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Distinguishing complicated from uncomplicated parapneumonic effusions

Porcel, José M.

Current Opinion in Pulmonary Medicine: July 2015 - Volume 21 - Issue 4 - p 346–351
doi: 10.1097/MCP.0000000000000164
DISEASES OF THE PLEURA: Edited by Richard W. Light
Editor's Choice

Purpose of review Treatment of parapneumonic effusions (PPEs) is challenged by the decision of whether or not to insert chest tubes. This review focuses on the factors that may aid in determining which patients require an immediate drainage of the pleural space, that is, have a complicated PPE.

Recent findings Clinical guidelines advocate the evaluation of radiological (large effusion or loculation), bacteriological (Gram-positive stain or culture), biochemical (pH < 7.20 or glucose <60 mg/dl), and macroscopic (pus) characteristics of the pleural fluid to assist in the identification of complicated PPEs. In the past few years, a number of new pleural fluid biomarkers have been tested for the same purpose, but with the exception of C-reactive protein (CRP), they should be considered investigative. A pleural fluid CRP higher than 100 mg/l or a serum CRP higher than 200 mg/l, when combined with pleural fluid pH or glucose, may greatly increase our capability to predict the need for instituting tube thoracostomy. Although some ultrasonographic and computed tomography features favor the diagnosis of pleural infection, their role in uncomplicated–complicated PPE discrimination has not been systematically evaluated.

Summary No pleural fluid tests, other than pH or glucose, have gained wide acceptance for the assessment of patients with PPE. However, if corroborated with further studies, the measurement of pleural fluid or serum CRP, in combination with the classical fluid parameters, may have the potential to be incorporated into medical decision making.

Pleural Medicine Unit, Department of Internal Medicine, Arnau de Vilanova University Hospital, Biomedical Research Institute of Lleida, Lleida, Spain

Correspondence to José M. Porcel, Professor and Chief, Pleural Medicine Unit, Department of Internal Medicine, Arnau de Vilanova University Hospital, Avda Alcalde Rovira Roure 80, Lleida 25198, Spain. Tel: +34 973 248100 x4498; e-mail:

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Parapneumonic effusions (PPEs) are defined as those associated with pneumonia or, less frequently, lung abscesses or bronchiectasis. In the past few years, the prevalence of PPE on chest radiographs has consistently been established in large cohorts of patients. In a prospective series of 4715 consecutive patients with community-acquired pneumonia, 882 (19%) went on to develop a PPE, of whom 261 (30%) were categorized as being complicated [1]. In another study, 214 patients with Legionella pneumophila pneumonia were found to be less likely to develop pleural effusions than the 1346 with pneumococcal pneumonia (15 vs. 21%) [2]. However, when more sensitive radiological image modalities are employed, the prevalence of PPE rises. For example, routine lung ultrasonography was able to detect basal pleural effusions with a median volume of 50 ml in 54.4% of 193 patients with community-acquired pneumonia [3].

A PPE should always be suspected in patients with pneumonia who fail to respond to antibiotics, that is, who do not achieve clinical stability or a 50% reduction of serum C-reactive protein (CRP) levels by day 3 or 4 [4]. PPEs may have a significant morbidity and mortality rate. About 13% of patients with PPE eventually require surgery due to failed chest drainage and intrapleural fibrinolysis [5]. Moreover, the presence of PPEs was reported to be one of the factors significantly related to the short-term occurrence of incident cardiac complications (i.e., new or worsening heart failure or arrhythmias, myocardial infarction) in 1343 hospitalized patients with community-acquired pneumonia (odds ratio = 1.6) [6]. Concerning death risk, data from a Danish registry showed that the overall mortality rate of 6878 hospitalized adult patients with empyema was around 10%, although it varied according to age and level of comorbidity, ranging from only 1.2% in patients aged 40 years or less up to 20.2% in those with 80 years or more [7].

PPE accounts for a large percentage of tapped pleural fluids. In a series of 3077 adult patients with pleural effusions who were subjected to a diagnostic thoracentesis, pneumonia represented the third leading cause (19%), behind cancer (27%) and heart failure (21%) [8]. Although some PPEs resolve with appropriate antibiotic therapy, others will require additional interventions, mainly serial therapeutic thoracenteses, tube thoracostomy, intrapleural fibrinolytics with or without DNAse, and, less frequently, thoracoscopy or thoracotomy. This review will focus on the factors the clinician should be aware of to decide whether a PPE will require a drainage procedure in addition to antibiotics.

Box 1

Box 1

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PPEs have traditionally been classified into three categories, which can be thought of as different stages from a continuum disease spectrum: uncomplicated PPEs, complicated PPEs, and empyemas. The term uncomplicated PPE denotes an effusion that resolves with the antibiotic therapy prescribed for pneumonia. Complicated PPEs are those that require semi-invasive (e.g., therapeutic thoracentesis and chest tube) or invasive (e.g., surgery) interventions for cure, in addition to antibiotics. Empyema is characterized as the aspiration of pus by thoracentesis and is considered the last stage of a PPE; as such, it must always be drained. Therefore, empyemas are, by definition, complicated PPEs. However, the challenge is in the identification of those patients whose fluids appear to be nonpurulent, yet in whom drainage of the pleural space will ultimately be necessary. Factors that influence the decision of whether to drain the effusion include the gross characteristics of the pleural fluid, pleural fluid biochemistries and bacteriology, and imaging.

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Pleural fluid sampling remains the most reliable diagnostic test to differentiate a complicated PPE requiring chest tube drainage from an uncomplicated effusion that may resolve with antibiotics alone.

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Pleural fluid appearance

The aspiration of pus is considered to be the most convincing argument for the immediate insertion of a chest drain. This owes to the fact that pus represents an advanced stage of pleural infection that is associated with a high risk of poor outcome without a drainage procedure [9]. Even so, it should be noted that small pockets of purulent fluid that are not amenable to tube drainage or are located in a difficult-to-access anatomical place (e.g., mediastinum) might occasionally not progress and will be cleared with a long-term course of antibiotics, with or without anti-inflammatory drugs. It goes without saying that management of such a scenario is challenging, as delaying a necessary surgical treatment for a nondrained or incompletely drained empyema increases the probability of requiring an open decortication rather than a simpler video-assisted thoracic surgery (VATS) procedure [10]. A strict serial surveillance of clinical (vital signs, general assessment), radiological (progression of the effusion's size, loculations), and analytical (serum CRP, leukocyte count) data may help the decision process on an individual basis.

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Pleural fluid analyses

Thoracentesis is mandatory for all patients with a suspected PPE of more than trivial size. The aspirated fluid should be sent for microbiological cultures and, if nonpurulent, also for biochemical analysis.

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Bacterial cultures

Although bacterial growth on a pleural fluid sample is typically another factor signaling complicated PPEs, microbiological results are frequently negative, even with the inoculation of standard blood culture bottles [11]. Thus, the sum of three series totaling 1003 patients with empyema yielded positive pleural fluid cultures in 587 (58.5%) cases [8,12,13]. However, when only nonpurulent complicated PPEs are considered, the bacterial isolation rate only reaches around 25% [8]. Overall, Streptococcus viridans accounted for approximately 25% of all microorganisms in three different large series that summed up 811 isolates [8,12,14]. In addition to having low sensitivity, pleural fluid cultures are not immediately available for speedy decisions.

The microscopic examination of Gram-stained specimens of pleural fluid, despite being a simple and rapid method, is not always routinely performed as a preliminary test, and specific data on its diagnostic accuracy for nonpurulent PPEs is lacking. What is true is that pleural fluid Gram stains are much less sensitive than cultures and very rarely (2%) the Gram stains are only positive [12]. Employing molecular techniques, such as PCR targeting 16S ribosomal ribonucleic acid gene, improves pathogen identification in comparison to the use of conventional cultures [15]. But whether this translates into a better categorization of PPEs as simple or complicated has not been explored.

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Classical biochemistries

The pleural fluid of patients with complicated PPEs contains many neutrophils, bacteria, and cellular debris. Local intense metabolic activity leads to a rise in lactate dehydrogenase (LDH) and a decline in fluid pH and glucose. These biochemical parameters have been adopted by professional society guidelines to aid drainage decisions [16,17]. Specifically, a pleural fluid pH lower than 7.20 or a glucose lower than 60 mg/dl are widely accepted as guides for the placement of chest tubes, but less agreement exists regarding when pleural fluid LDH is three times higher than the normal upper limit for serum (i.e., from 1000 to 1400 U/l, depending on the local laboratory). However, these thresholds are not supported by robust data and should not be rigidly utilized. For example, patients with diabetes often have such severe hyperglycemia in a pleural infection setting that their pleural fluid glucose levels are well above 60 mg/dl, even though a tube thoracostomy would be necessary. In our experience (Table 1), a pH 7.20 or less or a glucose 60 mg/dl or less in the pleural fluid convincingly argues for a complicated PPE (likelihood ratio positive ∼5), whereas greater values do not significantly decrease this probability (likelihood ratio ratio negative >0.4). In other words, pleural fluid pH and glucose lack sensitivity, so some complicated PPE cases can be overlooked. Moreover, about 10% of patients with PPEs who exhibit pleural acidosis or low glucose levels can be managed solely with antibiotics. When the pleural effusion is loculated, biochemical parameters may vary markedly from one locule to another [18], which may partially explain the limited discriminatory properties of fluid pH, glucose, and LDH. Finally, to be reliable, pH measurements must be done with a blood gas machine no later than 4 h after the extraction [19].

Table 1

Table 1

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New potential biomarkers

In recent years, many potential biomarkers of complicated PPEs have been tested focusing on the complex cascade of events that are related to the inflammatory and immune responses to bacterial infection [20]. These include complement byproducts (SC5b-9 and C3a-desArg), neutrophil-derived enzymes (elastase and myeloperoxidase), proinflammatory (tumor necrosis factor-α, interleukin-8, interleukin-1β, and vascular endothelial growth factor) and anti-inflammatory (interleukin-1ra, tumor necrosis factor sRI) cytokines, acute-phase reactants (CRP, pentraxin-3, and lipopolysaccharide-binding protein), and miscellaneous tests (soluble triggering receptor expressed on myeloid cells-1, matrix metalloproteinases, and the oxidative stress markers 8-isoprostane and copper and zinc-containing superoxide dismutase). Studies on these novel markers are limited by small sample sizes (Table 2) and the lack of further confirmatory findings (with the possible exception of interleukin-8 and CRP). Most importantly, none have been proven to be superior to the more traditional pleural biochemistries that, in addition, are supported by routine practice and are easier and faster to determine.

Table 2

Table 2

Among the new biomarkers, only CRP is likely to attain practical applicability in the identification of complicated PPEs, as it is inexpensive and widely available. Based on an increase in sample size, our previous study on pleural fluid CRP as being indicative of chest drainage [29] has been updated, as illustrated in Table 1. At a cutoff level of 100 mg/l, CRP exhibited good discriminative properties, with an area under the curve (∼0.80) overlapping those of LDH, glucose, and pH, thus arguing against the superiority of one parameter over the others. The combination of two tests using ‘or’ or ‘and’ rules increases sensitivity and specificity, respectively, for labeling complicated PPEs. For example, a patient having both a glucose lower than 60 mg/dl and a CRP higher than 100 mg/l in the pleural fluid almost certainly will need a tube thoracostomy (likelihood ratio positive 9). Moreover, in a study of 47 uncomplicated PPEs and 57 complicated PPEs, combining a serum CRP higher than 200 mg/l with either a fluid glucose lower than 60 mg/dl or pH lower than 7.20 using an ‘and’ rule (wherein a chest tube would be inserted if both tests were positive) also accurately predicted patients who were likely to require pleural space drainage (likelihood ratio positive >13) [35▪]. An earlier smaller study, comprising 34 uncomplicated and 20 complicated PPEs, displayed similar findings: a serum CRP higher than 83 mg/l along with a pleural fluid pH lower than 7.20 yielded an likelihood ratio positive of 23.2 and an likelihood ratio negative of 0.21 for the identification of complicated PPEs [30].

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As in thoracentesis, imaging may influence the management of PPEs. A small effusion is generally categorized into the noncomplicated subset. For instance, in a study of 63 PPE patients, only 3.5 and 9.5% of those having less than 2 and 3 cm in fluid width [as determined by means of computed tomography (CT)], respectively, required chest drainage as compared with 60 and 81% of the patients with a pleural fluid thickness above these cutoffs [36]. A subsequent study confirmed that just 5% of 95 patients with PPE measuring below 2.5 cm on CT had poor outcomes directly related to the pleural infection [37]. In contrast, an effusion's size equal to or greater than half the hemithorax on a chest radiograph, which is large enough to produce dyspnea, is an obvious reason to initially drain a nonpurulent PPE, regardless of what their biochemical and microbiological characteristics are. Large free-flowing PPEs (≥1/2 hemithorax), as well as those characterized by loculations or a thickened parietal pleura, fall into category 3 according to the American College of Chest Physicians classification, which implies an explicit draining recommendation [16].

The role of ultrasonography in uncomplicated–complicated PPE discrimination has not been completely established. Bedside thoracic ultrasound is considered to be a first-line investigative procedure in cases of suspected PPE. It is an excellent method for visualizing locutations, septations, homogenously echogenic effusions, and parietal pleural thickening. All these echographic signs are often indicative of PPEs [38], but by themselves do not necessarily predict drainage requirements. One study found a higher treatment failure rate of small-bore catheters for complex septated effusions compared with nonseptated effusions (49 vs. 20%) [39], yet the clinical implications of this finding are uncertain.

A contrast-enhanced CT scan is normally reserved for patients who have failed initial medical management and for whom an evaluation for multiloculated collections or underlying abnormalities, which were not seen on a pleural ultrasound, becomes imperative. Several CT features have been described in complicated PPEs [9,40]: the split pleural sign (i.e., enhancement of the thickened inner visceral and outer parietal pleura, with separation by a collection of pleural fluid), smooth thickening of parietal pleura, increased attenuation of extrapleural fat, loculations, microbubbles, or a combination of these. Nevertheless, whether these CT morphologic characteristics may help formulate management decisions about drainage has not been systematically studied.

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The early identification of patients with nonpurulent PPEs who will eventually require drainage of the pleural space is still challenging. In clinical practice, when and how to proceed with chest tube placement is left to the discretion of the attending physician. The presence of large or loculated effusions or the aspiration of fluids with a purulent appearance or certain microbiological (positive Gram stains or cultures) or biochemical (low pH or glucose, high CRP) characteristics are powerful indicators of the need for tube thoracostomy in the setting of PPEs. Moreover, the ease and low morbidity of inserting a small-bore chest catheter under ultrasound guidance makes the placement of an unnecessary chest tube a better choice rather than to omit one when it is necessary.

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The author appreciates the assistance of Dr Silvia Bielsa in the preparation of the article.

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Financial support and sponsorship


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Conflicts of interest

There are no conflicts of interest.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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    biomarkers; chest tube; C-reactive protein; empyema; parapneumonic effusion

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