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A pilot study of cytokine levels and white blood cell counts in the diagnosis of necrotizing fasciitis

A pilot study of cytokine levels and white blood cell counts in the diagnosis of necrotizing fasciitis
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  Brief Reports A pilot study of cytokine levels and white blood cell countsin the diagnosis of necrotizing fasciitis Robert M. Rodriguez MD a, *, Rabiatu Abdullah b , Robert Miller  b , Linda Barry c ,Kathrin Lungstras-Bufler  d , Phillip Bufler  d , Charles A. Dinarello d , Ed Abraham d a   Department of Emergency Services, San Francisco General Hospital, San Francisco, CA 94110, USA  b  Department of Emergency Medicine, Alameda County Medical Center, Oakland, CA 94602, USA c  Department of Surgery, UCSF East Bay Surgery Residency, Oakland, CA 94602, USA d  Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA AbstractStudy Objectives :  To characterize the early cytokine response of patients presenting to the emergencydepartment with necrotizing fasciitis (NF) and to determine whether serum cytokine levels and white blood cell (WBC) counts may be useful in distinguishing NF from other severe soft-tissue infections. Methods :  White blood cell counts and cytokine levels (IL-1 b , IL-1Ra, IL-6, IL-8, IL-18, and IFN- c )were measured in patients presenting to the emergency department with severe soft-tissue infections andhigh suspicion of NF. Necrotizing fasciitis was confirmed intraoperatively and by surgical pathology.Cytokines were measured via the liquid-phase electrochemiluminescence method. Results :  Thirty-five patients were enrolled, 18 were diagnosed with NF, and 17 were diagnosed withcellulitis and/or abscess (CAB). On admission, patients with NF had significantly higher WBC countsand lower levels of interleukin 1 b  (IL-1 b ) compared with patients with CAB. There were no statisticallysignificant differences in the levels of the other cytokines between the 2 groups. Conclusion :  Patients with NF have higher WBC counts and lower IL-1 b  levels compared with patientswith CAB. D  2006 Published by Elsevier Inc. 1. Introduction The incidence of necrotizing fasciitis (NF), a rapidlyspreading necrotic infection of the muscle, fascial planes,and subcutaneous fat, is relatively low—estimated at 0.4 cases per 100000 population [1]. Paralleling the risein black tar heroin injection drug use (IDU), however, thisincidence has been on the rise in California over the past decade [2]. Given that NF mortality may be as high as 76%[3] and that rapid sur gical debridement is associated with increased survival [4], prompt diagnosis of NF is critical.The diagnosis of NF and the distinction from other lessserious soft-tissue infections may be quite challenging. Evenin the presence of a fulminate myonecrosis and fascialinfection, overlying skin may resemble a benign cellulitis or abscess. We, and others, have reported that many of theclassically described signs of NF, such as fever, soft tissuegas on radiographs, and skin bullae, are often absent inIDU-associated NF [5,6].Cytokines are proteins or glycoproteins that serve as themediators of intracellular communication during immune 0735-6757/$ – see front matter   D  2006 Published by Elsevier Inc.doi:10.1016/j.ajem.2005.02.028 T  Corresponding author. Tel.: +1 510 437 8394.  E-mail address: (R.M. Rodriguez).American Journal of Emergency Medicine (2006)  24 , 58–  system activation. Proinflammatory cytokines such asinterleukins (IL) 1, 6, 8, 18, and interferon  c  (IFN- c ) have been implicated in the pathophysiology of multiple sepsissyndromes [7]. Their amplification and perhaps overampli-fication in sepsis may contribute to shock, multiple organfailure, and death.Cytokine profiles have been studied to elucidate the pathophysiology of various inflammatory diseases and may be useful for diagnostic and treatment decisions. Strecker et al [8] demonstrated that the extent of organ dysfunction andthe long-term outcome in patients with trauma could beestimated by early analysis of serum IL-6 and IL-8 levels.Keatings et al [9] have shown that levels of tumor necrosisfactor   a  and IL-8 in induced sputum samples of patientswith chronic obstructive pulmonary disease are elevatedcompared to levels in sputum of patients with asthma and of smokers without chronic obstructive pulmonary disease.The objectives of this study were (1) to characterize theearly (emergency department [ED]) cytokine response in NFand (2) to determine whether patients with NF havesignificant differences in cytokine levels or white bloodcell (WBC) counts in comparison to patients with non-NFsevere soft-tissue infection (cellulitis and/or abscess[CAB]). Confirmed significant differences in these serologictests could pave the way for further study of their use inmaking the notoriously difficult distinction between NF andother less serious soft-tissue infections. 2. Methods 2.1. Design and participants This was a prospective study of patients with severe soft-tissue infections performed at the Alameda County MedicalCenter Emergency Department, Oakland, Calif, which seesapproximately 65000 patients annually. The demographicsof this patient population include a high percent of injectionusers, with 20 NF cases associated with IDU encountered inthe ED in the year 2000. Institutional Review Boardapproval was obtained before the start of the study andwritten informed consent for study enrollment was obtainedfrom all study subjects. 2.2. Intervention From July 2000 to October 2001, all adult patients presenting to the ED with severe soft-tissue infections andhigh suspicion of NF were considered for enrollment. Giventhe fact that the skin signs of NF are subtle and veryinconsistent, and t hat f ever may occur in less than half of the patients with NF [5,6], these clinical signs were not used asabsolute inclusion criteria;  b high suspicion of NF  Q   wasdetermined by the ED physicians and surgeons caring for the patients. Patients with altered level of consciousnesswho were otherwise unable to consent were excluded.Because nearly all of our institution’s prior NF casesoccurred in IDU patients, history of IDU highly influencedsuspicion of NF. Use of injection drugs at the site of infection was determined by patient interview.Venous blood samples were obtained from study subjectsin the ED. White blood cell counts of these samples were performed in the Alameda County Medical Center labora-tory. Serum from blood samples was separated in thestandard fashion and then immediately frozen at    50 8 C.Serum samples were later thawed and analyzed by blindedcoinvestigators using the liquid-phase electrochemilumines-cence method for cytokines IL-11 b , IL-1Ra, IL-6, IL-8,IL-18, and IFN- c  at the Department of Infectious Diseasesof the University of Colorado Health Sciences Center,Denver, Colo.All enrolled patients were admitted to the surgical serviceand given systemic antibiotics. Debridement and incisionand drainage procedures were performed at the discretion of the surgical services. Necrotizing fasciitis was determined by intraoperative inspection of tissues and by officialsurgical pathology reports. 2.3. Statistical analysis Data from this study were entered into Microsoft ExcelVersion 98 (Microsoft Corporation, Redmond, Wash).Statview SE and Graphics (Abacus Concepts Inc, Berkeley,Calif) and STATA 7.0 Intercooled (STATA Cooperation,College Station, Tex) programs were used for data analysis.Analysis of variance was performed to compare mean WBCcounts and cytokine levels. 3. Results Thirty-five patients were enrolled of which 18 werediagnosed as NF and 17 as CAB. Seventy-seven percent were men, 56% were African American, 32% wereCaucasian, and 12% were Hispanic. The mean ages  F  SDwere 46.2 F 8.3 years for the NF group and 46.9 F 8.6 yearsfor the CAB group. Only 4 patients with NF and 7 patientswith CAB had fever in the ED, defined as  T   at 38 8 C or higher. No patients in either group presented with hypoten-sion defined as systolic blood pressure less than 90 mm Hg. Table 1  White blood cell counts and cytokine levels (mean F SD) of patients with NF vs patients with CAB NF (n = 18) CAB (n = 17)  P   valueWBC(  10 3 /mL)23.24  F  19.06 11.63  F  4.61 .006IL-1 b  45.53  F  22.06 68.21  F  23.7 .01IL-1Ra 8.76  F  13.22 3.22  F  5.28 .072IL-6 1800.17  F  4010.85 782.06  F  416.33 .368IL-8 1365.28  F  3393.3 475.47  F  293.79 .339IL-18 1151.06  F  1810.81 527.06  F  571.72 .257IFN- c  416.72  F  371.15 577.24  F  868.14 .327 A pilot study of cytokine levels and WBC counts in the diagnosis of NF 59  One patient with NF developed hypotension in the ED,which resolved with a fluid bolus. The mortality rate was28% in the NF group and zero in the CAB group.Only WBC counts and IL-1 b  levels were significantlydifferent between the 2 groups; WBC counts were signif-icantly elevated and IL-1 b  levels were significantly de-creased in the NF group. See Table 1 for mean cytokine andWBC levels for the 2 groups with corresponding  P   values. 4. Discussion In this prospective study, we found that patients with NFhad significantly elevated WBC counts and significantlydecreased IL-1 b  levels in comparison to patients with CAB.Levels of other interleukins were elevated in NF, but differences did not meet statistical significance—possiblydue to wide variations of levels and small sample size of the study.Produced in response to antigenic stimuli, cytokines arethe principal regulators of inflammatory and immuneresponse to infection. Although the cytokine response tomany infections has been characterized as significantly proinflammatory with elevated levels of IL-1, tumor necrosisfactor, and IL-6, others have demonstrated blunted inf lam-matory cytokine production in severe sepsis [7,10,11]. Our finding of low levels of IL-1 b  is most consistent with thisdepressed inflammatory cytokine response.The 2 forms of IL-1 (IL-1 b  and IL-1 a ) have identicalsystemic and local effects that include induction of fever,chemotaxis of neutrophils and mononuclear cells, andstimulation of  prostaglandin, nitric oxide, and other cyto-kine synthesis [12]. Two studies have noted a remarkablelack of fever in many severely ill patients with NF presenting to EDs [5,6]. It is possible that depression of IL-1 b  —the central endogenous pyrogen—may account for this notable lack of fever. Necrotizing fasciitis is a notoriously difficult diagnosis tomake if the clinician uses only clinical signs and radiogra- phy. A retrospective study by Bosshardt et al [6] revealedthat the classic signs of NF were not consistently reliable for diagnosis. In that study, only 47% of patients with NF hadclassic skin changes (bullae, vesicles, or necrosis), 51% hada temperature greater than 37.7 8 C, and 26% had subcuta-neous air on radiographs. In another recently publishedstudy conducted at our institution, we similarly found that fever, classic skin signs of NF, and gas on soft-tissueradiographs were very insensitive signs of NF [5].Considering the diagnostic difficulties and rapid pro-gression of NF, a reliable serum test distinguishing NFfrom other soft-tissue infections would be useful. Previousstudies have attempted to identify laboratory criterion that may be used in making this distinction. In a retrospectivecase review study of 17 patients with NF, Simonart et al[13] showed that C-reactive protein and creatinine kinaselevels were significantly elevated in patients with NFcompared with patients with cellulitis. Elevated sedimen-tation rate, normochromic anemia, normocytic anemia,hypocalcemia, acidosis, and elevated aldolase are nonspe-cific abnormalities that have been observed in NF [1], but no definitive associations have been found between theselabor atory values and biopsy-proven cases of NF. Wall et al[14] developed a simple model using WBC count andserum sodium levels to diagnose NF. Although this modeluses readily available laboratory assays, it has lowspecificity (76%) and poor positive predictive value(26%) for NF [14].Magnetic resonance imaging is more definitive in thediagnosis of NF t han plain radiography but may not bereadily available [15,16]. In a prospective study of 62 patients with NF, ultrasonographic findings of diffusethickening of subcutaneous tissue with a 4-mm or greater fluid layer had a sensitivity of 88% and a specificity of 93% in the detection of NF [17]. However, this modalityrequires considerable experience likely not available inmost institutions [17]. Tissue biopsy and explorativeinspection of tissues remain the gold standards in thediagnosis of NF. Necrotizing fasciitis is an uncommon disease, and our limited sample size may have precluded finding significant differences where they may truly exist, especially withregard to the other interleukins that were elevated but not significantly different. Furthermore, all but one of our  patients had IDU-associated NF; NF associated with other risk factors such as diabetes, vascular disease, or traumamay have different cytokine profiles.Atthistime,themostsignificantlimitationisthatcytokineanalysis is not widely available, therefore precluding its broaduseforscreening.Further characterization ofcytokinesin NF may enhance our understanding of this highly lethaldiseaseandcouldleadtothedevelopmentofrapidassaysthat may assist in the difficult task of distinguishing between NF and other non-NF soft tissue infections. References [1] Trent JT, Kirshner RS. Diagnosing necrotizing fasciitis. Wound Care2002;15:135-8.[2] Chen JL, Fullerton KE, Flynn NM. Necrotizing fasciitis associatedwith injection drug use. Clin Infect Dis 2001;33:6-15.[3] McHenry CR, Piotrowski JJ, Petrinic D, Malangoni MA. Determi-nants of mortality for necrotizing soft-tissue infections. Ann Surg1995;221:558-65.[4] Lille ST, Sato TT, Engrav LH, Foy H, Jurkovich GJ. Necrotizing soft tissue infections: obstacles in diagnosis. J Am Coll Surg 1996;182:7-11.[5] Lonergan S, Rodriguez RM, Schaulis M, et al. A case series of black tar heroin associated necrotizing fasciitis in injection drug users.J Emerg Med [in press].[6] Bosshardt TL, Henderson VJ, Organ Jr CH. Necrotizing soft-tissueinfections. Arch Surg 1996;131:846-52.[7] Oberholzer A, Oberholzer C, Moldawer LL. Cytokine signaling-regulation of the immune response in normal and critically ill states.Crit Care Med 2002;28:N3-N12. R.M. Rodriguez et al.60  [8] Strecker W, Gebhard F, Rager J, Bruckner UB, Steinbach G, Kinzl L.Early biochemical characterization of soft-tissue trauma and fracturetrauma. J Trauma 1999;47:358-64.[9] Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences ininterleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am JRespir Crit Care Med 1996;53:530-4.[10] Pruitt JH, Welborn MB, Edwards PD, et al. Increased solubleinterleukin-1 type II receptor concentrations in postoperative patientsand in patients with sepsis syndrome. Blood 1996;87:3282-8.[11] Terregino CA, Quin JV, Slotman GJ. Pilot study of cytokines inemergency department patients with systemic inflammatory responsesyndrome. Acad Emerg Med 1997;4:684-8.[12] Kaplan E, Dinarello CA, Gelfand JA. Interleukin-1 and the responseto injury. Immunol Res 1989;8:118-29.[13] SimonartT,SimonartJM,DerdelinckxI,DeDobbeleerG,VerleysenA,Verraes S, et al. Value of standard laboratory tests for the earlyrecognition of group A beta-hemolytic streptococcal necrotizingfasciitis. Clin Infect Dis 2001;32:E9-E12.[14] Wall DB, Klein SR, Black S, de Virgilio C. A simple model to helpdistinguish necrotizing fasciitis from nonnecrotizing soft tissueinfection. J Am Coll Surg 2000;191:227-31.[15] Wysoki MG, Santora TA, Shah RM, Friedman AC. Necrotizingfasciitis: CT characteristics. Radiology 1997;203:859-63.[16] Schmid MR, Kossmann T, Duewell S. Differentiation of necrotizingfasciitis and cellulitis using MR imaging. AJR Am J Roentgenol 1998;170:615-20.[17] Yen ZS, Wang HP, Ma HM, Chen SC, Chen WJ. Ultrasonographicscreening of clinically-suspected necrotizing fasciitis. Acad EmergMed 2002;9:1448-51. A pilot study of cytokine levels and WBC counts in the diagnosis of NF 61


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