Cabric, Sabrina

Maiolo, Elena

Morgenstern, Christian

Perka, Carsten

Renz, Nora

Trampuz, Andrej

English

Institutional Repository of the Freie Universität Berlin

CORRESPONDENCE Open AccessInvited reply to the letter to the editor byMcNally et al., 2021Christian Morgenstern* , Nora Renz, Sabrina Cabric, Elena Maiolo, Carsten Perka and Andrej TrampuzThank you for the opportunity to respond to the com-ments on our paper Morgenstern et al. 2020 [1]. The de-tection of microbial heat production (microcalorimetry)has been studied for several biological and medical appli-cations and has shown superior sensitivity and/or shortertime to microbial detection compared to conventionalculture [2–4]. In our study we aimed to evaluate the per-formance of microcalorimetric analysis of synovial fluidin comparison to synovial fluid culture for the preopera-tive diagnosis of periprosthetic joint infection (PJI).In their Letter to the Editor (McNally et al. 2021), theauthors raised their concern over the use of unvalidateddefinition criteria of PJI, which could potentially lead tooverdiagnosing of infection. It is correct that the defin-ition criteria we used for this study are highly sensitiveand could be prone to over-diagnosing rather thanunderdiagnosing infection. Still, this classification systemis presently being used in the clinical routine in manyinstitutions (including ours) and has also been employedin several other studies [5–16].In the last years, various PJI diagnostic criteria havebeen proposed and used by different authors. In the timeour prospective study was conducted (2014 to 2015), theInternational Consensus Meeting (ICM) criteria [17], theMusculoskeletal Infection Society (MSIS) criteria [18]and the Infectious Disease Society of America (IDSA)criteria [19] were the most popular criteria available forPJI definition. However, we believed that these criteriawere not appropriate for our study as they present cru-cial drawbacks. For instance, IDSA criteria do not con-sider an important criterion for PJI, namely the synovialfluid leukocyte count, which is inappropriate for a studythat focuses on the preoperative investigation of synovialfluid. The 2013 ICM criteria were mainly based on ex-pert opinion and studies with a low quality of evidence[20]. Furthermore, sonication of removed implants,which represents the most sensitive intraoperativemethod to detect low-virulent pathogens [21], was notconsidered neither in ICM nor in IDSA criteria, whichconsequently made them miss a considerable number ofPJI [9, 10]. In fact, in a cohort of 136 patients with apainful prosthetic joint, Huard et al. [10] reported 41 PJIapplying MSIS criteria, 50 with IDSA and 68 with pro-posed European Bone and Joint Infection Society (EBJIS)(our institutional) criteria, confirming the results pub-lished by Renz et al. [9]. ICM criteria predominantlymissed those infections caused by low-virulent patho-gens [9]. Another study showed that presence of a singleminor criterion (but not fulfilling the 2013 ICM criteriafor PJI) was associated with worse outcome of total jointrevision [22]. These observations resulted in the modifi-cation of the ICM PJI definition criteria in 2018 [23].In regard to the other comments, we are not ignoringthe value of preoperative synovial biopsies as claimed byMcNally et al. Still, we believe that this invasive proced-ure (requiring arthroscopy or open biopsy) should beperformed only exceptionally, i.e. in case of a dry tap orinconclusive arthrocentesis results, as it posesintervention-related risk of additional infection. Inaddition, arthroscopically collected samples are probablynot most representative for diagnosis of low-grade infec-tion, as the biofilm location at the prosthesis-bone inter-face cannot be easily reached. The additional risk ofperforming a biopsy needs to be weighed against themoderate gain of additional information compared toonly performing arthrocentesis. Some institutions stillperform open biopsy as part of diagnostic routine,which, in our opinion, should be done only in excep-tional cases with a good rational indication.© The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.* Correspondence: christian.morgenstern@charite.deCenter for Musculoskeletal Surgery (CMSC), Charité – UniversitätsmedizinBerlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zuBerlin and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, GermanyMorgenstern et al. BMC Musculoskeletal Disorders          (2021) 22:256 https://doi.org/10.1186/s12891-021-04118-7The optimal cutoff value for synovial fluid leukocytecount that allows discriminating chronic PJI (occurringafter > 4 weeks postoperatively or with a symptom dur-ation of > 4 weeks) from aseptic failure has been sug-gested by different investigators ranging from 1100/μl to4200/μl. When considering studies reporting a realisticrate of low-virulent causing pathogens (e.g. coagulase-negative staphylococci), referred cutoff values werebelow 2000/μl [24, 25]. Regarding the histopathology[26], the result of 1 to 10 granulocytes per high-powerfield was used for histopathological diagnosis of PJI. Thecutoff of 2 granulocytes per high-power field in thisstudy based on the recent report of Krenn et al. [27]demonstrating a cut-off of 23 granulocytes in a total of10 high-power fields as optimal threshold, which pro-portionally translates to 2 granulocytes per high-powerfield (averaged over 10 fields).Based on these facts, we firmly disagree with McNallyet al.’s assertion that our study could be misleading orbiased. The definition criteria in our study were delin-eated in the Methods section and individually listed inthe Results section, which allows for an adequate inter-pretation of the results by the reader. We agree that byusing highly sensitive criteria to define infection, the per-formance of all evaluated diagnostic tests could beunderestimated. However, as the performance of alldiagnostic tests was assessed using the same definitioncriteria, the alleged “bias” would therefore equally applyto all the evaluated diagnostic methods without a select-ive disadvantage to a particular method. In fact, the posi-tivity rate of synovial fluid culture and microcalorimetryin the present study was equal (39 and 39%, respect-ively), as it was in a previous study investigating cultureand microcalorimetry of synovial fluid of native joint forthe diagnosis of infection (46 and 46%, respectively) [3].Most recently, the PJI definition criteria of the EBJIS havebeen published by most of the authors that redacted the Let-ter we are herewith replying to [28]. Our institutional criteriawere presented by one author of our group (AT) during the36th Annual Meeting of EBJIS in 2017, and thereafter havebeen referred to in many studies as “proposed EBJIS criteria”[5–10, 12–16, 28, 29]). The meeting recommended a re-appraisal of the definition categories which resulted in thepublication of the official EBJIS criteria in 2021 [28]. In fact,in the recently published paper by EBJIS [28], the describedconfirmative definition criteria represent modified versionsof our institutional definition criteria.We believe that the new EBJIS definition criteria arerobust and superior to previously used criteria (MSIS,ICM, IDSA). We regret that our previous contributionin the development of the PJI definition criteria was notappropriately credited in the recent publication ofMcNally et al. [28] by indicating the originalpublications.In conclusion, PJI definition criteria are a matter ofcontinuous debate and there is not one set of criteriathat has been universally accepted or validated. Despitesome investigators claim to use validated PJI definitioncriteria [23, 29, 30], none of these criteria were appropri-ately validated on an independent large cohort withlong-term follow-up. Considering patient conditions andexpectations, microbiology, intervention-related risks,ethical considerations and functional outcome, the treat-ing physician needs to decide individually whether touse highly sensitive criteria (and thereby overdiagnoseinfection with a risk of overtreatment) or highly specificcriteria (and thereby miss some infections, potentiallyresulting in subsequent treatment failure with all relatedconsequences). In many institutions (including ours),highly sensitive definition criteria are used as clinical de-cision support tool. We must accept that it is not alwayspossible to establish a clear diagnosis of infection andaseptic failure, with a remaining “gray zone” of inconclu-sive cases. Therefore, each case must be individuallyevaluated before deciding on the most appropriate ther-apy, independently from the definition criteriaemployed.We hope that this response will contribute to the dis-cussions on finding the best PJI definition criteria in thefuture. For full transparency, raw data of this study areprovided as Supplementary Material.Yours sincerely,Christian Morgenstern.Nora Renz.Sabrina Cabric.Elena Maiolo.Carsten Perka.Andrej Trampuz.AbbreviationsEBJIS: European Bone and Joint Infection Society; IDSA: Infectious DiseaseSociety of America; ICM: International Consensus Meeting;MSIS: Musculoskeletal Infection Society; PJI: Periprosthetic joint infectionSupplementary InformationThe online version contains supplementary material available at https://doi.org/10.1186/s12891-021-04118-7.Additional file 1.AcknowledgementsNone.Authors’ contributionsAll authors compiled, edited and approved the contents of this invited reply.FundingNone. Open Access funding enabled and organized by Projekt DEAL.Availability of data and materialsFor full transparency, raw data of this study are provided as SupplementaryMaterial.Morgenstern et al. BMC Musculoskeletal Disorders          (2021) 22:256 Page 2 of 3DeclarationsEthics approval and consent to participateN/RConsent for publicationN/RCompeting interestsNoneReceived: 3 December 2020 Accepted: 25 February 2021Bibliography1. Morgenstern C, Cabric S, Maiolo E, et al. Thermogenic diagnosis ofperiprosthetic joint infection by microcalorimetry of synovial fluid. BMCMusculoskelet Dis. 2020;21:345.2. Butini ME, Moreno MG, Czuban M, et al. Real-time antimicrobialsusceptibility assay of planktonic and biofilm bacteria by isothermalmicrocalorimetry. Adv Exp Med Biol. 2019;1214:61–77.3. Morgenstern C, Renz N, Cabric S, Perka C, Trampuz A. Multiplex polymerasechain reaction and microcalorimetry in synovial fluid: can pathogen-baseddetection assays improve the diagnosis of septic arthritis? J Rheumatol.2018;45:1588–93.4. Borens O, Yusuf E, Steinrücken J, Trampuz A. Accurate and early diagnosis oforthopedic device-related infection by microbial heat production andsonication. 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Abdelaziz H, Rademacher K, Suero EM, et al. The 2018 internationalconsensus meeting minor criteria for chronic hip and knee periprostheticjoint infection: validation from a single center. J Arthroplast. 2020;35:2200–3.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Morgenstern et al. BMC Musculoskeletal Disorders          (2021) 22:256 Page 3 of 3

Invited reply to the letter to the editor by McNally et al., 2021

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Invited reply to the letter to the editor by McNally et al., 2021

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