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A new approach to pleural effusion in cats: markers for distinguishing transudates from exudates

A new approach to pleural effusion in cats: markers for distinguishing transudates from exudates
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  A new approach to pleural effusion in cats: markersfor distinguishing transudates from exudates Andrea Zoia  DVM 1 *, Linda A Slater  VN Dip AVN (Surgical) 2 , Jane Heller  BVSc, MVetClinStud 3 ,David J Connolly  BSc, Bvet Med, PhD, Dip ECVIM-CA (Cardiology) 2 , David B Church  BVSc, PhD, FHEA 2 1 UCD School of Agriculture, FoodScience and Veterinary Medicine,Belfield, Dublin 4, Ireland 2 Institute of Comparative Medicine,Division of Companion AnimalSciences, Faculty of Veterinary Medicine, University of Glasgow,Glasgow G61 1QH, UnitedKingdom 3 Department of Veterinary ClinicalSciences, Royal Veterinary College,University of London, North Mymms AL9 70A, United Kingdom Classification of pleural effusion (PE) is central to diagnosis. Traditionalveterinary classification has distinguished between transudates, modifiedtransudates and exudates. In human medicine PEs are divided into only twocategories: transudates and exudates. The aim of this study was to evaluate, in 20cats presented with PE, paired samples of serum and pleural fluid for thefollowing parameters: Light’s criteria (pleural fluid lactate dehydrogenaseconcentration (LDHp), pleural fluid/serum LDH ratio, pleural fluid/serum totalprotein ratio (TPr)), pleural fluid total protein, pleural fluid cholesterolconcentration, pleural fluid/serum cholesterol ratio (CHOLr), serum-effusioncholesterol gradient (serum cholesterol minus PE cholesterol concentration(CHOLg)), PE total nucleated cells count (TNCCp) and pleural fluid glucose(GLUp). LDHp and TPr were found most reliable when distinguishing betweentransudates and exudates, with sensitivity of 100% and 91% and specificity of 100%, respectively. When conflict between the clinical picture and laboratoryresults exists, calculation of CHOLr, CHOLg and TNCCp measurement mayhelp in the classification of the effusion. Measurement of serum albumin (in thecase of a transudate) may provide additional information regarding thepathogenesis of the effusion. Date accepted: 21 April 2009    2009 ESFM and AAFP. Published by Elsevier Ltd. All rights reserved. T he aetiopathogenic classification of pleural ef-fusion (PE) can be challenging. 1 In humanmedicine, PEs are categorised only as transu-dates, resulting from increased hydrostatic pressureor decreased osmotic pressure, or exudates, resultingfrom increased vascular permeability. 2 e 5 Simulta-neous evaluation of pleural fluid and serum protein,lactate dehydrogenase (LDH) and other biochemicalparameters has been proven reliable and effective inidentifying the pathophysiology of formation of a PE. 2 e 4,6 In the case of a transudate, subsequent eval-uation of the serum albumin will then clarify if the ef-fusion formed is due to a decrease in colloid osmoticpressure or the result of an increase in hydrostaticpressure.In veterinary medicine, PEs were srcinally classi-fied as transudates or exudates and specific gravity,protein content and cellularity of the effusion wereused to differentiate them. 7 Due to the common over-lap in values of these parameters between transudateand exudate Perman introduced the modified transu-date group to veterinary medicine 8 and defined it asclosely resembling an exudate based on protein con-tent and cellularity, but resulting from increased hy-drostatic pressure. 8,9 Another commonly reporteddefinition of  modified transudate is a ‘long standingtransudate’. 10 While the latter definition does notdescribe a pathophysiological mechanism of fluid for-mation, but instead an ‘in vivo ageing sample artifact’,Perman’s definition, also called obstructive effusion, 11 gives information on the pathophysiological mecha-nism of the fluid formation. A survey of the literatureneither reveals published evidence to support thisclassification nor studies showing how the cut-off values for the markers conventionally used to classifyPEs were derived. Studies assessing the sensitivityand specificity of these markers in classifying PEs cor-rectly are also lacking. The large and variable numberof disorders associated with modified transudates andthe fact that this category has overlapping proteincontent and cellularity with transudates and exudates,limit the current veterinary classification scheme of PEs.The aim of this study was to determine whether thesimultaneous evaluation of pleural fluid and serumprotein, LDH and other biochemical parameters is *Corresponding author. E-mail:  Journal of Feline Medicine and Surgery  (2009)  11 , 847 e 855doi:10.1016/j.jfms.2009.04.005 1098-612X/09/100847+09 $36.00/0    2009 ESFM and AAFP. Published by Elsevier Ltd. All rights reserved.  useful in the classification of feline PE based on thepathophysiological mechanism of formation, as al-ready demonstrated in human literature. 2 e 5 Material and methods This was a prospective study in which 20 consecutivecats presenting with PE between March 2002 and Sep-tember 2003 were enrolled. Fifteen cats were referredto the Royal Veterinary College, Queen Mother Hospi-tal for Animals (QMHA) and five cats were seen inprivate practices.Inclusion criteria included the presence of PE, abil-ity to collect a blood and a PE sample no more than2 h apart from each other and determination of the ae-tiology of the PE. A complete history, including priormedical treatment, was obtained. Patients that re-ceived any pharmacological treatment, which couldhave altered the aetiological diagnosis prior to sam-pling (eg, glucorticoids), were excluded. Animalsthat received diuretics before presentation were in-cluded. A full physical examination and complete blood count, serum biochemistry profile were per-formed on each cat. Pleural fluid samples, collected by thoracocentesis in all cats, were divided into threealiquots and stored in K 3 -EDTA, plain and fluorideoxalate tubes. The serum and plain pleural fluid sam-ples were centrifuged and separated within 30 minand processed within 48 h of collection. An automatedcell count and a cytological examination by a boardcertified clinical pathologist were performed. All bio-chemical parameters from the blood and pleural fluidwere measured with validated feline assays using anOpeRA Chemistry Analyzer (Bayer PLC, Berkshire,UK) at the QMHA. Thoracic radiographs were ob-tained from all cats. When PE volume precludedgood thoracic radiological assessment they wererepeated post-thoracocentesis. Further tests [eg, ab-dominal ultrasonography or radiography, echocardi-ography, electrocardiogram, serum total T 4 , felineleukaemia and feline immunodeficiency virus status(by rapid immunochromatographic method, SpeedDuo FeLV/FIV, Vetlab Supplies, UK), feline coronavi-rus (FCoV) antibody titre (by immunofluorescence aspreviously described)] 12 were performed as clinicallyindicated to achieve a definitive diagnosis. One catunderwent a full post-mortem examination.The cause of PE was identified with reference to thefollowing pre-determined criteria:a. Congestiveheartfailure(CHF)asacauseofPEwasdiagnosed if the patient had appropriate history,presenceofcardiacmurmur,severestructuralheartdiseasediagnosedonechocardiographybyaboardcertified cardiologist, moderately to severe en-largedleftatrium(leftatrialtoaorticdiameterratioof  > 1.5on2Dechocardiographyfromtheright-par-asternal short-axis heart base view) 13 and/or rightatrium and other causes of PE were excluded. Inone cat a full post-mortem examination confirmedin vivo findings. b. Malignant effusion required histopathological orcytological demonstration of neoplastic tissue inthe pleural cavity or fluid.c. Pyothorax required positive bacterial culture, orpresence of degenerate neutrophils and intracellu-lar bacteria on cytological preparations of pleuralfluid.d. Chylous effusion was characterised based on col-our (milky), turbidity (opaque), fluid triglyceri-des > 100 mg/dl, fluid to serum triglycerideratio > 1, fluid to serum cholesterol ratio < 1, fluidcholesterol to triglyceride ratio < 1, protein con-centration > 30.0 g/l and recognition of lympho-cytes or neutrophils as the predominant effusioncell type. 14 e 16 e. PE secondary to feline infectious peritonitis (FIP)was diagnosed when supportive history, signal-ment,clinicalandclinicopathologicaldataincludingnon-regenerative anaemia, lymphopenia, predomi-nance of non-degenerate neutrophils on cytologicalexamination of the effusion, serum and fluid totalprotein concentration > 80 g/l, serum and fluidglobulinconcentration > 50 g/l,serumandfluidal- bumin:globulin ratio < 0.45, serum and fluid FCoVantibody titres > 1:1280 and increased serum  a -1acid-glycoprotein were present and no other causesof PE could be identified.Effusions were then classified as transudates or ex-udates based on their pathophysiology. Transudateswere the effusions from animals with CHF. Exudateswere the effusions from animals with neoplasia, pyo-thorax and FIP. For the purposes of this study, chylouseffusions were classified in accordance with humanliterature as exudates. 17,18 Parametersmeasuredorcalculatedincluded:Light’scriteria (namely pleural fluid LDH (LDHp), pleuralfluid/serum LDH ratio (LDHr) and pleural fluid/se-rumtotalproteinratio(TPr)),pleuralfluidtotalprotein(TPp), PE total nucleated cells count (TNCCp), pleuralfluidcholesterol(CHOLp),pleuralfluid/serumcholes-terol ratio (CHOLr), serum-effusion cholesterol gradi-ent (serum cholesterol concentration minus CHOLp)(CHOLg), pleural fluid glucose (GLUp) and pleuralfluidredbloodcells(RBCp).Duetotheclinicalinstabil-ity of the cats and the difficulties in collecting the sam-ples, without further compromise to the clinical statusof the patients, not all the above tests were availablefor each animal (Table 1).For comparison the same effusions were also classi-fied using traditional veterinary method based onTPp and TNCCp (transudate: TPp < 25 g/l, TNC-Cp < 1500  m l; modified transudate: TPp ¼ 25 e 75 g/l,TNCCp 1000 e 7000  m l; exudate TPp > 30 g/l, TNN-Cp > 7000  m l). 15 The modified transudate was consid-ered, as first suggested by Perman, an effusionresultant from an increase in hydrostatic pressure. 8,9 848 A Zoia et al  Table 1 . Aetiology of PEs from 20 cats and values of the analytes measured and calculated in the PE and serum Case  n  Causes of PE PE Serum Calculated valuesLDHp(IU/l)TPp(g/l)GLUp(mmol/l)RBCp  10 12 /lTNCCp  10 9 /lCHOLp(mg/dl)LDH(IU/l)TP(g/l)CHOL(mg/dl)TPr LDHr CHOLr CHOLg1 CHF 26 3.2 8.5 0 1.5 3 163 71.9 274 0.04 0.15 0.01 2712 CHF 54 22.6 6.7 0.02 1.3 58 329 56 135 0.4 0.16 0.42 803 CHF 66 34.4 9.4 0.11 5.1 89 423 65.8  e  0.52 0.15  e e 4* CHF 79 35 12.8 0 3.6 81 402 68.4  e  0.51 0.19  e e 5* CHF 105 30.3 7.4 0 2.5 85 196 71 274 0.42 0.53 0.3 1896 CHF 114 30.1 5.1  e  3.5 42 538 59.6 89 0.5 0.21 0.47 477 CHF 177 44.6 6.1 0 5.9 127 284 78.5 236 0.56 0.62 0.53 1098 CHF 202 30.9 7.8 0 1.0 77 263 57.2 201 0.54 0.76 1.38 1249* CHF 226 13.8 10.2 0 0.3 27 1865 62.9 150 0.21 0.12 0.18 12310 Carcinoma 258 43.3 9.6  e  0.85 116 215 64.9 189 0.67 1.2 0.61 7311* Idiopathic C 276 54.8 6 0 8.3 65 360 72.6 92 0.75 0.76 0.7 2712 Lymphoma 363 29.9 5.2 0 9.2 46 200 59.7 108 0.5 1.81 0.42 6213 Carcinoma 364 54.3 9.5 0.03 9.0 112 513 76 174 0.71 0.7 0.64 6214 FIP 647 82.4  e  0.008 4.2  e  1499 82.4 208 0.69 0.43  e e 15 Idiopathic C 949 51.2 7.5 0.09 6.7 85 479 64.3 112 0.79 1.98 0.75 2716 Cardiogenic C 1701 62.3 10.3  e  6.9 89 266 52 185 1.19 6.39 0.48 9617* Carcinoma 2363 48.1 5 0.67 6.6 104 269 70.6  e  0.68 8.78  e e 18 Carcinoma 5837 64.2 0  e  22.1 119 375 84.7 162 0.75 15.6 0.73 4319 Pyothorax 13,010 27 0  e  297 34 3274 42.7 69 0.63 3.97 0.49 3520 Pyothorax 20,156 27.6 0.1 0.56 81.2 58 4875 34.1 112 0.8 4.1 0.51 54 n ¼ PE number; C ¼ chylothorax; TP ¼ total protein; GLU ¼ glucose; CHOL ¼ cholesterol; p ¼ pleural effusion; r ¼ ratio; g ¼ gradient.*Animals that received diuretics treatment before thoracocentesis.  8  4   9  A n e w a  p  p r  o a c  h  t   o  p l    e u r  a l    e f    f    u s  i    o n i    n c  a t   s   Statistical analysis  Median values for TPp, TPr, TNCCp, LDHp, LDHr,CHOLp, CHOLr and CHOLg were compared betweentransudatesandexudatesusingMann e Whitney U  tests.Using the cut-off value adopted in human medicine foreachoftheeightabovementionedbiochemicalparame-ters the accuracy [( Tp þ Tn )/( Tp þ Tn þ Fp þ Fn )] of each test in distinguishing exudates and transudatewasestablished,where Tp isthenumberoftruepositivediagnoses, Tn thenumberoftruenegativediagnoses, Fp the numberoffalse positivediagnosis, and  Fn the num- beroffalse negative diagnoses. Inaddition the utility of eachbiochemicalparameterinidentifyingexudateswasevaluated by calculating sensitivity [ Tp /( Tp / Fn )] andspecificity [ Tn /( Tn þ Fp )]. As transudates and exudatesare complementary terms, we must emphasise that forany given analyte, the specificity for exudates corre-sponds to the sensitivity for transudates.Receiver operating characteristic (ROC) curve anal-ysis, graphing sensitivity against (1-specificity) wasthen used to establish the optimal cut-off point of the above biochemical analytes measured and calcu-lated. Optimal cut-off points (to maximise both sensi-tivity and specificity) were established by selecting thepoints of test values that provided the greatest sum of sensitivity and specificity, corresponding to the pointclosest to the top left hand corner of the ROC curve.The three cut-off values of the Light’s criteria werealso used in parallel with an ‘or’ rule as in the srcinalstudy. 2 Performance of each test for diagnostic separa-tion of transudates and exudates was assessed againusing: sensitivity, specificity and overall accuracy atthe optimal cut-off point for each parameter.Median RBCp value between exudative neoplasticand non-neoplastic PEs was compared usingMann e Whitney  U   tests.Spearman’s rank correlation tests were used to as-sess correlations between: LDH and RBC and glucoseand TNCC in the PE.For all analyses,  P  values  < 0.05 were consideredsignificant. Results Based on pathophysiology of formation nine effusionswere transudates (all secondary to CHF) and 11 wereexudates (five caused by malignancies, three by chylo-thorax and three by infectious diseases) (Table 1). Fiveof the cats with transudates were male (one entire andfour neutered) and four were female (one entire andthree neutered), with an average age of 8.89  4.58years (range 3.0 e 14.41 years). Those with exudateswere five male (all neutered) and six female (one en-tire and five neutered), with an average age of 9.07  4.96 years (range 0.33 e 13.83 years).Using the traditional veterinary classification 8,9,15 of theninemodifiedtransudates,TPpandTNCCpvaluescaused misclassification of two effusions (effusionnumber: 2 and 9) as pure transudates and it was notpossible to clearly classify two more effusions (effu-sions number: 1 and 8) because of discordant informa-tion deriving from TPp and TNCCp (Table 1). Of the11 exudates TPp and TNCCp results caused misclassi-fication of four effusions. Three (effusion number: 15,16 and 17) were incorrectly classified as modified tran-sudates and one (effusion number: 10) was misclassi-fied as intermediate between a pure transudate andamodifiedtransudate.InadditionTPpandTNCCpre-sults prevented clearclassification offour moreexuda-tive effusions (effusion number: 12, 14, 19 and 20) because of discordant information deriving from TPpandTNCCp(Table1).Theoverallaccuracyofthetradi-tional veterinary classification was 40%. TPp and TPr  TPp and TPr values were significantly different be-tween transudate and exudates ( P ¼ 0.0251 and P ¼ 0.0002, respectively). TNCCp  TNCCp values were significantly different betweentransudate and exudates ( P ¼ 0.003). LDHp and LDHr  LDHp and LDHr values were significantly different between transudates and exudates ( P ¼ 0.0001 and P ¼ 0.0002, respectively). LDHp and RBCp  RBCp count was available for 15/20 cats. Statisticanalysis showed a statistically significant positive cor-relation between LDHp values and RBCp ( Rho ¼ 0.54, P ¼ 0.037). RBCp count was available for 7/11 exudateand median RBCp value between neoplastic and non-neoplastic PE was not statistically different ( P ¼ 0.95). CHOLp, CHOLr and CHOLg  CHOLp, CHOLr, and CHOLg were available for19/20, 16/20 and 16/20 cats, respectively. CHOLpvalues were not significantly different between tran-sudates and exudates ( P ¼ 0.2864). CHOLr andCHOLg values were significantly different betweentransudates and exudates ( P ¼ 0.0251 and  P ¼ 0.0047,respectively). GLUp  GLUp was available in 19/20 cases and showed a sta-tistically significant negative correlation with TNCCof the effusion ( Rho ¼ 0.56,  P ¼ 0.012).Results for sensitivity, specificity, accuracy, numberof misclassified transudate and exudate for TPp, TPr,TNCCp, LDHp, LDHr, Light’s criteria (used in paral-lel with an ‘or’ rule), CHOLp, CHOLr and CHOLgcalculated for each of the above parameters using 850 A Zoia et al  ROC plot for CHOLg 0.00 0.25 0.50 0.75       S     e     n     s      i      t      i     v      i      t     y 1-SpecificityROC plot for LDHp 0.00 0.25 0.50 0.75       S     e     n     s      i      t      i     v      i      t     y 1-SpecificityROC plot for TPp 0.00 0.25 0.50 0.75 0.751.       S     e     n     s      i      t      i     v      i      t     y 1-SpecificityROC plot for CHOLp 0.00 0.25 0.50 0.75       S     e     n     s      i      t      i     v      i      t     y 1-SpecificityROC plot for CHOLr  0.00 0.25 0.50 0.75       S     e     n     s      i      t      i     v      i      t     y 1-SpecificityROC plot for LDHr  0.00 0.25 0.50 0.75       S     e     n     s      i      t      i     v      i      t     y 1-SpecificityROC plot for TPr  0.00 0.25 0.50       S     e     n     s      i      t      i     v      i      t     y 1-Specificity 0.00 0.25 0.50 0.75       S     e     n     s      i      t      i     v      i      t     y 1-SpecificityROC plot for TNCCp ACBDEFGH Fig 1 . ROC plots of pleural fluid values for TPp, TPr, LDHp, LDHr, CHOLp, CHOLr, CHOLg and TNCCp. The optimumcut-off level ( B ) was determined by selecting points of test values that provided the greatest sum of sensitivity andspecificity. The optimum cut-off levels for TPp, TPr, LDHp, LDHr, CHOLp, CHOLr, CHOLg, TNCCp were 35.0 g/l, 0.56,226 IU/l, 0.62, 88 mg/dl, 0.47, 77.0 mg/dl and 5900  m l, respectively. TP ¼ total protein, LDH ¼ lactate dehydrogenase,CHOL ¼ cholesterol, TNCC ¼ total nucleated cell counts, p ¼ pleural effusion, r ¼ ratio, g ¼ gradient. 851A new approach to pleural effusion in cats
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