C rective protein: n id to ssessment nd monitoring of cute pncretitis J Clin Pthol 1984;37:27-211 AD MAYR,* MJ McMAHON,* MARGART BOWN,t H COOPRt From the *University Deprtment ofsurgery, Generl Infrmry, Leeds, nd the tunit for Cncer Reserch, University ofleeds, Leeds LS2 9JT SUMMARY An evlution of C rective protein s n indictor of the progress of cute pncretitis hs been mde, nd the dt hve been compred with the informtion given by the white cell count, erythrocyte sedimenttion rte, nd temperture nd by two ntiproteses-, protese inhibitor nd, ntichymotrypsin. The min vlue of C rective protein is.to provide guide to the severity of the inflmmtion nd to increse clinicins' wreness of the ptient's enhnced risk of developing pncretic collections when the C rective protein concentrtion remins high (>1 mg/l) t the end of the first week of the illness. In this respect C rective protein concentrtions re superior to white cell count, erythrocyte sedimenttion rte, nd temperture nd the concentrtions of ntiproteses. An incresed serum C rective protein concentrtion is well recognised s non-specific response to wide vriety of tissue injuries.' 2 Sequentil mesurements of C rective protein concentrtion cn be helpful in providing wrning of inflmmtory complictions in disese-for exmple, postopertive sepsis nd thrombosis-nd its response to tretment.3 4 But in complex inflmmtory diseses there is no priori wy of forecsting whether C rective protein is going to provide useful informtion in clinicl decision mking. Nevertheless, the rpid respohse of C rective protein to chnges in the intensity of the inflmmtory stimulus suggest tht it might be vluble in the ssessment nd monitoring of cute pncretitis. The clinicl problem of prticulr interest ws to test whether C rective protein mesurements could reflect the severity of the ttck nd thereby provide wrning of the likely development of pncretic collections (pseudocyst, bscess, nd necrosis), which cn rise insidiously nd be life thretening.5 6 Most pncretic collections probbly rise when prt of the duct system is ffected in n re of necrosis which forms erly in the ttck of cute pncretitis. Although collection of fluid or sequestrum my subsequently develop over the course of or weeks, it is probble tht Accepted for publiction 14 November 1983. inflmmtion round the necrotic focus exists throughout the period of evolution. For this reson we thought it might be possible to screen for "foccult' collections using plsm indictors of the inflmmtory response. We hve studied the intensity of the C rective protein response nd its rte of chnge in cses of cute pncretitis of vrying severity. The vlue of this test ws compred with the informtion provided by the concentrtion of, ntichymotrypsin nd, protese inhibitor. The white cell count nd erythrocyte sedimenttion rte, stndrd indices of inflmmtion, were used s reference dt. The design precluded using the new dt for clinicl decision mking; however, the results indicte tht C rective protein cn identify severe pncretitis which my not be obvious t its onset, nd ly the bsis for prospective trils. Ptients nd methods Fifty-five ptients with cute pncretitis were studied. The dignosis ws bsed on plsm mylse vlue in excess of 12 IU/ 1 combined with consistent clinicl fetures in 48 ptients nd on the findings t lprotomy in seven ptients. The ptients were treted conventionlly, which in 3 ptients included dignostic peritonel lvge. They were dischrged from hospitl when the 27 J Clin Pthol: first published s 1.1136/jcp.37.2.27 on 1 Februry 1984. Downloded from http://jcp.bmj.com/ on 7 October 218 by guest. Protected by
28 Tble 1 Fifty-five ptients with cute pncretitis Mild* Severe No of ptients 39 16 Men: Women 19:2 6:1 Age rnge (yr) 22-85 26-8 (medin) (6) (65) *See text for definition of mild nd severe. ttck ws thought to hve settled ccording to routine clinicl criteri. Investigtions such s ultrsound exmintion nd computed tomogrphy were crried out only when there ws clinicl suspicion of pncretic collection. After dischrge from hospitl ll ptients were followed up for six months. The first 49 ptients were consecutive, but in order to provide sufficient numbers for nlysis dt from further six ptients who hd developed pncretic collection were dded to the series. ch ttck ws clssified s mild or severe ccording to clinicl criteri. A severe ttck ws defined s one which resulted in more thn 14 in hospitl, one which gve rise to compliction such s pseudocyst or bscess, or one which ws ftl. According to these criteri, there were 39 mild nd 16 severe ttcks (Tble 1). Pncretic collections developed in 11 ptients (eight pseudocysts nd three bscesses), six of whom were treted by opertion. Two ptients in this study were dischrged without recognition of their collection, only to be redmitted six nd 1 lter. Pncretic collections were dignosed 4 to 29 fter dmission to hospitl with pncretitis nd confirmed by computed tomogrphy in six ptients, ultrsound in four, nd t lprotomy in one. During the initil 13 in hospitl, plsm smples were collected on roughly lternte nd stored t -2 C. C rective protein,,- protese inhibitor, nd ntichymotrypsin were mesured by rdil immunodiffusion,8 using ntiser nd stndrds obtined from Behringwerke AG, Mrburg/Lhn, FRG, nd Sewrd Immunostics, Tble 2 Prognostic techniques currently used to predict the severity ofcute pncretitis Proportion of ptents with correct prognostic criteri Initil Dignostic Imnie's Rnson's clinicl peritonel criteri' criteri9 ssessment lvge7 Severe ttcks 7 (44%) 4 (36%) 7 (44%) 1 (62%) (n= 16) (n= 11) Mild ttcks 33 (1%) 18 (1%) 28 (76%) 16 (43%) (n= 39) (n= 33) (n= 18) (n = 37) (n = 37) Myer, McMhon, Bowen, Cooper London, UK. White cell count nd erythrocyte sedimenttion rte were mesured t the time the blood smples were tken using stndrd methods. The highest sublingul temperture recorded during ech 24 h period ws noted. Dt were collected to enble the prognostic criteri of Rnson et 19 nd Imrie et ll to be clculted. Results The criteri which re currently used to mke n erly prediction of the severity of cute pncretitis filed to recognise severl of the severe ttcks in this study. This ws becuse of their filure to predict severe pncretitis (s defined) unless the ptient developed evidence of the erly shock like component of the illness. Only eight of the 16 severe ttcks exhibited this shock like pttern. Of the severe ttcks 36% were correctly recognised by peritonel lvge, nd the multiple criteri c U) CL 3 5- - Mild cm - K Severe O J I I I I I I I I I I I I n 1 2 3 4 5 6 7 8 9 1 11 12 Fig. 1 Plsm concentrtions ofntichymotrypsin in ptients with mild nd severe cute pncretitis. ch point shows the men vlue recorded on tht dy nd the htching indictes the 95 % confidence limits ofthe men of ech group. J Clin Pthol: first published s 1.1136/jcp.37.2.27 on 1 Februry 1984. Downloded from http://jcp.bmj.com/ on 7 October 218 by guest. Protected by
C rective protein: n id to ssessment nd monitoring of cute pncretitis n c 2- - Mild O Severe NY 1 2 3 4 5 6 7 8 9 1 l l Fig. 2 Leucocyte count in ptients with mild nd severe cute pncretitis. Htching indictes the 95 % confidence limits. of Rnson et l9 nd Imrie et l' recognised 62% nd 44% respectively (Tble 2). Body temperture, erythrocyte sedimenttion rte, nd, protese inhibitor concentrtions filed to discriminte between severe nd mild ttcks. Although high vlues were often found in severe ttcks, there ws overlp of the 95% confidence limits of the mens of the mild nd severe groups throughout the study. Better discrimintion ws provided by white blood cell count, ntichymotrypsin nd C rective protein concentrtions (Fig. 1, 2, 3). A difference in the white blood cell count between the severe nd mild ttcks ws pprent on the dy of dmission to hospitl, but the initil concentrtion of C rective protein nd ntichymotrypsin could not differentite the two groups. As the cute phse response becme estblished, higher concentrtions of C rective protein nd ntichymotrypsin were sustined in severe ttcks, reching their mximum vlues towrds the end of the first week nd then flling. C rective 2, Q _ C) 16 - Mild - m s Severe v l 12 4 5 6 7 8 9 1 11 12 Fig. 3 Plsm concentrtion of C rective protein in ptients with mild nd severe cute pncretitis. Htching indictes 95% confidence limits. 29 protein ppered to provide considerbly better discrimintion between mild nd severe pncretitis thn the white blood cell count or ntichymotrypsin concentrtion. The fll of C rective protein towrds norml in severe cses ws consistently delyed. Individul C rective protein dt re shown in Fig. 4. The overlp of C rective protein concentrtions between the two groups ws reltively smll. In nlysing these results severe ttcks hve been considered s single group. Fig. 5 shows men C rective protein concentrtions in severe ttcks subdivided into two groups ccording to the development of pncretic collection. The rise nd fll of C rective protein concentrtion in these two groups ws similr, indicting tht the concentrtions of C rective protein did not pper to differentite the ttcks which were severe becuse collection developed from those tht were severe for other resons. J Clin Pthol: first published s 1.1136/jcp.37.2.27 on 1 Februry 1984. Downloded from http://jcp.bmj.com/ on 7 October 218 by guest. Protected by
21 15-1 C.,) 5- ' 8 *-*- ~~8 x * *--* o * 5 t 5c 7 8 9 1 11 12 Fig. 4 Plsm C rective protein concentrtion in ptients with cute pncretitis during the second week ofthe ttck. Oblique line indictes suggested levels of discrimintion between mild nd severe ttcks. Discussion o Severe * Mild Of the indices of inflmmtion studied, C rective protein differentited mild nd severe ttcks with gretest precision. Differentition becme clerer fter the first week, nd the overlp in the dt during the initil phse of the disese is consistent with other findings.",-protese inhibitor, nother cute phse rectnt protein, usully rises more slowly nd reches its pek lter, the time course of ntichymotrypsin being intermedite. Both these types of reponse were reflected in the results of this study. C rective protein rose to higher concentrtions in ptients with severe disese, s hs been shown previously,'5 but it ws the rte of fll from pek concentrtions which provided greter differentition between grdes of severity. There ws no suggestion tht C rective protein ws ble to seprte ptients who developed pncretic collections from those who were clssified s severe but who did not develop collections. A high concentrtion of C rective protein (> 1 mg/l) t the end of the first week, however, suggests tht the cm. ol 167 Myer, McMhon, Bowen, Cooper _: Collection on n No collection I I I I I I I I I 1 2 3 4 5 6 7 8 9 1 11 12 Fig. 5 Plsm concentrtions of C rective protein in ptients with severe cute pncretitis. Closed circles re men vlues from 11 ptients who developed pncretic collection; open circles re men vlues from five ptients who did not. ptient will hve n illness needing two or more weeks to recover-hence, clinicl wreness of the risk of pncretic collection in the ptient is reinforced. Collections re more common in ptients with n overtly severe or prolonged ttck of pncretitis'2 nd their presence should be sought in such ptients using computed tomogrphy nd other pproprite rdiologicl nd ultrsonic investigtions. High concentrtions of C rective protein seem to give wrning of severe locl inflmmtion in the ptient whose initil illness is reltively mild nd whose clinicl course is pprently benign. This study supports the view tht pncretic collections which develop in such ptients hve their origins t n erly stge in the ttck. The C rective protein response is similr in mgnitude to tht in ptients with more overtly severe pncretitis. Our experience, nd tht of others, suggests tht the identifiction of pncretic collections in some ptients is problem'3 1' nd the dt from this pilot study support the concept tht sensitive mrker of continuing inflmmtion my be of vlue to select J Clin Pthol: first published s 1.1136/jcp.37.2.27 on 1 Februry 1984. Downloded from http://jcp.bmj.com/ on 7 October 218 by guest. Protected by
C rective protein: n id to ssessment nd monitoring of cute pncretitis ptients who re t high risk of compliction. We believe tht mesurement of C rective protein concentrtion during the second week of the illness my enble rdiologicl imging techniques to be used to serch fruitfully for pncretic collections in high risk group. Its mesurement before the ptient s dischrge from hospitl seems wise precution. A prospective study to exmine this thesis is being crried out. We would like to thnk the clinicins t the Generl Infirmry, Leeds for llowing their ptients to be included in this study. AD Myer ws supported by the Amelie Wring Foundtion, the Specil Trustees of the Generl Infirmry t Leeds, nd the West Riding Medicl Reserch Trust. References 'Pepys MB. C rective protein fifty yers on. Lncet 1981;1:653-7. 2 Gewurz H. C rective protein nd the cute phse response. Adv Intern Med 1982;27:345-77. Morley JJ, Kushner I. Serum C rective protein levels in disese. Ann NY Acd Sci 1982;389:46-15. 4 Ghoneim AT, Howrths, Ionescu MI. Seril C rective protein mesurements in infective complictions following c:dic opertion evlution nd use in monitoring response to therpy. Ann Thorc Surg 1982;34: 166-75. Fischer C, Gill LC, Forrester MG, Nkmur K. Quntittion of 211 "cute phse proteins" postopertively. Vlue in detection nd monitoring of complictions. Am J Clin Pthol 1979; 66:84-6. 6 Rnson JHC, Spencer FC. The role of peritonel lvge in severe cute pncretitis. Ann Surg 1978;187:565-75. 7 McMhon MJ, Plyforth MJ, Pickford IR. A comprtive study of methods for the prediction of severity of ttcks of cute pncretitis. Br J Surg 198;67:22-5. Mncini G, Crbonr AO, Heremns JF. Immunochemicl quntittion of ntigens by single rdil immunodiffusion. Immunochemistry 1965;2:235-54. 9Rnson JHC, Rifkind KM, Turner JW. Prognostic signs nd non-opertive peritonel lvge in cute pncretitis. Surg Gynecol Obstet 1976;143:29-19. 1 Imrie CW, Benjmin IS, Ferguson JC, McKy AJ, Mckenzie I, (YNeill JO, Blumgrt LH. A single centre double-blind tril of Trsylol therpy in primry cute pncretitis. Br J Surg 1978;65:337-41. "Cooper MJ, Whicher JT, Wlters G, Willimson RCN. Predictive vlue of C rective protein nd complement in severe cute pncretitis. Gstro Clin Biol 1981;5:92. 12 Rnson JHC, Spencer FC. Prevention, dignosis nd tretment of pncretic bcess. Surgery 1977;82:99-16. Donldson LA, Brodie MJ, McIntosh WB, Joffe SN. Amylse thermolbility s screening test for pncretic pseudocysts. Br J Surg 1978;65:413-5. 14 Collins RC, Frost SJ, Spittlehouse K. The P. iso-enzyme of serum mylse in the mngement of ptients with cute pncretitis. Br J Surg 1982;69:373-5. 5 McMhon MJ, Plyforth MJ, Rshid SA, Cooper H. The mylse-to-cretinine rtio- non-specific response to cute illness. Br J Surg 1982;69:29-32. Requests for reprints to: Dr MJ McMhon, University Deprtment of Surgery, Leeds Generl Infirmry, Leeds LS1 3X, nglnd. J Clin Pthol: first published s 1.1136/jcp.37.2.27 on 1 Februry 1984. Downloded from http://jcp.bmj.com/ on 7 October 218 by guest. Protected by