of physical findings; however, small pleural effusions may not be detected during the physical examination

Even though no serum laboratory tests are diagnostic of a parapneumonic effusion, serum total protein and lactic dehydrogenase (LDH) levels should be obtained to help determine whether the pleural fluid is an exudate or transudate. The ratio of pleural fluid/serum protein to LDH is used to distinguish between these two entities.

Sputum should be submitted for culture, especially if it is purulent. The infecting organism may be suggested by Gram stain results. A mixed flora is often seen in anaerobic infections.

As with any infection, leukocytosis may be present (>12,000/µL); however, it should decrease with adequate antibiotic therapy. Persistent fever and leukocytosis despite adequate antibiotic therapy may signal a persistent focus of infection (eg, complicated parapneumonic effusion or empyema), with subsequent evaluation as outlined in the following sections. Diagnosing a complicated parapneumonic effusion or empyema is crucial for optimal management because a delay in drainage of the pleural fluid substantially increases morbidity.

A retrospective study from a single center determined that pleural cytology has no additional value over traditional markers for distinguishing a complicated parapneumonic effusion from an uncomplicated parapneumonic effusion.^[14]

A small study determined that combining semiquantitative polymerase chain reaction (PCR) assay with next-generation sequencing of pleural fluids can help diagnose parapneumonic effusions and empyema and identify the causative bacteria.^[15]

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Chest Radiography

Lateral chest radiography usually demonstrates the presence of a significant amount of pleural fluid (see the image below).

View Image

Left lateral chest radiograph shows large left pleural effusion.

If either of the diaphragms is not visible throughout its entire length, the posterior costophrenic angles are blunted, or a lateral meniscus is visible, then bilateral decubitus chest radiographs should be obtained.

Free pleural fluid is seen as a dense linear shadow layering between the chest wall and the lung parenchyma.

Unchanging pleural-based linear densities, pleural-based masslike densities, or collections with obtuse angles suggest the presence of loculated fluid, especially if the differences in the fluid or the appearance between upright and lateral views are minimal.

If the pleural fluid distance measures more than 10 mm from the chest wall, sufficient free-flowing fluid is present to perform a diagnostic thoracentesis.

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Ultrasonography

Ultrasonography (US) can be employed to localize fluid for thoracocentesis. Fluid appears dark or black on ultrasonograms, and most bedside US devices permit measurement of the depth of its location from the chest wall. Other structures (eg, diaphragm or lung parenchyma) can provide landmarks to assist in needle placement for thoracentesis.

Complex fluid (purulent or viscous) may have more density or shadows within in the pleural fluid collection. Sometimes, fibrinous strands can be seen floating in the pleural fluid.

Loculated pleural effusions may be difficult to localize during physical examination, but they can usually be identified by means of US. US can effectively distinguish loculated pleural fluid from an infiltrate. The latter may have air bronchograms visible, but the distinction may be difficult if a dense consolidation is present. If a loculated pleural effusion is suspected, US examination is recommended for diagnosis and for marking the area for thoracocentesis.

View Image

Ultrasonogram of pleural space shows densely septated loculation in pleural space.

The 2017 American Association for Thoracic Surgery (AATS) guidelines for management of empyema recommended US in addition to chest radiography for diagnosis and for guidance of pleural interventions.^[16]  The 2023 European Respiratory Society (ERS)/European Society of Thoracic Surgeons (ESTS) statement on the management of pleural infection in adults found US to be adequate for initial assessment, clinical decision making and guiding diagnostic sampling.^[10]  The 2024 American College of Radiology (ACR) Appropriateness Criteria® for the workup of pleural disease included no recommendation regarding US for initial imaging, because of insufficient evidence of benefit.^[17]

US has been reported to outperform computed tomography (CT) in the identification of septated pleural effusion. In a study of 285 patients with suspected pleural effusion, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for diagnosing septated pleural effusion were higher with US than with CT (82.6% vs 59.8%, 100.0% vs 87.0%, 100.0% vs 68.8%, and 92.3% vs 82.0%, respectively).^[18]

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Computed Tomography

CT of the chest with contrast (see the images below) enhances the pleural surface and assists in delineating the pleural fluid loculations. The 2017 AATS guidelines recommended CT when pleural infection is suspected.^[16] The 2023 ERS/ESTS guidelines recommended contrast CT of the chest if pleural sepsis extends beyond 48 hours.^[10]

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CT scan of thorax shows loculated pleural effusion on left and contrast enhancement of visceral pleura, indicating etiology is likely empyema.

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Chest CT scan with intravenous contrast in patient with mixed Streptococcus milleri and anaerobic empyema following aspiration pneumonia, showing thic....

Pleural enhancement can be seen in patients with active inflammation and severe pleuropulmonary infections, providing another sign of the possibility of a complicated pleural effusion or empyema. The split pleura sign on contrast-enhanced chest CT, often seen in empyema, is enhancement of both pleural surfaces separated by a fluid collection (see the image below).

View Image

Chest CT scan with intravenous contrast (axial, coronal, and sagittal views) of alcoholic male patient with anaerobic empyema demonstrating split pleu....

CT of the chest may also help detect airway or parenchymal abnormalities, such as endobronchial obstruction or the presence of lung abscesses.

The 2024 ACR Appropriateness Criteria® for the workup of pleural disease stated that chest radiography and CT with IV contrast are usually appropriate and are equivalent alternatives for the initial imaging of suspected parapneumonic effusion or empyema.^[17] If CT is performed, imaging should occur 60 seconds after the IV contrast is administered so as to yield improved pleura images.

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Procedures

Thoracocentesis and evaluation of pleural fluid

A diagnostic thoracentesis is recommended for pleural fluid sampling when the effusion is suspected to be parapneumonic in nature. With the routine bedside use of US guidance for localization, there is no minimum safe size of effusion that should deter the procedure if it is clinically indicated. This determination, however, should be made on the basis of the clinician's skill level. Generally, pleural effusion greater than or equal to 10 mm thick on a lateral decubitus chest radiograph is considered safe.^[19]  For large-volume pleural effusion, the procedure may also serve a therapeutic purpose in relieving the dyspnea related to the effusion.

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Right lateral decubitus chest radiograph shows free-flowing pleural effusion, which should be sampled with thoracentesis for pH determination, Gram st....

Assessment of gross appearance

Pleural fluid may range in appearance from a clear yellow liquid to an opaque turbid fluid to grossly purulent thick, viscous, foul-smelling pus. Foul-smelling fluid indicates an anaerobic infection.

Pleural fluid testing

Studies used in the evaluation of pleural fluid include the following:

• Cell count and differential - Results generally are not diagnostic, but most transudates are associated with a white blood cell (WBC) count lower than 1000/µL; in contrast, elevated cell counts with neutrophil predominance are typically noted in the early inflammatory phase of complicated parapneumic effusions, including empyema (>50,000/µL); simple parapneumonic effusions (>10,000/µL); and chronic exudative effusions, such as tuberculosis (< 5000/µL)
• Pleural fluid chemistry - Total protein, LDH, and glucose (in addition to the corresponding serum protein and LDH) should be requested on all samples; exudates are defined according to Light's criteria, with the presence of one criterion being sufficient for classifying fluid as an exudate^[20]
• Pleural fluid pH (collected in blood gas syringe and transported on ice to be analysed on a blood gas analyzer within 1 hour) - Values lower than 7.20 suggest a complicated pleural effusion^{[16, 10]}
• Pleural fluid cytology - This can help rule out malignancy, in addition to some uncommon pathogens (eg, Actinomyces and Nocardia)
• Other laboratory results suggestive of complicated pleural effusion or empyema - LDH >1000 U/L, pH < 7.00, and glucose < 40 mg/dL

Gram staining and culture

Pleural fluid is cultured in the aerobic and anerobic blood culture bottles, ideally at the time of collection so as to maximize diagnostic yield.^[21] An additional sample in a sterile container should be collected for Gram stain analysis or for inoculation by laboratory personnel if institutional policy does not accept the culture bottles inoculated at bedside. Blood cultures may reveal concomitant bacteremia and thus help identify the culprit pathogen. Culture yields a diagnosis in only about 60% of cases, for several reasons: Some organisms are difficult to culture, sterile pockets may exist adjacent to infected pockets in loculated effusions, or samples may have been obtained after initiation of antibiotic therapy.^[22]

Acid-fast bacilli and fungal infections may cause pleural effusions or empyema, but these organisms are even more difficult to culture from pleural fluid.

Commercial tests for molecular analysis of pathogens may be helpful in the evaluation of pleural fluids. Such tests (including multiplex bacterial PCR) are widely available for testing on blood samples. They have been investigated for use in pleural effusions; one study found multiplex bacterial PCR to be more sensitive than traditional culture-based tests for the identification of pathogens in pleural fluid.^[23]  

Serum and pleural fluid biomarkers

Several serum and pleural fluid biomarkers have been evaluated for the purpose of distinguishing parapneumonic pleural effusions from other causes of exudative effusions or distinguishing complicated from uncomplicated parapneumonic pleural effusions in nonpurulent effusions. Of these biomarkers, the most promising and most readily applicable one is CRP in both pleural fluid and serum. A pleural fluid CRP value higher than 100 mg/L or a serum CRP value higher than 200 mg/L has been shown to increase the chance of complicated parapneumonic pleural effusion and predicting the need for a drainage procedure.^{[24, 25, 26]}

The data on pleural fluid procalcitonin have been less consistent; this biomarker was found to be not very sensitive in a systematic review and meta-analysis,^{[26, 27]}  though it is widely available in many laboratories.

Other biomarkers are pleural fluid tumor necrosis factor (TNF)-α,^[28] pleural fluid defensins,^[29] pleural fluid neutrophil gelatinase–associated lipocalin (NGAL),^[30] serum and pleural fluid matrix metalloproteinases (MMP-2, MMP-8, MMP-9),^[31] pleural fluid myeloperoxidase,^[32] and pleural fluid pentraxin-3 (PTX3).^{[33, 34]}  To date, most studies have been limited by small sample sizes, a lack of confirmatory findings, unproven superiority to traditional pleural biochemistries, and limited availability of the biomarker test.

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Histologic Findings

Multiple granulocytes are typically identified on histologic examination. Necrotic debris may be present. In severe infections, bacteria are seen in the pleural fluid.

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Approach Considerations

Antibiotic therapy and drainage constitute the initial management of complicated pleural effusion. In many cases, however, a more aggressive approach is required, involving one of the following: 

• Intrapleural enzymatic therapy^[10] (IET) - 10 mg of tissue plasminogen activator (TPA) and 5 mg of deoxyribonuclease (DNase) delivered twice a day through the chest tube, left in the pleural cavity for 1 hour, and followed by drainage; this is often intiated and managed by a pulmonary specialist or a thoracic surgeon to monitor clinical reponse and potential adverse effects.
• Surgery - This often entails a surgical decortication^[16] performed by a thoracic surgeon via either an open approach or video-assisted thoracoscopic surgery (VATS); additionally, medical thoracoscopy performed by an interventional pulmonologist has been noted to be a safe and effective minimally invasive endoscopic technique for treating severe pleural infection

Consensus guidelines on the management of community-acquired pneumonia (CAP), hospital-associated pneumonia (HAP), ventilator-associated pneumonia (VAP), and healthcare-associated pneumonia (HCAP) in adults have been published by the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS).^{[35, 36]}

Recommendations for the management of pleural infection and empyema have been published by the American Association for Thoracic Surgery^[16] (AATS)^[16] and the European Respiratory Society (ERS)/European Society for Thoracic Surgery (ESTS).^[10]

Medical vs surgical care

At present, there is only a limited amount of direct comparative data on medical care with a combination of chest tube drainage and intrapleural enzymatic therapy vs surgical management with early VATS. However, several trials are under way that could shed light on this issue in coming years.

In 2023, the third Multicenter Intrapleural Sepsis Trial (MIST3), a study aimed at assessing the feasibility of randomization in a comparison of surgery with no surgery, concluded.^[37] The phase III randomized controlled trial (RCT) enrolled 97 patients, of whom 60% were eligible to be randomized to one of the following three treatment arms:

• Continued standard care
• Early IET
• A surgical opinion with regard to early VATS

The median time to intervention was 1.0 day in the IET group and 3.5 days in the surgery group.^[37] Despite this difference, the length of stay from randomization was similar in the two intervention arms (7 d) as compared with the standard care arm (10 d). The IET group had a larger improvement in the mean EuroQol five-dimension health utility index from baseline (0.35) to 2 months (0.83). Although the coronovirus pandemic posed logistical challenges, the study met its feasibility criteria and demonstrated a potential shorterning of length of stay with early surgery, as well as an earlier resolution of pain and shortened recovery with IET.

A 2023 pilot RCT enrolled 20 patients with 1:1 randomization to either intrapleural fibronolytic therapy (IPFT) or surgery.^[38] The median duration of chest tube use in the IPFT group (5 d) was found to be comparable to that in the surgery group (4 d). The median hospital stay was longer in the IPFT group (11 d) than in the surgery group (5 d), though the difference was not statistically significant. No 30-day readmissions or 30- or 90-day deaths were reported.

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Medical Care

The initial treatment of a patient with pneumonia and pleural effusion involves two major decisions. The first decision involves selection of an appropriate antibiotic that will cover likely pathogens; the second involves determination of the need for drainage of pleural fluid. 

Antibiotic therapy

The initial antibiotic selection is usually based on whether the patient has CAP or HAP and on the severity of the patient's illness.

For a patient with CAP, the recommended agents are second- or third-generation cephalosporins in addition to a macrolide. For patients hospitalized with severe CAP, treatment is initiated with a macrolide plus a third-generation cephalosporin that has antipseudomonal activity. Enteric gram-negative bacilli frequently cause pneumonia acquired in institutions (eg, hospitals and nursing homes); therefore, initial antibiotic coverage for HAP should include an antibiotic effective against pseudomonads. If aspiration is evident or suspected, coverage for oral anaerobic microorganisms should be provided.

The duration of the course of antibiotics depends primarily on the type of effusion, with uncomplicated effusions requiring 1-2 weeks, complicated effusions requiring 2-3 weeks, and empyema requiring 4-6 weeks. Other factors influence the duration as well, including clinical or radiographic response, drainage of effusion, and immunocompromised status.

In two RCTs that compared the effectiveness of shorter courses of antibiotics with that of longer courses in the treatment of community-acquired pleural infections, the shorter courses were found to be to be equally effective and to cause fewer adverse effects in patients who did not require surgery.^{[39, 40]}

Effusions with pleural fluid layering less than 10 mm on decubitus chest radiographs almost always resolve with appropriate systemic antibiotics. Patients with pleural effusions that have a pleural fluid layering greater than 10 mm on lateral decubitus radiographs should have a diagnostic thoracocentesis unless there is a contraindication to the procedure. If the diagnostic thoracentesis yields thick pus, the patient has an empyema thoracis and definitive pleural drainage is absolutely required. If the pleural fluid is not thick pus, then results of pleural fluid Gram stain or culture, pleural fluid pH and glucose levels, and the presence or absence of pleural fluid loculations should guide the course of action.^[19]

The 2023 ERS/ESTS guidelines made the following recommendations for an optimal antibiotic strategy to treat pleural infections^[10] :

• An initial intravenous (IV) course of 5-7 days is commonly administered to dampen the initial systemic inflammatory response
• A total course of at least 3 weeks is recommended, based on clinical, biochemical and radiologic response
• The choice of antibiotic depends on whether the infection is community- or hospital-acquired
• For fungal pleural infection, nonliposomal formulations of antifungal therapy are preferred to liposomal formulations

Pleural fluid drainage via chest tube

It is recommended to drain the complicated parapneumonic pleural effusion or empyema thoracis as soon as possible. A delay in removal can lead to the formation of loculated pleural fluid.

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Chest CT scan with intravenous contrast in patient with mixed Streptococcus milleri and anaerobic empyema following aspiration pneumonia, 3 days follo....

The clinician should attempt to position the chest tube in a dependent part of the pleural effusion. Historically, large-bore (38-32F) tubes were recommended, but smaller tubes have been found to be similarly effective.^[10] These can be placed with either a guide wire–assisted serial dilatation technique or the more traditional technique of cutdown followed by blunt dissection.

Smaller pigtail catheters (8-14F) can also be placed under the guidance of either ultrasonography (US) or computed tomography (CT). These should be considered for smaller, difficult-to-access, multiple-loculated effusions and for nonloculated, nonpurulent effusions. They have also been successfully used for draining empyemas. The variation in success rates for these catheters (72-82%) is associated with patient selection, operator expertise, and the stage of the parapneumonic pleural effusions. The major advantages of small-bore catheters are better patient tolerance and avoidance of major complications.^[2]

Closed chest tube drainage should be continued as long as clinical and radiologic improvement are observed. The chest tube can be removed once the volume of the pleural drainage is less than 100 mL/24 hr, with clearance of the pleural fluid turbidity seen in complicated pleural effusions.

If the patient does not demonstrate clinical or radiologic improvement with declining pleural fluid drainage, US of the pleural space or CT of the chest should be performed to look for pleural fluid loculations and ensure proper tube placement.

Undrained pleural fluid may respond to intrapleural thrombolytic therapy or may necessitate placement of another tube. Closed chest tube drainage yields satisfactory results in approximately 60% of patients with aerobic infections and 25% of patients with anaerobic infections.

Intrapleural thrombolytic agents

Since the 1970s, several studies have reported success of thrombolytic therapy for loculated complicated parapneumonic pleural effusions.^{[41, 42, 43, 44, 45, 46, 47, 48, 49]} The thrombolytic agents used in parapneumonic pleural effusions were noted to be more effective if administered in the early fibrinopurulent stage of parapneumonic pleural effusions. Success rates of 70-90% have been reported.

Streptokinase has been successfully used in a dose of 250,000 IU in 100 mL of normal saline given once or twice daily. Urokinase has also been effective; in a randomized trial that included patients with multiloculated pleural effusions, subjects in the urokinase group drained significantly more pleural fluid, required less surgical intervention, and required fewer days in the hospital.

Streptokinase may lead to sensitization with production of an antibody response and subsequent allergic reaction if used for systemic thrombolysis. Streptokinase and urokinase are probably equally effective, though the two agents have not been directly compared with each other in a research trial. The potential for developing antibodies to streptokinase has generally favored urokinase as a pleural thrombolytic. Following instillation, the chest tube is clamped for 2-4 hours. These agents may be administered daily for as long as 14 days. 

It should be noted that streptokinase and urokinase are no longer available in the United States. 

The first MIST (MIST1; N = 454) was a prospective randomized double-blind trial in which patients with pleural infection (either purulent pleural fluid or pleural fluid with a pH < 7.20 with signs of infection) received either intrapleural streptokinase (250,000 IU twice daily for 3 days) or placebo, in addition to antibiotics, chest tube drainage, surgery, and other treatment as part of routine care.^[45] No benefit was reported for streptokinase in terms of mortality, rate of surgery, radiographic outcomes, or length of hospital stay; serious adverse events (chest pain, fever, or allergy) were more common with streptokinase.

Tokuda et al performed a meta-analysis (five studies; N = 575) of all properly randomized trials comparing intrapleural thrombolytic agents with placebo in adults with empyema thoracis and complicated parapneumonic pleural effusions.^[46] The outcome of primary interest was reduction of mortality and surgical intervention. MIST1 accounted for the largest portion of the patients in the meta-analysis, and its nonbeneficial findings contributed significantly to the final conclusion.

The meta-analysis did not support routine use of thrombolytic therapy for all patients who required chest tube drainage for empyema thoracis or complicated parapneumonic pleural effusions.^[46] It should be noted that the meta-analysis described a nonsignificant reduction in death and surgery even with the inclusion of the MIST1 trial. In view of the significant heterogeneity of the treatment effects, it is reasonable to suggest that selected patients might benefit from thrombolytic treatment.

The significant heterogeneity caused by MIST1 could have resulted from differences in the patient population studied and the study design employed. First, the proportion of loculated pleural effusions enrolled was low (70%). Second, unlike other studies, MIST1 used only plain chest radiography, not US or CT, to document radiographic improvement. Third, the median size of the chest tube used was smaller, only 12F, and there was no mention of whether US guidance was used for placement. Finally, the criteria for surgical intervention were more subjective and were based on physicians' clinical judgment, whereas other studies had more objective criteria.

Subsequently, intrapleural recombinant TPA (r-TPA) or alteplase was successfully evaluated in pediatric patients with complicated parapneumonic pleural effusion and pleural empyema. Some authors have suggested that r-TPA might be a more effective therapeutic agent than streptokinase. A small noncomparative study of consecutive adult patients using r-TPA or alteplase administered intrapleurally in a single daily dose of 25 mg reported that the treatment was well tolerated and effective.^[47]  

A 2008 Cochrane Database systematic review on this topic (seven studies; N = 761) identified a significant reduction in the need for surgical intervention but also pointed out the discrepancy between this conclusion and the results of MIST1.^[49] Subgroup analysis suggested that the greatest benefit is in patients with loculated effusions; however, the authors noted that the data were very limited and thus advised due caution. Thrombolytic therapy was not found to be associated with an increase in adverse events.

MIST2 (N = 210), conducted in 2011, included a comparison with intrapleural recombinant human DNase, a potential treatment for pleural infection that may help prevent biofilm formation and increased viscosity by destroying extracellular DNA.^[50] Patients with pleural infection were randomly assigned to receive a 3-day study treatment with double placebo, r-TPA (alteplase) and placebo, DNase and placebo, or r-TPA and DNase.

In this study,^[50] the combination of 10 mg of intrapleural r-TPA and 5 mg of DNase, compared with double placebo, reduced the length of hospital stay, decreased the need for thoracic surgery, and produced a greater improvement in pleural opacity on day 7. Stay length and pleural opacity change for DNase alone and for r-TPA alone did not significantly differ from those for double placebo. One possible explanation is that the fibrinolytics help lyse the pleural fibrinous septation and the DNase is required to reduce the viscosity of the pus. The results of this study suggested that DNase monotherapy should be avoided because it increases the need for thoracic surgery.

In 2012, Janda et al published a systematic review and meta-analysis (seven RCTs; N = 801) of fairly good–quality studies comparing fibrinolytic therapy with placebo, including both MIST1 and MIST2.^[51] The results showed significant reduction of treatment failure (surgical intervention or death) and surgical intervention alone but not for death alone or hospital length of stay. The MIST1 was also the one that caused significant heterogeneity in this meta-analysis.

The authors also addressed potential publication bias due to missing large positive studies, as well as small and large negative studies.^[51] Their conclusion was not greatly different from those of previous meta-analyses: Although fibrinolytic therapy could not be routinely recommended, it could be considered in patients with loculated pleural effusions on the grounds that it might prevent the need for surgical intervention.

More RCTs with adequate power are needed. However, pleural thickening greater than 2 mm on CT might predict failure of intrapleural fibrinolytic therapy.^[52]

According to the 2023 ERS/ESTS statement, there is no evidence-based role for fibrinolytic or DNase monotherapy in adult pleural infection.^[10] When given, IET (TPA and DNase) should be initiated within 48 hours of standard care (chest tube drainage and antibiotics) as a potential surgery-sparing modality if there is evidence of treatment failure. In cases of pleural infection where IET is strongly contraindicated, saline irrigation may be considered on a case-by-case basis.

• References

Surgical Care

The 2023 ERS/ESTS statement made the following recommendations regarding surgical therapy in this setting^[10] :

• Outcomes may be improved when surgical referral and discussion are initiated as early as possible, with the goal of surgical treatment (if found necessary) taking place within 10 days of presentation
• Surgical intervention is first-line therapy for retained hemothorax and posttraumatic empyema, but medical therapy (eg, IET) may be considered in patients at high operative risk
• Medical thoracoscopy can be considered as an option for treating multiloculated pleural infection in elderly and frail patients at high operative risk, provided that sufficient local expertise and resources are available
• If pleural infection develops after surgical resection, :tube drainage followed by bronchoscopy to confirm or rule out bronchopleural fistula (BPF) is usual; reoperation with fistual closure and space obliteration utilizing tissue flaps is preferred in the early postoperative phase and in patients fit for reoperation; in cases of late presentation, persistent BPF, or patients unfit for reoperation, open window thoracostomy with or without intrapleural vacuum-assisted closure may be a favorable option

Thoracoscopy

Thoracoscopy is an alternative means of treating multiloculated empyema thoracis. In patients with multiloculated parapneumonic pleural effusions, the loculations in the pleural space can be disrupted with a thoracoscope, and the pleural space can be drained completely. If extensive adhesions are present or thick pleural peel entraps the lung, the procedure may be converted to open thoracotomy and decortication.

Video-assisted thoracoscopic surgery

A study (N = 234; 108 women, 126 men) by Luh et al addressed the use of VATS to treat complicated parapneumonic pleural effusions and empyema thoracis.^[53]  Of the 234 patients, 200 (85.5%) received preoperative diagnostic or therapeutic thoracocentesis, tube thoracostomy, or fibrinolytic therapy. VATS yielded satisfactory results in 202 patients (86.3%), and only 40 patients required open decortication or repeat procedures. VATS is safe and effective for treatment; earlier intervention with VATS can produce better clinical results.

Hope et al reviewed outcomes of surgical treatment for parapneumonic empyema thoracis, comparing VATS with thoracotomy.^[54] Morbidity and mortality were similar among all groups. The rate of conversion to open thoracotomy was 21%. On the basis of a shorter postoperative length of stay with similar morbidity and mortality in patients operated on within 11 days of admission, the authors recommended early aggressive surgical treatment of complicated parapneumonic effusions or empyema thoracis.

Casali et al retrospectively evaluated the results of two different surgical procedures (decortication vs debridement) and two different approaches (VATS vs thoracotomy) in the treatment of parapneumonic thoracic empyema.^[55] Of the 119 patients included in the study, 51 underwent debridement (52% via VATS, 48% via thoracotomy) and 68 underwent decortication (all via thoracotomy).

In this study, VATS debridement had a lower postoperative hospital stay and shorter duration of chest drainage and greater improvement in a subjective dyspnea score.^[55] The long-term spirometric evaluation was normal in 58 patients (56%). Age greater than 70 years was the only variable associated with poor long-term results (forced expiratory volume in 1 second [FEV₁] < 60% and/or dyspnea Medical Research Council grade ≥2) at multivariate analysis. VATS is associated with less postoperative mortality and shorter postoperative hospital stay.

Studies by Potaris et al^[56]  and by Chan et al^[57] also supported the use of VATS as a primary drainage procedure.

Wang et al proposed a new technique in which an electronic endoscope (bronchoscope or gastroscope) inserted through the chest tube was effective for directly visualizing, irrigating, and breaking down the loculation in various pleural diseases, including 13 cases of empyema thoracis.^[58]

In a small prospective randomized study (N = 36) comparing VATS with thrombolytic therapy in children with empyema, no differences in outcomes were noted between the two methods.^[59] Thrombolytic therapy consisted of 4-mg doses administered three times over a 48-hour period. Three (16.7%) of the patients treated with thrombolytic therapy eventually required VATS for management.

Medical thoracoscopy

Several studies have also evaluated the efficacy and safety of medical thoracoscopy for treatment of pleural infections. 

In a retrospective series (N = 127) evaluating the treatment of multiloculated empyema as identified by chest US medical thoracoscopy was primarily successful in 91% of cases.^[60]  Complications occurred in 9% of patients (subcutaneous emphysema, n = 3; air leak of 3-7 days, n = 9) but no mortality was observed; however, 49% of patients received intrapleural fibrinolytic therapy post intervention.

In a descriptive case series of 160 patients who underwent medical thoracoscopy under local anesthesia for management of multiloculated empyema, complete resolution was achieved in 92 (57.5%) and partial resolution in 58 (36.25%).^[61]  

A 2021 meta-analysis of eight studies found that thoracoscopy had a pooled treatment success rate of 85% when used as first-line intervention or after failure of chest tube drainage.^[62]

Open rib resection and drainage of pleural space

Open drainage of the pleural space may be indicated when closed-tube drainage of the infection is inadequate and the patient does not respond to intrapleural thrombolytic agents. It is recommended only when the patient is too ill to tolerate decortication. One to three ribs overlying the lower part of the empyema thoracis cavity are resected, a large-bore chest tube is inserted into the empyema thoracis cavity, and the tube is drained into a colostomy bag. Patients treated by open drainage have an open chest wound for a prolonged period (median in one series, 142 d). With decortication, the convalescence period is much shorter.

In decortication, all fibrous tissue is removed from the visceral pleural peel, and all pus is evacuated from the pleural space. It is a major thoracic operation requiring full thoracotomy and therefore is not tolerated by critically ill patients. It is the procedure of choice when pleural sepsis is not controlled by closed-tube thoracostomy, intrapleural thrombolytic agents, or, possibly, thoracoscopy. Mortality may be as high as 10%. Decortication should not be performed solely to remove the thickened pleural peel, which usually resolves over several months. It can appropriately be considered if the pleura remains thickened with symptom-limiting reduction in pulmonary function after approximately 6 months, .

Postpneumonectomy empyema thoracis, an uncommon but life-threatening complication, is often associated with a BPF. Treatment of BPF depends on several factors, including the extent of dehiscence, the degree of pleural contamination, and the patient's general condition. Early diagnosis and aggressive therapeutic strategies for controlling infection, closing the fistula, and sterilizing the closed pleural space are mandatory. Repeated debridement, VATS, endoscopic application of tissue glue, and stenting may be additional management strategies.^[63]

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Diet

No dietary restrictions are recommended for patients with parapneumonia effusions and empyema, other than what may be dictated by any comorbid conditions present.

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Activity

No specific activity restrictions are recommended for patients with parapneumonic effusions and empyema. Their activity level may be limited by comorbid conditions and any interventions that are required to treat the infection.

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Complications

Complications are related to adverse events related to incomplete drainage of infected pleural fluid. These include chronic indolent infections, chest-tube site infections, trapped lung, BPFs, and pneumothoraces.

Untreated infections may lead to sepsis, septic shock, and death.

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Prevention

Early diagnosis and intervention (thoracocentesis, a drainage procedure, or both), may render surgical treatment unnecessary.

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Consultations

Most patients can be treated by pulmonary or infectious disease specialists. A general pulmonary or interventional pulmonology specialist can help place a small- or large-bore chest tube and guide interpleural therapy and management of the tube. Alternatively, a general or thoracic surgery team can perform this procedure, depending on hospital preferences. Occasionally, an interventional radiologist may be needed to place small-bore drainage catheters under CT guidance for difficult-to-access loculated effusions.

Patients with persistently loculated effusions despite drainage or intrapleural therapy and unresolving empyema thoracis often require surgery and should be seen by a thoracic surgeon.

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Long-Term Monitoring

Often, prolonged antibiotic therapy is required, particularly for patients who have anaerobic infections. The length of antibiotic therapy is generally dictated by the response to antibiotics and clinical and radiologic resolution.

The 2023 ERS/ESTS statement on management of pleural infections suggests follow-up time points at 2-4 weeks to detect early treatment failure and 8-12 weeks to confirm complete radiologic resolution.^[10]

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Guidelines Summary

The following organizations have released guidelines for the management of pleural infection, empyema, community-acquired pneumonia (CAP), hospital-associated pneumonia (HAP), ventilator-associated pneumonia (VAP), and healthcare-associated pneumonia (HCAP). Key diagnostic and treatment recommendations have been reviewed and integrated throughout the article.

• European Respiratory Society (ERS)/European Society of Thoracic Surgeons (ESTS)^[10]
• American Association for Thoracic Surgery (AATS)^[16]
• Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS)^{[35, 36]}

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Clindamycin (Cleocin, Cleocin Pediatric, Clindamax)

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Ertapenem (Invanz)

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Imipenem/cilastatin (Primaxin)

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Meropenem (Merrem IV)

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Cefaclor (Ceclor (DSC), Raniclor (DSC))

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Cefoxitin

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Cefprozil (Cefzil)

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Cefuroxime (Ceftin, Zinacef)

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Ceftriaxone (Rocephin (DSC))

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Cefepime (Maxipime)

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Dornase alfa (Pulmozyme)

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Levofloxacin (Levaquin, Levofloxacin Systemic)

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Moxifloxacin (Moxifloxacin Systemic, Avelox)

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Vancomycin (Firvanq, Vancocin)

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Clarithromycin (Voquezna Triple Pak)

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Azithromycin (Zithromax, Zmax)

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Metronidazole (Flagyl, Flagyl ER, Flagyl IV RTU)

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Linezolid (Zyvox)

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Amoxicillin (Amoxil, Moxatag (DSC), Trimox)

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Amoxicillin/clavulanate (Augmentin, Augmentin ES-600, Augmentin XR)

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Ampicillin/sulbactam (Unasyn)

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Piperacillin/tazobactam (Zosyn)

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Penicillin G aqueous (Penicillin G sodium, Crystapen, Penicillin G potassium)

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Penicillin VK (Pen Vee K, Penicillin V, Veetids)

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Alteplase (TPA, Activase, Cathflo Activase)

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