Pleural fluid interleukin-8 and C-reactive protein for discriminating complicated non-purulent from uncomplicated parapneumonic effusions

Background and objective:   This study was designed to test the hypothesis that measurement of IL-8 and CRP in pleural fluid could improve the identification of patients with non-purulent parapneumonic effusions that ultimately require chest tube drainage.
Methods:   We assessed IL-8, CRP and three classical parameters (pH, glucose and LDH) in the pleural fluid of 100 patients with parapneumonic effusions. Forty-nine of these patients had non-purulent complicated effusions (complicated parapneumonic pleural effusion, CPPE), and 51 had uncomplicated parapneumonic pleural effusions (UPPE). Receiver-operating characteristic curves were used to assess the sensitivity and specificity of pleural fluid biochemical parameters for differentiating among the two patient groups. IL-8 production was determined using a commercially available ELISA kit, and CRP was measured by immunoassay.
Results:   At a cutoff value of 1000 pg/mL, IL-8 differentiated CPPE from UPPE with a sensitivity of 84% and a specificity of 82%. Likewise, CRP levels were higher in CPPE than in UPPE, and showed 72% sensitivity and 71% specificity at a cutoff value of 80 mg/L. We found that all five pleural fluid tests showed similar diagnostic accuracies when evaluated by receiver-operating characteristic analysis. However, multivariate analysis indicated that the size of the effusion, as well as pleural fluid pH and IL-8 concentration, were the best discriminatory parameters, with likelihood ratios of 6.4, 4.4 and 3.9, respectively.
Conclusions:   Pleural fluid IL-8 is an accurate marker for the identification of non-purulent CPPE.     

Pleural fluid pH in parapneumonic effusions.

The pH and carbon dioxide tension were measured in 24 consecutive parapneumonic effusions, along with the leukocyte count, leukocytic differential count, and levels of glucose and protein. Three categories of parapneumonic effusions were characterized: (1) empyemas; (2) benign (nonloculated) effusions; and (3) loculated effusions. A pH greater than 7.30 was present in all ten benign effusions, and spontaneous resolution occurred in each case. All ten empyemas and the four loculated effusions had a pH less than 7.30. All four loculated effusions required drainage with a chest tube for resolution. The pH of the pleural fluid alone separated the empyemas and loculated effusions from benign effusions. The early separation of parapneumonic effusions on the basis of the pleural fluid appears useful. If the pH is greater than 7.30, a benign effusion is present, and spontaneous resolution is likely. If the pH is less than 7.30, loculation of the pleural space may occur regardless of whether the effusion fulfills the criteria for empyema.     

Pleural fluid parameters identifying complicated parapneumonic effusions

BACKGROUND: Controversy exists regarding the clinical utility of pleural fluid parameters as prognosticators of complicated parapneumonic effusions that require drainage. OBJECTIVES: The purpose of this prospective study is to further assess the utility of these parameters in the management of a larger series of parapneumonic effusions and to determine appropriate binary decision thresholds. METHODS: We studied 238 consecutive patients with parapneumonic effusions who underwent diagnostic thoracentesis. RESULTS: We found that pleural fluid pH had the highest diagnostic accuracy (area under the curve, AUC: 0.928; 95% confidence interval, CI: 0.894-0.963) compared with pleural fluid glucose (AUC: 0.835; 95% CI: 0.773-0.897), LDH (AUC: 0.824; 95% CI: 0.761-0.887) or pleural fluid volume (AUC: 0.706; 95% CI: 0.634-0.777). The optimal binary decision threshold for pleural fluid pH identifying complicated effusions requiring drainage was 7.15. Binary, multilevel and continuous likelihood ratios (LRs) for pH were calculated to estimate the likelihood of complication of the pleural effusion. Values for the LRs were compared for each of the three strategies, and relative clinical and statistical significances were assessed. Binary LRs provided significantly less information than continuous strategies. CONCLUSION: The pH has the highest diagnostic accuracy for identifying complicated parapneumonic pleural effusions. The binary decision threshold determining the need for chest drainage is 7.15 in our patient series. We recommend continuous LRs to estimate the post-test probability of the complication as they provide the most information compared with binary LRs. Our results do not support the use of pleural fluid LDH as independent predictor of complicated parapneumonic effusions.     

Prognostic value of C-reactive protein in parapneumonic effusions

Background and objective: Parapneumonic effusions (PPE) that require drainage are referred to as complicated parapneumonic effusions (CPPE). Following resolution of these effusions, residual pleural thickening (RPT) may persist. We hypothesize that the concentrations of CRP in pleural fluid (CRP_pf) and serum (CRP_ser) can be used to identify CPPE and to predict RPT. Methods: All patients with non‐purulent PPE, who were admitted to two tertiary hospitals during a 30‐month period, were enrolled in the study. Baseline CRP_pf and CRP_ser levels were compared between patients with complicated or uncomplicated PPE, as well as between patients with or without RPT of >10 mm, 6 months after discharge from hospital. Cut‐off values for identification of CPPE and prediction of RPT were determined by receiver operating characteristic curve analysis. Logistic regression analysis was performed to assess the association between CRP levels and RPT. Results: Fifty‐four patients were included in the study. Patients with CPPE (n = 23) had significantly higher levels of both CRP_pf and CRP_ser than those with uncomplicated PPE. For identification of CPPE, a CRP_pf level >78.5 mg/L and a CRP_ser level >83 mg/L gave 84% and 47% sensitivity, with 65% and 87% specificity, respectively. Classical criteria (pleural fluid pH <7.20, LDH >1000 IU/L, glucose <600 mg/L) were superior for this purpose. A combination of classical biomarkers with CRP levels using an ‘AND’ or ‘OR’ rule improved the positive and negative predictive values, respectively. CRP_ser was an independent predictor for development of RPT (adjusted OR 1.18). A CRP_ser level >150 mg/L had 91% specificity and 61% sensitivity for prediction of RPT. Conclusions: This study demonstrated the value of CRP_ser for prediction of RPT in patients with PPE. Moreover, when used in combination with classical biomarkers, CRP levels may be a useful adjunct for decision‐making in relation to treatment of patients with non‐purulent PPE.     

Pleural fluid adenosine deaminase/serum C-reactive protein ratio for the differentiation of tuberculous and parapneumonic effusions with neutrophilic predominance and high adenosine deaminase levels

Purpose

Tuberculous pleural effusion (TPE) and parapneumonic effusion (PPE) are usually distinguished by cellular predominance and pleural fluid adenosine deaminase (ADA) levels. However, both diseases may occasionally show similar neutrophilic predominance and high ADA levels. In such cases, the differential diagnosis between TPE and PPE is challenging and has been rarely investigated.

Methods

A retrospective study was conducted on TPE and PPE patients with neutrophilic exudate and pleural fluid ADA levels ≥40 U/L. Individual and combined parameters of routine blood and pleural fluid tests were compared between the two groups, and receiver operating characteristic (ROC) curves were constructed for identifying TPE.

Results

Thirty-six TPE and 41 PPE patients were included. White blood cell counts, serum C-reactive protein (S-CRP), and pleural fluid pH, lactate dehydrogenase, and ADA levels showed significant difference between the two groups (p < 0.001). Among multiple parameters, pleural fluid ADA/S-CRP ratio, which best reflected different local and systemic characteristics between TPE and PPE, provided the highest diagnostic accuracy with an area under the ROC curve of 0.93. At a cutoff value of 5.62, ADA/S-CRP ratio had a sensitivity of 89 %, specificity of 88 %, positive likelihood ratio of 7.29, and negative likelihood ratio of 0.13 for identifying TPE. Additionally, more than half of TPE patients had a ratio above 15.82, while none of PPE patients showed such findings.

Conclusions

Pleural fluid ADA/S-CRP ratio, as a simple method using routine laboratory tests, may be helpful in discriminating between TPE and PPE patients with neutrophilic predominance and ADA ≥40 U/L.

     

Use of pleural fluid C-reactive protein in diagnosis of pleural effusions

The aims of the study were to assess whether C-reactive protein (CRP) is a sensitive marker for discriminating between transudative and exudative and pleural effusions to evaluate whether it can be used to distinguish inflammatory pleural effusions from other types of effusion. Pleural fluid and serum CRP levels were obtained in 97 patients with pleural effusion, using an immunoturbidimetric method (Olympus AU-600 autoanalyser). We compared CRP levels between transudates and exudates, inflammatory effusions and other types of effusion. According to the criteria used, 16 patients were included in the transudate group and 81 patients in the exudate group. Pleural fluid CRP levels were significantly lower in the transudate group (P<0.04; 14.9 +/- 4.9 mg l(-1) and 35.5 +/- 4.9 mg l(-1) respectively). Also, the ratio of pleural fluid to serum was significantly lower in the transudate group (P<0.009; 0.8 +/- 0.5 mg l(-1) and 2.8 +/- 0.7 mg l(-1), respectively). In the exudate group, 35 patients had neoplastic effusions, 10 chronic non-specific pleurisy, 19 tuberculous pleurisy, 16 parapneumonic effusion and one Dressler Syndrome. When these sub-groups were compared, the parapneumonic effusion subgroup CRP levels (mean 89 +/- 16.3 mg l(-1)) were significantly higher than those in the other subgroups, other exudate of neoplastic effusion, tuberculous pleurisy and chronic non-specific effusion and the transudate group (P<0.0001; P<0.0001; P<0.0004 and P<0.0001, respectively). The ratio between pleural fluid and serum CRP was significantly higher in the parapneumonic effusion subgroup than in the neoplastic subgroup (P<0.0002; 6.6 +/- 2.7 mg l(-1) and 1 +/- 0.2 mg l(-1), respectively). Pleural fluid CRP levels > 30 mg l(-1) had a high sensitivity (93.7%) and specificity (76.5%) and a positive predictive value of 98.4%. In the differential diagnosis of pleural effusions, higher CRP levels may prove to be a rapid, practical and accurate method of differentiating parapneumonic effusions from other exudate types. Although the high level of CRP obtained in the exudate group may be due to the number of patients with parapneumonic effusion who were included, the pleural CRP level may also be helpful in discriminating between exudative and transudative pleural effusions.     

C-反应蛋白对胸腔积液诊断的临床意义

目的探索C-反应蛋白(CRP)对胸腔积液诊断的临床意义。方法采用透射比浊度法测定68例不同性质胸腔积液患者的胸水CRP和血清CRP水平,以及其比值。结果漏出液中CRP水平(6.1±3.1)mg/L明显低于渗出液中CRP水平(24.7±4.5)mg/L,(P<0.001)。同时,胸水CRP水平与血清CRP水平的比值,漏出液(0.7±0.5)明显低于渗出液(2.1±0.6)(P<0.001)。另外,化脓性胸膜炎胸水CRP水平(38.2±7.7)mg/L显著升高,其胸水CRP水平与血清CRP水平之比值(4.8±2.5)也明显升高。胸水CRP水平高于35.0mg/L对于化脓性胸腔积液的诊断灵敏度81.25%,特异性61.9%。结论　胸水CRP水平测定有助于鉴别胸腔积液之渗出液和漏出液,而且,高水平的胸水CRP被证明是诊断化脓性胸腔积液较为迅速且准确的方法。     

Contribution of C-reactive protein to the diagnosis and assessment of severity of community-acquired pneumonia

STUDY OBJECTIVE: To assess the usefulness of serum C-reactive protein (CRP) in the diagnosis and treatment approach of patients with community-acquired pneumonia (CAP). DESIGN: Population-based case-control study. SETTING: A mixed residential-industrial urban area of 74,368 adult inhabitants in the Maresme region (Barcelona, Spain). PATIENTS: From December 1993 to November 1995, all subjects who were > 14 years of age, were living in the area, and had received a diagnosis of CAP, which had been confirmed by chest radiographs and compatible clinical outcome, were registered. Patients from residential care facilities were excluded. Serum samples were assayed for CRP in the acute phase of the disease. Data from 201 patients with CAP were compared with 84 healthy control subjects matched by age, sex, and municipality, as well as with 25 patients with initially suspected pneumonia that was not confirmed at follow-up. Median CRP levels were 110.7, 1.9, and 31.9 mg/L, respectively. The thresholds of the test for discriminating among these three groups of subjects were 11.0 and 33.15 mg/L. RESULTS: Eighty-nine patients (44.8%) had an identifiable etiology. The most common pathogens were Streptococcus pneumoniae, viruses, and Chlamydia pneumoniae, followed by Mycoplasma pneumoniae, Legionella pneumophila, and Coxiella burnetii. There were statistically significant differences in the median CRP levels in pneumococcal (166.0 mg/L) and L pneumophila (178.0 mg/L) etiologies compared to other causative pathogens. Lower levels of CRP were found in pneumonia caused by viruses and C burnetii as well as in negative microbiological findings. The median CRP levels in hospitalized patients were significantly higher than in outpatients (132.0 vs 76.9 mg/L, respectively; p < 0.001). Considering a cut point of 106 mg/L in men and 110 mg/L in women for deciding about the appropriateness of inpatient care, CRP levels showed a sensitivity of 80.51% and a specificity of 80.72%. CONCLUSIONS: Serum CRP level is a useful marker for establishing the diagnosis of CAP in adult patients with lower respiratory tract infections. High CRP values are especially high in patients with pneumonias caused by S pneumoniae or L pneumophila. Moreover, high CRP values are suggestive of severity, which may be of value in deciding about the appropriateness of inpatient care.     

Pleural fluid characteristics of tuberculous pleural effusions

Mycobacterium tuberculosis (TB) infection of the pleural space is an important cause of pleural effusion in areas of high TB prevalence. Microbiological analyses of pleural fluid in the acute setting may be negative. Consequently, investigations may proceed to more invasive techniques, such as pleural biopsy or thoracoscopy. Ongoing research has led to implementing a number of additional fluid analyses that may lead to a diagnosis without a need for further invasive procedures. In this review, we discuss the characteristics of tuberculous pleural fluid that may assist in this important diagnosis, and we highlight the benefits of specific biomarker analyses. English-language publications from a MEDLINE search and references from relevant articles from January 1, 1990 to September 1, 2009 were reviewed. The key words searched included tuberculosis, pleural fluid, effusion, diagnosis, adenosine deaminase, and interferon.     

Multilevel and continuous pleural fluid pH likelihood ratios for draining parapneumonic effusions

BACKGROUND: Although clinical practice guidelines endorse the use of pleural fluid pH to select patients with parapneumonic effusions for pleural drainage, no studies have reported likelihood ratios for pleural fluid pH. OBJECTIVES: We derived and tested the value of continuous likelihood ratios for selecting pneumonia patients for pleural drainage. METHODS: Patient level pleural fluid pH results were obtained from a registry of primary studies that assessed the discriminative properties of pH. Multilevel likelihood ratios were calculated for four pH intervals. Continuous likelihood ratios were derived from logistic regression using discrete pH values. Binary, multilevel and continuous likelihood ratios were compared to evaluate the statistical (chi2) and clinical advantages of continuous likelihood ratios. RESULTS: Hundred and ninety-seven pleural fluid pH results were retrieved from published reports and categorized into four pH ordinal intervals. Multilevel likelihood ratios ranged from a low of 0.13 (95% CI, 0.04-0.41) for pH values >7.40 to a high of 15.80 (95% CI, 7.04-35.45) for pH values < or =7.00. Logistic regression derived the following equation for continuous likelihood ratios: exp[-7.168(measured pH - 7.207)]. Continuous likelihood ratios offered more diagnostic information both statistically (p < 0.005) and clinically compared with binary and multilevel likelihood ratios. CONCLUSIONS: Analysis of a patient registry allows the derivation of an exponential equation that calculates continuous likelihood ratios for discrete pleural fluid pH values. Continuous likelihood ratios provide more clinically and statistically significant information compared with binary and multilevel likelihood ratios for calculating posttest probabilities of the need to drain parapneumonic effusions.     

Diagnosis and management of parapneumonic effusions

Parapneumonic effusions affect many patients and are associated with considerable morbidity and mortality. It is necessary to differentiate complicated effusions requiring intervention from uncomplicated effusions. Differentiation is achieved using clinical, pleural fluid, and imaging parameters. Intervention takes the form of blind catheter placement and drainage, image-guided catheter placement and drainage, and surgical decortication [video-assisted thoracoscopic surgery (VATS) or open thoracotomy]. Image-guided drainage and management of complicated effusions in adults and pediatric patients are safe and highly effective in select patients. The use of intrapleural fibrinolytic agents to facilitate resolution of complicated effusions is widespread and considered effective by many despite a lack of conclusive data supporting this method. We propose an algorithmic approach to patients with parapneumonic effusions and advocate image-guided drainage and management in patients likely to benefit from this treatment.     

Management of parapneumonic pleural effusions and empyema

Parapneumonic pleural effusions, the most common causes of exudative pleural fluid, are a frequent finding with bacterial pneumonia. Progression to empyema is related to delay in appropriate antimicrobial therapy. Once an empyema develops, therapy consists of early sterilization of the empyema space with appropriate antibiotics, early and adequate pleural space drainage, and obliteration of the empyema cavity by adequate lung expansion, surgical decortication, or enzymatic debridement.     

Tumor necrosis factor-alpha in pleural fluid: a marker of complicated parapneumonic effusions

STUDY OBJECTIVES: We sought to determine whether pleural fluid tumor necrosis factor (TNF)-alpha is a more accurate parameter to identify nonpurulent complicated parapneumonic effusion (CPPE) than the classical chemistries, namely pH, glucose, or lactate dehydrogenase (LDH). METHODS: We studied 80 consecutive patients with parapneumonic effusions (35 with uncomplicated parapneumonic effusion [UPPE], 23 with nonpurulent CPPE, and 22 with empyema). Concentrations of standard biochemical parameters together with TNF-alpha were measured in pleural fluid, the latter by using an immunoenzymometric assay. RESULTS: Pleural TNF-alpha was significantly higher in CPPE (133.0 pg/mL) and empyema (142.2 pg/mL) than in UPPE (39.1 pg/mL). A cut-off value of 80 pg/mL for pleural TNF-alpha resulted in a sensitivity, specificity, and area under receiver operating characteristic curve (AUC) of 78%, 89%, and 0.87, respectively, for the diagnosis of nonpurulent CPPE. A multivariate analysis selected both pleural TNF-alpha > or = 80 pg/mL and LDH > or = 1,000 U/L (sensitivity, 74%; AUC = 0.86), but excluded pleural glucose < or = 60 mg/dL (sensitivity, 39%; AUC = 0.82) and pH < or = 7.20 (sensitivity, 41%; AUC = 0.78), for identifying the need for drainage. The combined sensitivity of pleural fluid TNF-alpha and LDH was found to be 91%. CONCLUSIONS: Pleural TNF-alpha may contribute to the identification of patients with nonpurulent CPPE with at least the same diagnostic accuracy, if not better, than the use of pH, glucose, or LDH.     

Pleural fluid myeloperoxidase as a marker of infectious pleural effusions

Background: The aim of this study was to establish the diagnostic accuracy of neutrophil markers (elastase, lysozyme, myeloperoxidase) found in pleural fluid in differentiating between infectious and non-infectious pleural effusions (PE). Methods: We studied 184 patients over 18 years of age with PE, classified as either infectious (34 complicated parapneumonic, 32 non-complicated parapneumonic, 45 tuberculous) or non-infectious (31 neoplasms and 42 undiagnosed exudates). Polymorphonuclear elastase (PMN-E) was determined using an immunoactivation method and lysozyme using a turbidimetric method. Myeloperoxidase (MPO) was measured by double antibody competitive radioimmunoassay. Receiver operating characteristic (ROC) curves were used to evaluate diagnostic accuracy. Results: Pleural fluid MPO was the biochemical marker that best differentiated between infectious and non-infectious PE. The ROC area under the curve (AUC) for myeloperoxidase was 0.86. MPO values over 550 &mgr;g/l diagnosed infectious PE with a specificity of 90.4% and a sensitivity of 77.4%. After excluding purulent parapneumonic PE, the sensitivity of a pleural MPO value >/=550 &mgr;g/l was 72.6%. Conclusions: Pleural fluid MPO was the marker that best differentiated between infectious and non-infectious PE.     

Utility of pleural fluid analysis in predicting tube thoracostomy/decortication in parapneumonic effusions

Recommended criteria for surgical drainage of parapneumonic effusions include evidence of frank purulence, a glucose level less than 40 mg/dl, a pH of less than 7.00, or an LDH greater than 1,000 IU/L. To test the utility of these criteria, we reviewed the three-year experience of three Rochester, NY, hospitals. We identified 133 patients undergoing thoracentesis for putative parapneumonic effusions. Of 91 patients with neutrophilic exudates, 43 met one or more criteria for tube thoracostomy: 48 did not. Twenty-one of the 43, including 9 with frank empyema, underwent immediate drainage. Of the 22 who did not, 11 eventually required tube thoracostomy and/or decortication. Of the 48 not meeting any of the criteria, 7 also came to surgery. Using whether the patients eventually underwent surgery as a measure of outcome, we calculated for those patients not undergoing immediate drainage the sensitivity, specificity, positive predictive values, and negative predictive values for each of the criteria. The four criteria have relatively high specificity ranging from 82 to 96 percent, but have low sensitivity varying from only 18 percent for a positive Gram stain to 53 percent for a fluid LDH greater than 1,000 IU/L. We conclude that these criteria have limited usefulness in predicting the need for eventual chest tube drainage/decortication. Patients not meeting the criteria require close follow-up as well.     

Management of complicated parapneumonic effusions and thoracic empyema

The optimal management of loculated parapneumonic effusions and empyema includes breakdown of adhesions to effect drainage of infected pleural fluid. The use of fibrinolytics intrapleurally appears to enhance intercostal tube drainage, reducing the requirement for subsequent surgical mechanical debridement. This article discusses the evidence for intrapleural fibrinolytics, their good safety profile and the practicalities of dose and administration. It also reviews early surgical intervention, which may be indicated for medical treatment failure and, some would argue, as a suitable alternative to other medical interventions.     

Real-time polymerase chain reaction for microbiological diagnosis of parapneumonic effusions in Canadian children

BACKGROUND:

Community-acquired pneumonia (CAP) complicated by parapneumonic effusion/empyema is an infectious syndrome commonly encountered by physicians caring for children in Canada.

OBJECTIVE:

To investigate the incremental benefit of novel molecular testing for the microbiological diagnosis of pediatric CAP complicated by parapneumonic effusion/empyema in Canada.

METHODS:

A convenience sample of pleural fluid from 56 children who had been admitted to hospital in Ontario with CAP complicated by parapneumonic effusion between 2009 and 2011 was examined. Multiple uniplex real-time polymerase chain reaction (PCR) testing was performed on these pleural fluids and compared with traditional culture-based testing of blood and pleural fluid samples.

RESULTS:

Molecular methods detected a pathogen in 82% of cases, whereas traditional cultures of blood and pleural fluids detected a pathogen in only 25%. The majority of parapneumonic effusions were associated with pneumococcal infection; Streptococcus pneumoniae was detected in 62% of the samples using molecular methods but in only 14% of samples using culture-based methods. Streptococcus pyogenes, detected in 16% of samples using PCR, was the second most common pathogen found. No patients were found to have empyema caused by Staphylococcus aureus.

DISCUSSION:

The results showed that multiple uniplex real-time PCR performed substantially better than traditional culture methods for microbiological diagnosis of CAP complicated by effusion/ empyema. S pneumoniae and S pyogenes were found to be responsible for the majority of infections. The approach detected pathogens in a similar proportion of pleural fluid samples as previously reported nested PCR assays; furthermore, the real-time closed-well approach also minimized the risk of nonspecificity due to cross-contamination relative to nested PCR.

CONCLUSIONS:

Real-time PCR for the detection of bacterial DNA in pleural fluids has the potential to better define the microbiological cause of pediatric CAP. This approach could help clinicians provide targeted antimicrobial therapy.