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January 2018, VOL. 76, NO. 1, ISSN 0300-2977 Management of community-acquired pneumonia in adults • Conversion from tacrolimus to everolimus after kidney transplantation • Simethicone in small bowel capsule endoscopy • Crowding at the emergency department published in collaboration with the netherlands association of internal medicine The Netherlands Journal of Medicine A referral from the dentist; what is your diagnosis? JANUARY 2018, VOL. 76, NO. 1 © Van Zuiden Communications B.V. All rights reserved. The Netherlands Journal of Medicine MISSION STATEMENT To serve the need of the physician to practice up-to-date medicine and to keep track of important issues in health care. To promote and to enhance clinical knowledge by publishing editorials, original articles, reviews, papers regarding specialty training, medical education and correspondence. EDITORIAL INFORMATION CITED IN Biosis database; embase/excerpta medica; index medicus (medline) science citation index, science citation index expanded, isi alerting services, medical documentation services, current contents/clinical medicine, PubMed. Editor in chief Paul van Daele, Department of Internal Medicine and Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands Editorial team Mark Eijgelsheim Femme Harinck Tim Korevaar Sanne Lugthart Sharif Pasha Casper Rokx Associate editors Jelmer Alsma Hannelore Bax Ingrid Boere Virgil Dalm Teun van Gelder Laura de Graaff Wouter de Herder Dennis Hesselink Mandy van Hoek Janneke Langendonk Mirjam Langeveld Frank Leebeek Rob de Man Stephanie Klein Nagelvoort Christian Oudshoorn Roos Padmos Robin Peeters Marianne van Schie Jorie Versmissen Marijn Vis Bob Zietse Carola Zillikens Editorial board G. Agnelli, Perugia, Italy J.T. van Dissel, Leiden, the Netherlands R.O.B. Gans, Groningen, the Netherlands A.R.J. Girbes, Amsterdam, the Netherlands D.E. Grobbee, Utrecht, the Netherlands E. de Jonge, Leiden, the Netherlands D.L. Kastner, Bethesda, USA M.H. Kramer, Amsterdam, the Netherlands E.J. Kuipers, Rotterdam, the Netherlands Ph. Mackowiak, Baltimore, USA J.W.M. van der Meer, Nijmegen, the Netherlands B. Lipsky, Seattle, USA B. Lowenberg, Rotterdam, the Netherlands G. Parati, Milan, Italy A.J. Rabelink, Leiden, the Netherlands D.J. Rader, Philadelphia, USA J.L.C.M. van Saase, Rotterdam, the Netherlands M.M.E. Schneider, Utrecht, the Netherlands J. Smit, Nijmegen, the Netherlands Y. Smulders, Amsterdam, the Netherlands C.D.A. Stehouwer, Maastricht, the Netherlands J.L. Vincent, Brussels, Belgium R.G.J. Westendorp, Leiden, the Netherlands Editorial office Erasmus MC, University Medical Center Rotterdam Department of Internal Medicine ’s-Gravendijkwal 230 3015 CE Rotterdam The Netherlands Tel.: +31 (0)10-703 59 54 Fax: +31 (0)10-703 32 68 E-mail: p.l.a.vandaele@erasmusmc.nl http://mc.manuscriptcentral.com/ nethjmed The Netherlands Journal of Medicine JANUARY 2018, VOL. 76, NO. 1 © Van Zuiden Communications B.V. All rights reserved. The Netherlands Journal of Medicine ISSN: 0300-2977 Copyright © 2018 Van Zuiden Communications B.V. All rights reserved. Except as outlined below, no part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior written permission of the publisher. Permission may be sought directly from Van Zuiden Communications B.V. 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PO Box 2122 2400 CC Alphen aan den Rijn The Netherlands Tel.: +31 (0)172-47 61 91 Email: mouton@vanzuidencommunications.nl Internet: www.njm-online.nl Contents EDI TOR I A L The need for collaborative research in transplantation medicine: illustrated by the immunosuppression conversion trials 2 M. Eijgelsheim, J.S. Sanders SPECIAL REPORT Management of community-acquired pneumonia in adults: 2016 guideline update from the Dutch Working Party on Antibiotic Policy (SWAB) and Dutch Association of Chest Physicians (NVALT) 4 W.J. Wiersinga, M.J. Bonten, W.G. Boersma, R.E. Jonkers, R.M. Aleva, B.J. Kullberg, J.A. Schouten, J.E. Degener, E.M.W. van de Garde, T.J. Verheij, A.P.E. Sachs, J.M. Prins OR IGINA L A RT ICL ES Conversion from tacrolimus to everolimus with complete and early glucocorticoid withdrawal after kidney transplantation: a randomised trial 14 R. Bouamar, N. Shuker, J.A.J. Osinga, M.C. Clahsen-van Groningen, J. Damman, C.C. Baan, J. van de Wetering, A.T. Rowshani, J. Kal-van Gestel, W. Weimar, T. van Gelder, D.A. Hesselink Addition of simethicone improves small bowel capsule endoscopy visualisation quality 27 M.S. Krijbolder, K.V. Grooteman, S.K. Bogers, D.J. de Jong Hurry up, it’s quiet in the emergency department 32 E. ter Avest, B.T. Onnes, T. van der Vaart, M.J. Land C ASE R EPORTS Glucarpidase treatment for methotrexate intoxication: a case report and review of the literature 36 A.D. Boelens, R.A.A. Mathôt, A.P.J. Vlaar, C.S.C. Bouman Fulminant presentation of oral mucosal leishmaniasis as severe stomatitis and periodontitis 40 M.H.T. de Ruiter, C. Stijnis, J.W. Nolte, A. Bart, S.L. Croonen, J. de Lange, M.P. Grobusch PHOTO QUIZZES Pancytopenia in a young girl with skin lesions 43 S.K. Bhavya, N.P. Prakash, T.M. Anoop, N. Rakul From dentist to internist 45 J. Hanssen, F. Toonen Fever, abdominal erythema and subcutaneous emphysema 47 M.L. van Schaik, P.H.P. Groeneveld 2 JANUARY 2018, VOL. 76, NO. 1 © Van Zuiden Communications B.V. All rights reserved. The Netherlands Journal of Medicine EDITORIAL The need for collaborative research in transplantation medicine: illustrated by the immunosuppression conversion trials M. Eijgelsheim*, J.S. Sanders Department of Nephrology, Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands, *corresponding author: email: m.eijgelsheim@umcg.nl In this issue of the Netherlands Journal of Medicine, Bouamar et al.1 report the results of their prematurely terminated randomised controlled trial in renal transplantation recipients on the early conversion of tacrolimus, a calcineurin inhibitor (CNI), to everolimus, a mammalian target of rapamycin inhibitor (mTORi), with concomitant withdrawal of steroids. An excess in acute rejections (30% versus 6.7%) resulted in the decision to terminate the study after the inclusion and randomisation of 60 of the intended 194 subjects. Current standard immunosuppressive regimens in renal transplantation include CNIs and result in low rates of allograft rejection, and good long-term allograft survival. However, CNIs have chronic nephrotoxic effects and there is a search for further improvement of immunosuppressive regimens to reduce these adverse long-term effects. Late (i.e. more than one year after transplantation) conversion from CNI to mTORi showed no improvement in long-term renal function. Early conversion studied in the ZEUS trial showed better renal function with a benefit of 6.4 ml/ min/1.73 m2 for everolimus compared with cyclosporine five years after transplantation.2 However, cyclosporine is no longer the most prescribed CNI in current transplantation care, as immunosuppression with low-dose tacrolimus, mycophenolic acid and prednisolone after daclizumab induction was found to result in superior renal allograft survival after 12 months compared with low-dose cyclosporine and low-dose sirolimus after induction or standard dose cyclosporine without induction.3,4 The recently published ELEVATE trial is the largest study to date on early conversion from CNI to mTORi and included 715 subjects. No difference in renal function after one year was observed.5 However, CNI and in particular tacrolimus treatment resulted in superior prevention of biopsy-proven acute rejection (BPAR) with a 2.4-fold increased risk in the everolimus arm. Long-term effects are awaited and are the main outcome of interest, especially with the tacrolimus subgroup as comparator, since tacrolimus is the standard CNI of choice. Tacrolimus was used as sole CNI in the study by Bouamar et al. and this could partially explain the high relative risk of rejection for everolimus. Another important issue that needs to be mentioned is the concomitant withdrawal of steroids. The ELEVATE trial did not eliminate steroids which could be relevant for explaining the lower overall rate of biopsy-proven acute rejection. A recent Cochrane review discussed the effects of steroid withdrawal and concluded that there is no scientific basis to advise in favour of steroid withdrawal since it resulted in higher biopsy proven rejection rates and did not reduce the number of adverse effects. However, the overall quality of included studies was poor.6 The study by Bouamar et al. resulted in an unacceptable acute rejection rate in the intervention arm within the first year after renal transplantation. This was obviously not the trial’s intention, but a design based on the prevailing institutional protocol including steroid withdrawal unintentionally illustrated the lower limit of acceptable immunosuppression in an everolimus-based regimen. This negative trial is therefore relevant and should be published, even if one can question the initial design in hindsight. THE NEXT STEP Alternative strategies are being explored in order to reduce CNI exposure. The combination of lower tacrolimus dosing plus mTORi in combination with steroids seems promising. In the Cochrane review on CNI avoidance this strategy seems non-inferior in acute rejection risk and is associated with a lower incidence of viral infections.7 The recently presented TRANSFORM study (2037 subjects) supports these data with similar allograft function and BPAR rates at one year after transplantation.8 A more 3 JANUARY 2018, VOL. 76, NO. 1 © Van Zuiden Communications B.V. All rights reserved. The Netherlands Journal of Medicine definitive answer regarding the long-term effects on renal function is awaited. It should be noted that both tacrolimus and cyclosporine are used as CNI in the TRANSFORM study.9 In this editorial, we would like to highlight two observations that can be made with respect to the discussion above. First, few large collaborative efforts with harmonised protocols studying alternative strategies in immunosuppression after renal transplantation to optimise efficiency, validity and quality were initiated to address this topic. Looking back at the history of the CNI-mTORi conversion trials and steroid withdrawal studies, it is striking that there are multiple small studies with different designs, missing information and absent long-term follow-up data. A publication bias is likely to exist with negative results that never reached publication. Also, the inclusion of cyclosporine as CNI of choice does not aid in deciding whether the studied strategy is superior to tacrolimus-based regimens. Sub-analysis could address this issue, but only if studies are sufficiently powered. Second, in the study of Bouamar et al. there were individuals that fared well by the studied regimen. What characterised them? Can they be identified shortly after transplantation to benefit from this regimen? The term transplantomics was coined several years ago; this suggests an aim of collective characterisation and quantification of the biology that translates into the function and dynamics of the graft and its recipient. In the mentioned trials deep phenotyping and genotyping of recipients and donors is lacking. Larger trials should include thorough (immuno)phenotyping and genotyping in order to come to individualised immunosuppression. To maximise yield and optimise outcome for future renal transplant recipients, collaborations with molecular biology as well as between clinical institutions should be intensified. REFERENCES 1. Bouamar R, Shuker N, Osinga JAJ, et al. Conversion from tacrolimus to everolimus with complete and early glucocorticoid withdrawal after kidney transplantation: a randomised trial. Neth J Med. 2018;76:14-26. 2. Budde K, Lehner F, Sommerer C, et al. Five-year outcomes in kidney transplant patient converted from cyclosporine to everolimus: the randomized ZEUS study. Am J Transplant. 2015;15:119-28. 3. Webster AC, Taylor RRS, Chapman JR, Craig JC. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD003961. 4. Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. Neth J Med. 2007;357:2562-75. 5. De Fijter JW, Holdaas H, Øyen O, et al. Early conversion from calcineurin inhibitor- to everolimus-based therapy following kidney transplantation: Results of the randomized ELEVATE trial. Am J Transplant. 2017;17:1853-67. 6. Haller MC, Royuela A, Nagler EV, et al. Steroid avoidance or withdrawal for kidney transplant recipients. Cochrane Database Syst Rev. 2016 Aug 22;8:CD005632. 7. Karpe KM, Talaulikar GS, Walters GD. Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients. Cochrane Database Syst Rev. 2017 Jul 21;7:CD006750. 8. Pascual J, Berger SP, Witzke O, et al. Oral presentation (Abstract ID # 3805491) at the European Society for Organ Transplantation Congress; Barcelona, Spain; September 24-27, 2017. 9. https://clinicaltrials.gov/ct2/show/NCT01950819. 4 JANUARY 2018, VOL. 76, NO. 1 © Van Zuiden Communications B.V. All rights reserved. The Netherlands Journal of Medicine SPECIAL REPORT Management of community-acquired pneumonia in adults: 2016 guideline update from the Dutch Working Party on Antibiotic Policy (SWAB) and Dutch Association of Chest Physicians (NVALT) W.J. Wiersinga1 *, M.J. Bonten2 , W.G. Boersma3 , R.E. Jonkers4 , R.M. Aleva5 , B.J. Kullberg6 , J.A. Schouten7 , J.E. Degener8 , E.M.W. van de Garde9, T.J. Verheij10, A.P.E. Sachs10, J.M. Prins1 1 Department of Internal Medicine, Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands, 2 Department of Medical Microbiology, University Medical Center, Utrecht, the Netherlands, 3 Department of Pulmonary Diseases, Northwest Hospital Group, Alkmaar, the Netherlands, 4 Department of Respiratory Medicine, Academic Medical Centre, Amsterdam, the Netherlands, 5 Department of Pulmonary Diseases, Máxima Medical Center, Eindhoven, the Netherlands, 6 Radboud Center for Infectious Diseases and Department of Internal Medicine, Radboudumc, Nijmegen, the Netherlands, 7 Department of Intensive Care, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands, 8 Department of Medical Microbiology, University Medical Center, Groningen, the Netherlands, 9 Department of Clinical Pharmacy, St. Antonius Hospital, Utrecht/Nieuwegein, the Netherlands, Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands, 10Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands, *corresponding author: email: w.j.wiersinga@amc.uva.nl ABSTRACT The Dutch Working Party on Antibiotic Policy in collaboration with the Dutch Association of Chest Physicians, the Dutch Society for Intensive Care and the Dutch College of General Practitioners have updated their evidence-based guidelines on the diagnosis and treatment of community-acquired pneumonia (CAP) in adults who present to the hospital. This 2016 update focuses on new data on the aetiological and radiological diagnosis of CAP, severity classification methods, initial antibiotic treatment in patients with severe CAP and the role of adjunctive corticosteroids. Other parts overlap with the 2011 guideline. Apart from the Q fever outbreak in the Netherlands (2007-2010) no other shifts in the most common causative agents of CAP or in their resistance patterns were observed in the last five years. Low-dose CT scanning may ultimately replace the conventional chest X-ray; however, at present, there is insufficient evidence to advocate the use of CT scanning as the new standard in patients evaluated for CAP. A pneumococcal urine antigen test is now recommended for all patients presenting with severe CAP; a positive test result can help streamline therapy once clinical stability has been reached and no other pathogens have been detected. Coverage for atypical microorganisms is no longer recommended in empirical treatment of severe CAP in the non-intensive care setting. For these patients (with CURB-65 score >2 or Pneumonia Severity Index score of 5) empirical therapy with a 2nd/3rd generation cephalosporin is recommended, because of the relatively high incidence of Gram-negative bacteria, and to a lesser extent S. aureus. Corticosteroids are not recommended as adjunctive therapy for CAP. KEYWORDS Antimicrobial therapy, community-acquired pneumonia, guidelines 5 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine Wiersinga et al. SWAB/NVALT community-acquired pneumonia guideline. INTRODUCTION Community-acquired pneumonia (CAP) is defined as an acute symptomatic infection of the lower respiratory tract in patients outside a hospital or a long-term care facility, whereby a new infiltrate is demonstrated.1,2 CAP is a common condition that carries a high burden of mortality and morbidity, particularly in the elderly.2,3 In the Netherlands, approximately 250,000 patients develop pneumonia each year (https://www.volksgezondheidenzorg.info, 2 August 2017). This translates into an incidence of 15 per 1000 person-years. Worldwide, CAP remains the second cause of death and life years lost.3 The Dutch Working Party on Antibiotic Policy (SWAB; Stichting Werkgroep Antibiotica Beleid), established by the Dutch Society for Infectious Diseases (VIZ), the Dutch Society for Medical Microbiology (NVMM) and the Dutch Society for Hospital Pharmacists (NVZA), coordinates activities in the Netherlands aimed at optimising antibiotic use, and containment of the development of antimicrobial resistance. In 2011 the SWAB and the Dutch Association of Chest Physicians (NVALT) published a joint guideline on the management of CAP. The present guideline is an update of this guideline, prepared by SWAB in collaboration with NVALT, the Dutch Society of Intensive Care (NVIC), and the Dutch College of General Practitioners (NHG).1 See textbox 1 for the methods. Revision was considered necessary because in the past few years new – for a significant part Dutch – data have been published on the differences between the various disease severity classification systems on the percentage of patients treated as severe CAP, the sensitivity of chest computed tomography (CT scan) for diagnosis, the role of atypical coverage in patients with severe CAP, and the role of adjunctive prednisone therapy. Therefore, the Guideline committee decided to update the recommendations on imaging, empirical treatment, and the use of corticosteroids in CAP. It should be stressed that other parts of the guideline were not updated and show a large overlap with the previously published 2011 guideline.1 This is indicated for the relevant sections. See textbox 2 for a short summary of all the new recommendations compared with the 2011 guideline. The CAP guideline focusses on the initial treatment of suspected CAP in adult patients who present to the hospital, and are treated as outpatients, and hospitalised patients up to 72 hours after admission. Pneumonia in immunocompromised patients is outside the scope of this guideline. C A U S A T I V E B A C T E R I A L S P E C I E S O F C A P I N T H E N E T H E R L A N D S A N D THEIR ANTIBIOTIC SUSCEPTIBILITY Streptococcus pneumoniae remains the most commonly isolated bacterial pathogen causing CAP and should therefore always be covered in empirical treatment.1 The annual number of registered Legionella infections in the Netherlands is stable at around 300 cases per year (http://www.rivm.nl/Onderwerpen/L/Legionella). From 2007 to 2010 the Netherlands experienced a large Q fever outbreak, caused by Coxiella burnetii, leading to a large number of hospital admissions, mostly for CAP, in those years. No other major shifts in the aetiology of CAP were observed in the last five years, although it should be emphasised that in up to half of CAP episodes no causative microorganism can be identified (table 1).4-7 In patients with severe CAP and in patients who are admitted to the intensive care unit (ICU), Legionella spp., Staphylococcus aureus and Gram-negative infections are encountered more frequently compared with patients with mild to moderately severe CAP (table 1).4-7 Recent retrospective data points to the need for increased awareness of Aspergillus infection as a complication of H1N1 influenza A virus infection in critically ill patients on the ICU.8 It should be noted that the occurrence of atypical pathogens (Legionella spp., C. burnetii, Mycoplasma pneumoniae, and Chlamydia/ Chlamydophila species) in patients admitted to the ward with a CURB-65 score of ≥ 3 is very low (table 1).9 The resistance percentage of S. pneumoniae for erythromycin is 12%, for co-trimoxazole 7% and for Textbox 1 Methods and systemic literature review The methods were identical to those of the previous version of these guidelines.1 In short, these guidelines were drawn up according to the EBRO (Evidence Based Richtlijn-Ontwikkeling) and AGREE (Appraisal of Guidelines Research and Evaluation) recommendations for the development of guidelines.43 A review of the existing national and international guidelines24,25 was performed in addition to a literature search in PubMed database, Cochrane Register of Controlled Trials (CENTRAL), EMBASE, BMJ’s Best Practice® and in Sumsearch® engine. For resistance surveillance data we utilised NethMap 2016.10 Preparation of the guidelines text was carried out by a multidisciplinary committee consisting of experts delegated from the above-mentioned professional societies. After consultation with the members of the relevant professional societies, the definitive guidelines were drawn up by the delegates and approved by the boards of SWAB and NVALT. The full guidelines text, literature review and rebuttal of the received commentaries are available at www.swab.nl. 6 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine Wiersinga et al. SWAB/NVALT community-acquired pneumonia guideline. doxycycline 9%.10 Resistance to levofloxacin and moxifloxacin is very uncommon. In the Netherlands, high-level penicillin-resistant S. pneumoniae is extremely rare (< 1%) and thus does not require coverage by empirical antibiotic therapy. High-level resistance to penicillin should be considered in patients not – or insufficiently – responding to empirical treatment with penicillin or amoxicillin and with a recent travel history abroad. In such patients, increasing the dosage of penicillin or a switch to a cephalosporin should be considered. S E V E R I T Y O F D I S E A S E U P O N P R E S E N T A T I O N I S U S E D F O R T H E CHOICE OF INITIAL TREATMENT Patients with CAP may be classified according to severity: mild, moderate-severe and severe CAP. Selection of empirical antibiotic therapy should be guided by the severity of the disease at presentation. Three scoring systems are in use. The Pneumonia Severity Index (PSI or Fine score) and the CURB-65 score (table 2) 1,11-13 are validated scoring systems, equally reliable in predicting Textbox 2 • What’s new since the 2011 guidelines were published? S. pneumoniae remains the most common isolated bacterial cause of CAP in the Netherlands. In patients with severe CAP or patients who must be admitted to the ICU, Legionella spp. (up to 6%), S. aureus (up to 10%) and Gram-negative infections (up to 20%) are encountered more frequently than in patients with mild or moderate severe CAP. No aetiological agent can be identified in up to half of the episodes of CAP. The large Q fever outbreak in the Netherlands, which started in 2007, came to an end in 2010. No major shifts in resistance patterns of the most common causative agents of CAP were observed in the past 5 years in the Netherlands. • Patients with CAP may be classified according to severity: I) mild, II) moderately severe, III) severe CAP admitted to the ward and IV) severe CAP admitted to the intensive care unit (ICU). Two validated scoring systems are in use: the Pneumonia Severity Index and the CURB-65. Alternatively, a pragmatic classification (treatment at home; admission to a general medical ward and admission to ICU) can be used. The committee does not recommend any of these scoring systems over the others; however, we recommend that each hospital uses only one scoring system consistently in daily practice. • For patients with risk category III (severe CAP – ward admission; CURB-65: 3-5; PSI: 5; hospitalised on non-ICU ward) therapy should be started with a 2nd or 3rd generation cephalosporin. No empirical coverage for atypical microorganisms is given. A Legionella and pneumococcal urinary antigen test should be carried out as a routine procedure within 12-24 hours of admission. If the Legionella test is positive, monotherapy directed against Legionella spp. is recommended. If the pneumococcal urinary antigen test is positive, therapy can be narrowed to penicillin or amoxicillin. If both are negative, therapy is continued with a 2nd or 3rd generation cephalosporin, to provide additional coverage for Enterobacteriaceae and to a lesser extent S. aureus. • For patients with category IV (severe CAP – ICU admission; hospitalised on ICU ward) it is always recommended to cover S.  pneumoniae, Legionella spp. and Gram-negative infections. For this purpose there are two equally acceptable choices, both with excellent antimicrobial activity against all expected causative agents: (a) monotherapy with moxifloxacin or (b) combination therapy with a 2nd or 3rd generation cephalosporin and ciprofloxacin. Macrolides are no longer recommended in this patient category. For all patients in category IV, a Legionella urinary antigen and S.  pneumoniae urine antigen test is carried out as a routine procedure within 12-24 hours of admission. If the Legionella test is positive, monotherapy directed against Legionella spp. is recommended. If the Legionella test is negative, the patient is still treated further with combination therapy (coverage of both S.  pneumoniae and Legionella spp.) because the sensitivity of the urinary antigen test is not 100%. Since the specificity of the pneumococcal urine antigen test is < 100%, antibiotic treatment can be streamlined to penicillin or amoxicillin only in patients with a positive test result and without another pathogen detected once clinical stability (often within 48 hours) has been reached. • Corticosteroids are not recommended as adjunctive therapy for treatment of CAP. 7 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine Wiersinga et al. SWAB/NVALT community-acquired pneumonia guideline. 30-day mortality in patients hospitalised with CAP.14-16 Alternatively, a pragmatic classification (treatment at home; admission to a general medical ward and admission to an ICU) can be used. It should be noted that there can be marked differences in the categorisation of severity using these different scoring systems. For instance, a Dutch study among 1047 patients admitted with CAP showed that using a CURB-65 score > 2 as cut-off, almost twice as many patients were classified as having severe CAP as compared with the PSI score.17 However, with a cut-off CURB-65 score of > 3 less patients were classified as severe CAP compared with the PSI. As there is no gold standard, the committee does not recommend any of the scoring systems over the other; however, it is recommended that each hospital consistently uses only one of these scoring systems in daily practice. These recommendations are identical to the previous guideline.1 R A D I O L O G I C A L I N V E S T I G A T I O N S I N T H E D I A G N O S T I C W O R K - U P O F PATIENTS SUSPECTED FOR CAP The chest X-ray does not allow prediction of the causative microorganism in CAP.18,19 The wider availability of low-dose CT scan facilities at emergency departments will likely lead to increased use of CT scanning of the chest in patients presenting with respiratory symptoms, and may ultimately replace the conventional chest X-ray. Recent data show that an early CT scan can improve diagnostic accuracy compared with chest X-ray.20 However, at present, there is not enough evidence to advocate the use of CT scanning as the new standard in patients evaluated for CAP. For patients with clinical features of CAP but without signs of infection on the initial chest X-ray, an additional chest X-ray within 48 hours may help to establish the diagnosis of CAP.21 MICROBIOLOGICAL INVESTIGATIONS Although interpretation of Gram’s stain of sputum may allow early identification of the bacteriological cause of CAP, it is not recommended for guiding initial treatment. However, before starting antimicrobial therapy, blood and, if possible, sputum specimens should be obtained for culture, because culture results enable streamlining of antibiotic therapy and a switch to oral therapy if a specific pathogen is isolated. PCR results from nasopharyngeal swabs are considered the most reliable indicator for influenza virus replication in the human body.22,23 Validated PCR tests for respiratory viruses and atypical Table 1. Most common aetiologies of community-acquired pneumonia in the Netherlands according to study population Study population Community Hospital ICU 1 study4 * 2 studies5,9 1 study7 S. pneumoniae 6% 8-24% 22% H. influenzae 9% 3-5% 7% Legionella spp. 0% 1-6% 1% S. aureus 0% 1-2% 10% M. catarrhalis 0% 0-1% 0% Enterobacteriaceae 0% 2-5% 8% Pseudomonas aeruginosa 0% 0-2% 5% M. pneumoniae 9% 1-3% 0% Chlamydophila spp. 2% 0-7% 0% C. burnetii 0% 0-14% 1% Viral (e.g. Influenza) 37% 3-5% 17% Other 2% 2-3% 10% No pathogen identified 33% 63-65% 25% Data on the hospital and intensive care unit study populations were derived from studies published between 2011 and 2016, data on the community were derived from a study published in 2004. *This study included patients with a lower respiratory tract infection in general practice, no standard chest X-ray was performed for the diagnosis of CAP. 8 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine Wiersinga et al. SWAB/NVALT community-acquired pneumonia guideline. pathogens are preferred over serological tests. A urinary antigen test for Legionella spp. should be performed in all patients with severe CAP.24-27 One should, however, be aware that in the early stages of the disease the Legionella urinary antigen test may be falsely negative, especially in patients with mild pneumonia. In addition, with the current widely used test (immunochromatographic assay) only L. pneumophila type 1, which accounts for approximately 90% of Legionella cases, can be detected. While the above recommendations have not changed compared with the previous guidelines,1 the usefulness of the urinary pneumococcal antigen test has been reconsidered. The sensitivity of the urinary pneumococcal antigen test for demonstrating a causative role of S. pneumonia in adult patients is low, but the test is highly specific.28-31 It has to be noted, however, that urinary pneumococcal antigens may be detectable in children, and also in adult patients with exacerbations of chronic obstructive pulmonary disease Table 2. Validated scoring systems to measure the severity of disease in patients with CAP: the CURB-65 and Pneumonia Severity Index1,11,12 CURB-65 CURB-65 criteria Confusion: defined as a new disorientation in person, place or time Urea > 7 mmol/l Respiratory rate ≥ 30 / min Blood pressure: Systolic blood pressure < 90 mmHg or diastolic blood pressure ≤ 60 mmHg Age ≥ 65 Core criteria Score CURB-65 30-day mortality No core criteria 0 0.7% One core criterion 1 3.2% Two core criteria 2 3% Three core criteria 3 17% Four core criteria 4 41.5% Five core criteria 5 57% Pneumonia Severity Index (PSI or Fine score) Step 1: Patient with community-acquired pneumonia If presence of any of the following proceed to step 2, if all are absent assign to risk class I: over 50 years of age; altered mental status; pulse ≥ 125/min; respiratory rate > 30/min; systolic blood pressure < 90 mmHg; temperature < 35°C or ≥ 40°C and/or a history of neoplastic disease, congestive heart failure, cerebrovascular disease, renal disease, liver disease Step 2: Point scoring system (Characteristic and points assigned) Age: Age in years (male); Age in years –10 (female) Coexisting conditions: Neoplastic disease + 30; liver disease + 20; congestive heart failure + 10; cerebrovascular disease +10; renal disease + 10 Physical examination: Altered mental status + 20; respiratory rate ≥ 30 / min + 20; systolic blood pressure < 90 mmHg + 20; temperature < 35°C or ≥ 40°C + 15; pulse ≥ 125 / min + 10 Laboratory and radiological findings: arterial pH < 7.35 + 30; urea ≥ 11.0 mmol/l + 20; sodium < 130 mmol/l + 30; glucose ≥ 14.0 mmol/l + 10; haematocrit < 30% + 10; partial oxygen pressure < 60 mmHg + 10; pleural effusion + 10 Step 3. Calculation of 30-day mortality Risk class Total score Mortality I Not applicable 0.1% II ≤70 0.6% III 71-90 0.9% IV 91-130 9.3% V >130 27.0% 9 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine Wiersinga et al. SWAB/NVALT community-acquired pneumonia guideline. without pneumonia.32 It is now recommended to perform an urinary antigen test for S. pneumoniae in all patients treated for severe CAP. In patients with a positive test result and without another pathogen detected, antibiotic treatment can be simplified to amoxicillin or penicillin when the patient is treated on the ward. For patients on the ICU, therapy is de-escalated once clinical stability has been reached, which is often within 48 hours (figure 1). E M P I R I C A L A N T I B I O T I C T H E R A P Y FOR CAP As compared with the previous guidelines, the most important change in the recommended empirical antibiotic therapy for CAP is to start with 2nd or 3rd generation cephalosporin monotherapy instead of combination therapy with amoxicillin or penicillin together with a quinolone or erythromycin in patients with severe CAP who are treated in a non-ICU ward. From an antibiotic stewardship perspective this is an important gain. The main reason for this change is the very low incidence of atypical pathogens in patients admitted to the ward with CURB-65 score ≥ 3 as outlined above. This is supported by the recent findings from the Dutch CAP-START study, involving more than 2000 patients with clinically suspected CAP admitted to non-ICU wards; in this study empirical treatment with beta-lactam monotherapy was non-inferior to strategies with a beta-lactam-macrolide combination or 4th generation f luoroquinolone Figure 1. Flow chart of guideline recommendations on empirical antibiotic treatment of CAP • When no improvement is seen after two courses of antibiotics in the primary care setting, is it advised to consult an expert (internist-infectiologist, microbiologist or pulmonologist). • Macrolides should not be used as initial therapy in mild CAP. They can be used in the event of penicillin allergy and when doxycycline cannot be used due to pregnancy or lactation. If doxycycline is given, start with a loading dose of 200 mg. • In the event of penicillin allergy in moderately severe CAP, administer a 2nd or 3rd generation cephalosporin or moxifloxacin. • High-level resistance to penicillin should be considered in patients not – or insufficiently – responding to empirical treatment with penicillin or amoxicillin and with a recent travel history abroad. In such patients increasing the dosage of penicillin (2 million IU 6 dd, or continuous infusion) or a switch to a cephalosporin (e.g. ceftriaxone 2 g once daily) should be considered. • In the event of aspiration, the possibility of anaerobes or Enterobacteriaceae should be taken into account: penicillin or cephalosporins are replaced by amoxicillin-clavulanate. • In the case of fulminant pneumonia after an episode of influenza, penicillin is replaced by a beta-lactam antibiotic with activity against S. aureus. • In patients with moderately severe or severe CAP with documented colonisation of the respiratory tract with Pseudomonas spp., ceftazidime or ciprofloxacin should be added if not otherwise given. • Antiviral treatment with oseltamivir is recommended for patients with confirmed or suspected influenza who have complicated illness with respiratory insufficiency (please refer to the guidelines from the National Institute for Public Health and Environment ‘LCI richtlijn influenza’, 2011). • The recommended treatment options for severe CAP on the ICU are considered to be two equally acceptable choices. • Legionella pneumonia should be treated with a fluoroquinolone. Most evidence is available for levofloxacin. • De-escalate empirical antibiotic therapy when clinically improved or definitive microbiological diagnosis is made. Please also refer to SWAB Guidelines for Antimicrobial Stewardship, 2017. 10 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine Wiersinga et al. SWAB/NVALT community-acquired pneumonia guideline. monotherapy with regard to 90-day mortality.9 However, these data also indicated that Gram-negative bacteria and S. aureus are a more frequent cause of CAP among patients on the ward admitted with severe CAP when compared with patients with moderately severe CAP (CAP-START study, unpublished data) and, therefore, these pathogens should be covered in empirical therapy. Especially in patients with severe CAP, Legionella infection can be reliably ruled out with the urinary antigen test. To summarise, the recommendations for the empirical antibiotic therapy of the following four categories of CAP are as follows (table 3, figure 1): Risk category I (mild CAP): CURB-65: 0-1, PSI: 1-2, non-hospitalised For this group, initial therapy with a narrow spectrum beta-lactam antibiotic (1st choice) or doxycycline (2nd choice) is recommended. This is in accordance with the previous guidelines1 and the 2011 guidelines for patients treated by GPs.33 Doxycycline is not a first choice for this group in view of the 9% resistance of S. pneumoniae against doxycycline. The choice of a drug active against the most frequently occurring causative agent (S. pneumoniae) is essential in this case. Oral penicillin is not considered a first choice in view of the suboptimal gastrointestinal resorption. As a result of the increasing resistance of pneumococci against macrolides (10-14%), monotherapy with macrolides is discouraged unless the patient is allergic to penicillin and it is not possible to administer doxycycline (e.g. because of pregnancy or lactation). In that case, either clarithromycin or azithromycin are preferred. If there is a strong clinical suspicion of Legionella infection, then the Legionella urine antigen test must be carried out and empirical therapy must be adjusted. For patients in risk category I who receive amoxicillin or penicillin as initial therapy but do not improve within 48 hours, therapy should be switched to monotherapy with a macrolide or doxycycline. If therapy was initiated with doxycycline a switch to macrolides is not rational. In that case, referral to a hospital must be considered.1 In the outpatient setting, coverage for S. aureus in the influenza season, e.g. by amoxicillin-clavulanate, is not indicated. Risk category II (moderate-severe CAP): CURB-65: 2, PSI: 3-4, admitted to non-ICU ward For this category, initial therapy should be beta-lactam monotherapy, and the first choice is either intravenous penicillin or amoxicillin. Doxycycline and macrolides cannot be recommended because of the increasing pneumococcal resistance. Broad-spectrum antibiotics such as amoxicillin-clavulanate, cefuroxime, ceftriaxone or cefotaxime are not recommended because the expected Table 3. Guidelines for the choice of initial therapy for community-acquired pneumonia Severity Antibiotic Route Dose Frequency Category I: mild pneumonia 1st choice Amoxicillin Oral 750 mg q8h 2nd choice Doxycycline Oral 100 mg (first dose 200 mg) q24h Category II: moderately severe pneumonia Penicillin IV 1 MU q6h Amoxicillin IV 1000 mg q6h Category III: severe pneumonia (ward) Monotherapy Cefuroxime or Ceftriaxone or Cefotaxime IV IV IV 1500 mg 2000 mg 1000 mg q8h q24h q6h Category IV: severe pneumonia (ICU) Monotherapy Moxifloxacin IV / oral 400 mg q24h Combination therapy Cefuroxime or Ceftriaxone or Cefotaxime and Ciprofloxacin IV IV IV IV 1500 mg 2000 mg 1000 mg 400 mg q8h q24h q6h q12h 11 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine Wiersinga et al. SWAB/NVALT community-acquired pneumonia guideline. pathogens do not justify the broader spectrum. In case of penicillin allergy, the best alternatives are a 2nd or 3rd generation cephalosporin or a 4th generation quinolone. If a patient of category II has one or more of the following risk factors for Legionella spp. a Legionella antigen test should be performed within 24 hours: 1) a recent visit to a foreign country, 2) coming from an epidemic setting of Legionella spp. infections, 3) failure to improve despite ≥ 48 hours of treatment with a beta-lactam antibiotic at an adequate dosage without evidence of abnormal absorption or non-compliance. If the Legionella antigen test is positive, therapy must be switched to monotherapy directed against Legionella spp. For Legionella pneumonia, levofloxacin has the most clinical evidence to support its use. Risk category III (severe CAP): CURB-65: 3-5, PSI: 5, admitted to non-ICU ward Therapy should be started with a 2nd or 3rd generation cephalosporin, because of the higher incidence of Gram-negative bacteria, and to a lesser extent S. aureus, in this patient group. For all patients in category III, a Legionella and pneumococcal urinary antigen test should be carried out as a routine procedure within 12-24 hours of admission. If the Legionella test is positive, monotherapy directed against Legionella spp. is recommended. If the pneumococcal urinary antigen test is positive, therapy can be narrowed to penicillin or amoxicillin. If both are negative, therapy should be continued with a 2nd or 3rd generation cephalosporin. Risk category IV (severe CAP): admission to ICU In this category, it is always recommended to cover S. pneumoniae, Legionella spp., S. aureus and Gram-negative bacteria. For this purpose there are two equally acceptable choices, both with excellent antimicrobial activity against all the expected causative agents. The choice is dependent, on the one hand, on the risk of development of antimicrobial resistance at the population level; on the other hand, the costs, the ease of administration and the profile of side effects play an important role: • Monotherapy with moxifloxacin or • Combination therapy with a 2nd or 3rd generation cephalosporin and ciprofloxacin. Moxifloxacin is preferred over levofloxacin because of its high activity against pneumococci, favourable pharmacodynamic characteristics and good tissue penetration. Potential prolongation of the QT interval should be taken into account. Because of the high rate of side effects associated with their intravenous administration, macrolides are no longer recommended in this patient category. For all patients in category IV, a Legionella urinary antigen and S. pneumoniae urine antigen test is carried out as a routine procedure within 12-24 hours of admission. If the Legionella test is positive, monotherapy directed against Legionella spp. is recommended. If the Legionella test is negative, the patient is still treated further with combination therapy (coverage of both S. pneumoniae and Legionella spp.) because the sensitivity of the urinary antigen test is not 100%. Since the specificity of the pneumococcal urine antigen test is < 100%, antibiotic treatment can be streamlined to penicillin or amoxicillin only in patients with a positive test result and without other pathogens detected if clinical stability (often within 48 hours) has been reached, or pneumococci have been cultured. In the event of a culture-proven causative agent, pathogen-directed antibiotic treatment is to be preferred at all times. T I M I N G O F F I R S T D O S E O F A N T I B I O T I C S , T R E A T M E N T D U R A T I O N A N D S W I T C H F R O M I N T R A V E N O U S T O ORAL ROUTE This section has not been altered compared with the 2011 guidelines.1 All patients should receive antibiotics as soon as the diagnosis of CAP is established. For patients with severe CAP admitted through the emergency department (ED), the first antibiotic dose should be administered within four hours of presentation and preferably while still in the ED. In patients with sepsis and septic shock, the recommendation of the Surviving Sepsis Campaign guidelines applies.34 Although the guidelines emphasise the importance of initiating antibiotic treatment rapidly, maximal efforts should be made to avoid inaccurate diagnosis of CAP and/or inappropriate utilisation of antibiotics. If adult patients with mild to moderate-severe CAP are treated with a beta-lactam antibiotic or fluoroquinolones, the length of antibiotic treatment can be shortened to five days in those patients who have substantially improved after three days of treatment.35-37 Pneumonia caused by S. aureus should be treated for at least 14 days.25 Pneumonia caused by M. pneumoniae or Chlamydophila spp. is generally treated for 14 days,25 but no studies on treatment duration have been performed for these agents. For Legionella pneumonia a treatment duration of 7-10 days is sufficient in patients with a good clinical response. Patients should be switched from intravenous to oral therapy when they have substantially improved clinically, have adequate oral intake and gastrointestinal absorption 12 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine Wiersinga et al. SWAB/NVALT community-acquired pneumonia guideline. and are haemodynamically stable.38,39 For patients who fulfil these criteria, inpatient observation after switching to oral therapy is not needed.25,40 T H E R O L E O F A D J U N C T I V E C O R T I C O S T E R O I D S F O R P A T I E N T S W I T H C A P Over the last decade a whole range of potential immunomodulating therapies as adjunctive to antibiotics have been investigated in patients with CAP. Most data are available on the potential efficacy of corticosteroids. The three largest studies on adjunctive therapy with corticosteroids in patients with CAP5,41,42 yielded statistically significantly faster defervescence and, thereby, a shorter time to clinical stability and/or a shortening of length of hospital stay by one day for patients treated with corticosteroids. However, symptom resolution, overall cure rates, complication rates, ICU admission and mortality did not differ between patients with or without corticosteroid treatment. In all studies, the risk of hyperglycaemia was significantly higher in the corticosteroid-treated patients. In addition, treatment with short-term, high-dose corticosteroids may lead to other side effects, once applied routinely in larger populations. Therefore, the guidelines committee concluded, based on the available data, that the relatively small short-term benefits of adjunctive corticosteroids do not outweigh the potential disadvantages. As a result, the guidelines do not recommend corticosteroids as adjunctive therapy for treatment of CAP. ACKNOWLEDGMENT The Guidelines Committee would like to thank all individuals and societies who contributed to the development of these guidelines. DISCLOSURES Members of the preparatory committee reported the following potential conflicts of interest: MJB: Novartis Europe advisory board Daptomycin, Pfizer Netherlands advisory board vaccines, grant from Pfizer Netherlands for investigating aetiology of CAP; WGB: received a grant from GSK and Astra Zeneca for research and a fee from Pfizer for medical advice; EMWG: grant from GSK for investigating aetiology of CAP; TJV: received two grants for research and a fee for consultation from Pfizer; APES: received support for conference attendance from Pfizer and AstraZeneca. The other authors have no competing interests. REFERENCES 1. Wiersinga WJ, Bonten MJ, Boersma WG, et al. SWAB/NVALT (Dutch Working Party on Antibiotic Policy and Dutch Association of Chest Physicians) guidelines on the management of community-acquired pneumonia in adults. Neth J Med. 2012;70:90-101. 2. Wunderink RG, Waterer GW. Clinical practice. Community-acquired pneumonia. N Engl J Med. 2014;370:543-51. 3. Prina E, Ranzani OT, Torres A. Community-acquired pneumonia. Lancet. 2015;386:1097-108. 4. Graffelman AW, Knuistingh NA, le Cessie S, Kroes AC, Springer MP, van den Broek PJ. Pathogens involved in lower respiratory tract infections in general practice. Br J Gen Pract. 2004;54:15-9. 5. Meijvis SC, Hardeman H, Remmelts HH, et al. Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. Lancet. 2011;377:2023-30. 6. Bohte R, van Furth R, van den Broek PJ. Aetiology of community-acquired pneumonia: a prospective study among adults requiring admission to hospital. Thorax. 1995;50:543-7. 7. Van Vught LA, Scicluna BP, Wiewel MA, et al. Comparative Analysis of the Host Response to Community-acquired and Hospital-acquired Pneumonia in Critically Ill Patients. Am J Respir Crit Care Med. 2016;194:1366-74. 8. Van de Veerdonk FL, Kolwijck E, Lestrade PP, et al. Influenza-Associated Aspergillosis in Critically Ill Patients. Am J Respir Crit Care Med. 2017 Apr 7. doi: 10.1164/rccm.201612-2540LE. [Epub ahead of print] 9. Postma DF, van Werkhoven CH, van Elden LJ, et al. Antibiotic treatment strategies for community-acquired pneumonia in adults. N Engl J Med. 2015;372:1312-23. 10. Nethmap 2016, SWAB, Bergen, 2016 (www.swab.nl) 11. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med. 1997;336:243-50. 12. Lim WS, van der Eerden MM, Laing R, et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax. 2003;58:377-82. 13. Bont J, Hak E, Hoes AW, Macfarlane JT, Verheij TJ. Predicting death in elderly patients with community-acquired pneumonia: a prospective validation study reevaluating the CRB-65 severity assessment tool. Arch Intern Med. 2008;168:1465-8. 14. Chalmers JD, Singanayagam A, Akram AR, et al. Severity assessment tools for predicting mortality in hospitalised patients with community-acquired pneumonia. Systematic review and meta-analysis. Thorax. 2010;65:878-83. 15. Aujesky D, Auble TE, Yealy DM, et al. Prospective comparison of three validated prediction rules for prognosis in community-acquired pneumonia. Am J Med. 2005;118:384-92. 16. Buising KL, Thursky KA, Black JF, et al. A prospective comparison of severity scores for identifying patients with severe community acquired pneumonia: reconsidering what is meant by severe pneumonia. Thorax. 2006;61:419-24. 17. Huijts SM, van Werkhoven CH, Boersma WG, et al. Guideline adherence for empirical treatment of pneumonia and patient outcome. Treating pneumonia in the Netherlands. Neth J Med. 2013;71:502-7. 18. Boersma WG, Daniels JM, Lowenberg A, Boeve WJ, van de Jagt EJ. Reliability of radiographic findings and the relation to etiologic agents in community-acquired pneumonia. Respir Med. 2006;100:926-32. 19. Kauppinen MT, Lahde S, Syrjala H. Roentgenographic findings of pneumonia caused by Chlamydia pneumoniae. A comparison with streptococcus pneumonia. Arch Intern Med. 1996;156:1851-6. 20. Claessens YE, Debray MP, Tubach F, et al. Early Chest Computed Tomography Scan to Assist Diagnosis and Guide Treatment Decision for Suspected Community-acquired Pneumonia. Am J Respir Crit Care Med. 2015;192:974-82. 21. Hagaman JT, Rouan GW, Shipley RT, Panos RJ. Admission chest radiograph lacks sensitivity in the diagnosis of community-acquired pneumonia. Am J Med Sci. 2009;337:236-40. 22. Writing Committee of the WHOCoCAoPI, Bautista E, Chotpitayasunondh T, et al. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Engl J Med. 2010;362:1708-19. 13 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine 23. Fiore AE, Uyeki TM, Broder K, et al. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Recomm Rep. 2010;59:1-62. 24. Lim WS, Baudouin SV, George RC, et al. BTS guidelines for the management of community acquired pneumonia in adults: update 2009. Thorax. 2009;64 Suppl 3:iii1-55. 25. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44 Suppl 2:S27-S72. 26. Lettinga KD, Verbon A, Weverling GJ, et al. Legionnaires’ disease at a Dutch flower show: prognostic factors and impact of therapy. Emerg Infect Dis. 2002;8:1448-54. 27. Yzerman EP, Den Boer JW, Lettinga KD, Schellekens J, Dankert J, Peeters M. Sensitivity of three urinary antigen tests associated with clinical severity in a large outbreak of Legionnaires’ disease in The Netherlands. J Clin Microbiol. 2002;40:3232-6. 28. Gutierrez F, Masia M, Rodriguez JC, et al. Evaluation of the immunochromatographic Binax NOW assay for detection of Streptococcus pneumoniae urinary antigen in a prospective study of communityacquired pneumonia in Spain. Clin Infect Dis. 2003;36:286-92. 29. Sordé R, Falcó V, Lowak M, et al. Current and Potential Usefulness of Pneumococcal Urinary Antigen Detection in Hospitalized Patients With Community-Acquired Pneumonia to Guide Antimicrobial Therapy. Arch Intern Med. 2011;171:166-72. 30. Roson B, Fernandez-Sabe N, Carratala J, et al. Contribution of a urinary antigen assay (Binax NOW) to the early diagnosis of pneumococcal pneumonia. Clin Infect Dis 2004;38:222-6. 31. Stralin K, Kaltoft MS, Konradsen HB, Olcen P, Holmberg H. Comparison of two urinary antigen tests for establishment of pneumococcal etiology of adult community-acquired pneumonia. J Clin Microbiol. 2004;42:3620-5. 32. Andreo F, Ruiz-Manzano J, Prat C, et al. Utility of pneumococcal urinary antigen detection in diagnosing exacerbations in COPD patients. Respir Med. 2010;104:397-403. 33. Verheij T, Hopstaken RM, Prins JM, et al. NHG-standaard Acuut hoesten. Eerste herziening. Huisarts en Wetenschap. 2011;54:68-92. 34. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43:304-77. 35. File TM, Jr., Mandell LA, Tillotson G, Kostov K, Georgiev O. Gemifloxacin once daily for 5 days versus 7 days for the treatment of communityacquired pneumonia: a randomized, multicentre, double-blind study. J Antimicrob Chemother. 2007;60:112-20. 36. Tellier G, Niederman MS, Nusrat R, Patel M, Lavin B. Clinical and bacteriological efficacy and safety of 5 and 7 day regimens of telithromycin once daily compared with a 10 day regimen of clarithromycin twice daily in patients with mild to moderate community-acquired pneumonia. J Antimicrob Chemother. 2004;54:515-23. 37. El Moussaoui R, de Borgie CA, van den Broek P, et al. Effectiveness of discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community acquired pneumonia: randomised, double blind study. BMJ. 2006;332:1355. 38. Oosterheert JJ, Bonten MJ, Schneider MM, et al. Effectiveness of early switch from intravenous to oral antibiotics in severe community acquired pneumonia: multicentre randomised trial. BMJ. 2006;333:1193. 39. Schuts EC, Hulscher ME, Mouton JW, et al. Current evidence on hospital antimicrobial stewardship objectives: a systematic review and meta-analysis. Lancet Infect Dis. 2016;16:847-56. 40. Nathan RV, Rhew DC, Murray C, Bratzler DW, Houck PM, Weingarten SR. In-hospital observation after antibiotic switch in pneumonia: a national evaluation. Am J Med. 2006;119:512-7. 41. Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2015;385:1511-8. 42. Snijders D, Daniels JM, de Graaff CS, van der Werf TS, Boersma WG. Efficacy of corticosteroids in community-acquired pneumonia: a randomized double-blinded clinical trial. Am J Respir Crit Care Med. 2010;181:975-82. 43. Everdingen JJE, Burgers JS, Assendelft WJJ, et al. Evidence-based richtlijnontwikkeling. Een leidraad voor de praktijk. Houten: Bohn Stafleu van Loghum; 2004. Wiersinga et al. SWAB/NVALT community-acquired pneumonia guideline. 14 JANUARY 2018, VOL. 76, NO. 1 © Van Zuiden Communications B.V. All rights reserved. The Netherlands Journal of Medicine ORIGINAL ARTICLE Conversion from tacrolimus to everolimus with complete and early glucocorticoid withdrawal after kidney transplantation: a randomised trial R. Bouamar1 , N. Shuker1,2, J.A.J. Osinga1,2, M.C. Clahsen-van Groningen3 , J. Damman3 , C.C. Baan2 , J. van de Wetering2 , A.T. Rowshani2 , J. Kal-van Gestel2 , W. Weimar2 , T. van Gelder1,2, D.A. Hesselink2 * 1 Department of Hospital Pharmacy, Erasmus MC, Rotterdam, the Netherlands; 2 Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands; 3 Department of Pathology, Erasmus MC, Rotterdam, the Netherlands, *corresponding author: email: d.a.hesselink@erasmusmc.nl The first two authors contributed equally to this study ABSTRACT Background: While conversion from cyclosporine to everolimus is well documented, conversion from tacrolimus has been poorly studied. In this randomised, controlled trial the safety and tolerability of switching from tacrolimus to everolimus with glucocorticoid withdrawal after living-donor kidney transplantation was studied. Methods: A total of 194 patients were planned to be randomised 1:1 to either continue tacrolimus or to convert to everolimus at month 3 after transplantation. At randomisation, all patients received tacrolimus, mycophenolate mofetil and prednisolone. Everolimus was started in a dose of 1.5 mg twice daily, aiming for predose concentrations of 4-7 ng/ml. Prednisolone was gradually withdrawn in both groups. Results: The trial was stopped prematurely after the inclusion of 60 patients. The interim analysis showed an unacceptably high rejection rate in the everolimus group as compared with the control group: 30.0% vs. 6.7% (95% CI: 0.047-0.420; p = 0.045). An additional 8 patients stopped everolimus because of toxicity. At the end of follow-up (month 12) only 12 (40%) patients assigned to everolimus were still on the study drug. Conclusions: Conversion from tacrolimus to everolimusbased immunosuppression with withdrawal of prednisolone three months after kidney transplantation results in an unacceptably high risk of acute rejection and causes considerable toxicity. Based on our findings, such a switch strategy cannot be recommended. KEYWORDS Everolimus, kidney, randomised-controlled trial, tacrolimus, transplantation INTRODUCTION Everolimus is an immunosuppressive drug that lacks the chronic nephrotoxic effects of the calcineurin inhibitors (CNIs) tacrolimus and cyclosporine and has the potential to improve long-term outcomes of kidney transplantation.1,2 In the first clinical trials, everolimus was combined with cyclosporine in de novo kidney transplant recipients. These trials did not demonstrate a significant improvement in renal function compared with standard CNI-based immunosuppression. Everolimus was found to have considerable toxicity, including delayed wound healing, the formation of lymphoceles, dyslipidaemia and cytopenia.2-4 An alternative strategy that has been tested in clinical studies is to convert patients from a CNI-based immunosuppressive regimen to an everolimus-based immunosuppressive regimen longer (i.e. >1 year) after transplantation. The results of these studies have been disappointing as the majority failed to demonstrate a significant improvement in renal function.5,6 At present, switching kidney transplant recipients sometime after the critical early post-transplant phase, when rejection risk is highest, from a CNI to everolimus seems to have the most potential in terms of improving 15 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine Bouamar et al. Conversion from tacrolimus to everolimus. long-term renal transplant function without risking excess acute rejection. In the randomised, controlled ZEUS trial, patients were randomised to either continue cyclosporine or were converted to everolimus 4.5 months after transplantation.7 This trial demonstrated that conversion to everolimus resulted in superior renal function 1, 3 and 5 years after transplantation, despite a moderately increased risk of acute rejection (13.6% vs. 7.5% after 5 years).7-9 However, in the ZEUS study, everolimus was compared with a cyclosporine-based immunosuppressive regimen.7 At present, in most transplant centres in the United States and in Europe, tacrolimus is the cornerstone immunosuppressant. It remains to be determined if switching from tacrolimus to everolimus will result in equally good outcomes and what the optimal timing of such a conversion would be. The objective of this randomised, controlled clinical trial was to investigate if conversion from a tacrolimusbased immunosuppressive regimen to an everolimusbased regimen at month 3 after living-donor kidney transplantation in low to moderate immunological risk patients with complete and early elimination of glucocorticoids results in an improvement of renal transplant function. MATERIALS AND METHODS Study design This was an investigator-initiated, prospective, randomised, controlled, parallel group, open label, single centre trial that was conducted in the Erasmus MC, University Medical Centre Rotterdam, the Netherlands. Adult patients (≥ 18 years) who received a blood group AB0-compatible kidney transplant from a living donor (excluding HLA-identical siblings), who were transplanted in our hospital and on continued follow-up in our clinic, were eligible for participation. The patients had to be treated with immunosuppressive therapy consisting of tacrolimus, mycophenolate mofetil and prednisolone at month 3 after transplantation. All patients received induction therapy with basiliximab (Simulect®, Novartis Pharma B.V., Arnhem, the Netherlands) in a dose of 20 mg intravenously on days 0 and 4. None of the patients received induction therapy with lymphocyte depleting antibodies. Exclusion criteria were 1) an acute rejection episode less than 4 weeks prior to the planned randomisation; 2) proteinuria ≥ 1.0 g/day; 3) estimated GFR (eGFR) ≤ 30 ml/min; 4) recipient of multiple organ transplants; 5) a positive pre-transplant complement-dependent cytotoxicity cross-match; 6) human immunodeficiency virus seropositivity; 7) recipients of an allograft from a hepatitis B surface antigen or a hepatitis C virus seropositive donor; 8) severe allergy / hypersensitivity to drugs similar to everolimus (such as macrolides); 9) severe, uncontrollable hypercholesterolaemia or hypertriglyceridaemia; 10) a white blood cell count ≤ 2000/mm3 or a platelet count ≤ 50,000/mm3 ; 11) ongoing wound healing problems; 12) clinically significant infections; 13) severe surgical problems in the opinion of the investigator; 14) intractable immunosuppressant complications or side effects; 15) pregnant or lactating patients; 16) patients who were planning to become pregnant or were unwilling to use effective means of contraception. Donor-specific anti-HLA antibodies were not measured at the time of inclusion (nor thereafter during the course of the trial) and were thus not considered as a possible exclusion criterion. Interim analyses were planned after the inclusion of 60 patients and again after the inclusion of 120 patients. A data safety monitoring board was instituted to analyse the interim analyses and decide on continuation or modification of the trial. The study was approved by the institutional review board of the Erasmus MC (Medical Ethical Review Board number 2010-235) and was registered in the Dutch National Trial Registry (http://www.trialregister.nl/trialreg/index.asp; number: NTR2545, registered 6 September 2010). Written informed consent was obtained from all patients before randomisation. The study was performed in compliance with the Good Clinical Practice guidelines and in accordance with the declaration of Helsinki. Intervention and randomisation The patients were enrolled and randomised on a 1:1 basis by one of the coordinating investigators (R.B., N.S., T.v.G., or D.A.H.) to either continue tacrolimus or to switch to everolimus-based maintenance immunosuppressive therapy. The randomisation was performed by use of sealed, opaque, sequentially-numbered envelopes containing treatment allocation. The random-allocation sequence was generated by an independent statistician using a random number generator on a computer. Data were collected, monitored and entered by the coordinating investigators and stored in a hospital-based electronic study database. All patients received tacrolimus (Prograf®, Astellas Pharma, Leiden, the Netherlands), mycophenolate mofetil (Cellcept®, Roche Pharmaceuticals, Basel, Switzerland) and prednisolone triple immunosuppressive therapy at the time of enrolment and randomisation which was month 3 ± 3 weeks. After randomisation, patients either continued treatment with tacrolimus (aiming for pre-dose concentrations of 5-10 ng/ml) or were converted to everolimus (Certican®, Novartis Pharma B.V., Arnhem, the Netherlands) therapy. The everolimus starting dose was 1.5 mg twice daily and thereafter the everolimus dose was 16 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine Bouamar et al. Conversion from tacrolimus to everolimus. adjusted aiming for whole blood pre-dose concentrations of 4-7 ng/ml. Tacrolimus was reduced to 50% on the day of initiation of the everolimus therapy. One week after the introduction of everolimus, tacrolimus was withdrawn. Following our standard immunosuppressive protocol, prednisolone was tapered from 20 mg orally (started on day 3 after transplantation; all patients received 100 mg prednisolone intravenously for the first 3 days) to 5 mg over the course of the first three postoperative months. Prednisolone was tapered from 5 mg daily at the time of conversion to 0 mg in one month’s time following randomisation in both groups. The reason for complete glucocorticoid elimination in both arms was the fact that combination therapy of tacrolimus plus mycophenolate mofetil with complete cessation of glucocorticoids has been the standard of care in our centre for more than 10 years. Continuation of prednisolone in the control arm was therefore considered unethical. Renal transplant biopsies All patients included in this trial were asked to undergo a protocol biopsy at month 3 and again at month 12 after transplantation. However, this protocol biopsy was not mandatory and patients could be included in the trial without a baseline protocol biopsy. All biopsies (both for cause and protocol) were assessed locally by two pathologists (M.C.C.-v.G. and J.D.) and scored according to the most recent Banff criteria.10 For the trial reported here, only renal transplant biopsies to determine cause were considered and analysed. Endpoints The primary endpoint of the trial was renal function (eGFR) at month 12 ± 6 weeks after transplantation calculated by the 4-variable MDRD formula.11 Secondary endpoints were graft survival, the incidence of biopsy-proven acute rejection (BPAR) between month 3 and month 12 (based on for cause biopsy findings only), adverse events (AE), serious adverse events (SAE) and renal histology on protocol biopsy (including signs of CNI-related nephrotoxicity at month 12). Safety The incidence of adverse events was registered. An adverse event was defined as serious when 1) it necessitated or prolonged patient hospitalisation; 2) caused persistent or significant disability or incapacity; 3) was life-threatening; 4) caused the death of a patient or 5) required an intervention to prevent an event listed under point 1) to 4). Patients were followed until month 12 ± 6 weeks after transplantation. Tacrolimus and everolimus concentration measurements Tacrolimus concentrations were measured in ethylene diamine tetra-acetic acid (EDTA) blood using the affinity chrome-mediated flex-immunoassay (ACMIA) on a Dimension Xpand analyser (Siemens HealthCare Diagnostics Inc., Newark, DE) in accordance with the manufacturer’s instructions.12 Everolimus concentrations were determined using the sirolimus ACMIA kit from Siemens that highly cross-reacts with everolimus.13 Statistical analysis It was estimated that a total of 194 patients had to be included in the trial in order to detect a difference in eGFR of 8 ml/min per 1.73 m2 between the two groups with a 90% power and accounting for a 30% dropout rate. Because the trial was terminated prematurely (after the first interim analysis), the focus of this report is on the safety aspects of conversion from tacrolimus to everolimus. Data on the primary endpoint (eGFR) will be presented for completeness. For the analysis, an intention-to-treat approach was followed, which included all randomised patients who received at least one dose of the assigned drug. All summary statistics are presented by treatment group. Frequency distributions are provided for categorical variables. The two treatment groups were compared using c2 tests or Student’s t test to evaluate the null hypothesis of no difference in eGFR (and the secondary endpoints) between the tacrolimus and everolimus groups. For 2 x 2 tables, Yates’ correction for continuity was used. If the minimal expected value in a 2 x 2 table was below 5, Fisher’s exact test was used. The Shapiro-Wilk test was used to assess the normality of data. When this assumption was violated, the median and range are displayed and the Mann-Whitney U test was used to evaluate the null hypothesis of no relationship between secondary endpoints. All statistical tests were two-sided and used the 0.05 level of statistical significance. The statistical analyses were conducted using IBM SPSS Statistics version 21.0. Armonk, NY: IBM Corp. Role of the funder This was an investigator-initiated study. The trial was financially supported by Novartis Pharma B.V., Arnhem, the Netherlands, the producer of everolimus. Novartis Pharma B.V. had no role in the study design, data collection, data analyses, data interpretation, or writing of the report. All authors had full access to all the data, had final responsibility for the contents of this publication and the decision to submit for publication. 17 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine Bouamar et al. Conversion from tacrolimus to everolimus. RESULTS Patient population and trial progress This study was conducted between 17 February 2011 (first patient, first visit) and 14 March 2014 (last patient, last visit). A total of 457 patients were screened for participation in the trial of which 136 were eligible, as shown in figure 1. Sixty patients gave written informed consent and were subsequently included and randomised. The characteristics of these 60 patients are summarised in table 1. Patients were enrolled in the study at a median of 96 days (range 83-111) after transplantation. A total of 58 patients (96.7%) completed the 9 month (± 6 weeks) follow-up. At the end of follow-up, 100% in the control group were on the assigned therapy, while only 40% of the patients in the intervention group were still on everolimus (p < 0.001). The primary reasons for discontinuing everolimus were acute rejection (number in group (n) = 9) and toxicity (n = 8); see figure 1 and below. The trial was ended prematurely after the first, pre-planned interim analysis. The reasons for discontinuation were twofold. First, the interim analysis showed a significantly and unacceptably high incidence of BPAR in the everolimus group compared with the tacrolimus group: 30.0% vs. 6.7%; p = 0.042 (figure 2) (for details see below: under ‘Acute rejection’). Second, because the clinical condition of these patients required re-conversion to tacrolimus and because a considerable number of non-rejecting patients stopped taking everolimus for other reasons (see below), the overall dropout rate was 60%, which was much higher than the anticipated 30%. Acute rejection Overall, the BPAR rate in the everolimus group was 30.0% vs. 6.7% in the control group (95% CI: 0.048; 0.420; p = 0.045) (figure 2). Banff grades and frequencies are depicted in table 2. No cases of presumed acute rejection (i.e. clinically suspected rejection without histological confirmation) occurred. Baseline characteristics between rejectors and non-rejectors in the everolimus group are listed in Supplementary table 1. Estimated GFR at month 3 (baseline) was significantly lower among rejectors (U = 59.5; p = 0.04). There were no significant differences in everolimus dosages and concentration measurements between rejectors and non-rejectors. Safety and tolerability One patient (randomised to tacrolimus) died 272 days after transplantation due to metastasised gastric carcinoma. Figure 1. Trial flowchart (all patients randomised received at least one dose of the assigned drug) 457 Screened 321 Not included 136 Eligible patients 1 Discontinued study drug 1 Death 18 Discontinued study drug 9 Rejection episode 8 Toxicity 1 Recurrent disease 1 Death (3.33%) 1 Graft loss (3.33%) 30 Tacrolimus group 30 Everolimus group 60 Randomised 76 No informed consent 29 Completed 9 months follow-up (29 on study drug) 29 Completed 9 months follow-up (12 on study drug) Not treated with tacrolimus, corticosteroids and mycophenolate mofetil at three months after tranplantation Acute rejection episodes less than 4 weeks prior to randomisation Proteinuria ≥ 1.0 g/day GFR ≤ 30 mL/min Recipient of multiple organ transplants Recipient of ABO incompatible allograft or a positive cross-match Patient who is human immunodeficiency virus (HIV) positive Ongoing wound healing problems, severe infections or other surgical complications Presence of intractable immunosuppressant complications or side effects Postmortal donor Deemed not eligible for participation by treating physician Deceased before reaching t = 3 months post-transplantation 45 15 3 19 4 23 2 36 1 146 24 3 18 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine Bouamar et al. Conversion from tacrolimus to everolimus. This resulted in a patient survival of 97% and 100%, in the tacrolimus and everolimus groups, respectively (p = 0.41). One patient (randomised to everolimus) lost his graft as a result of uncontrollable acute rejection. The AEs are listed in table 3. A total of 406 adverse events were observed. Of these, n = 52 (12.8 %) were considered severe. A total of 238 vs. 168 AEs occurred in the everolimus and tacrolimus group, respectively (χ2 (1df) = 12,069; p = 0.001). There was no difference in the incidence of SAEs in the everolimus and tacrolimus group: 25 vs. 26 (χ2 (1df) = 0.020; p = 0.89). Peripheral oedema and oral ulcers occurred more frequently among everolimus-treated patients. The incidence of all other AEs was not significantly different between the two groups. A dropout rate of 60% (n = 18) was observed in the everolimus group. Of the patients, 30% were reconverted to tacrolimus because of acute rejection (n = 9). Another 26.7% were reconverted because of toxicity (n = 8). Of these eight patients, three were reconverted to tacrolimus because of severe peripheral oedema, one because of peripheral oedema in combination with leucopenia and exanthema, one because of oral ulcers and peripheral oedema, one because of exanthema, one because of pancytopenia, and in one case due to severe pneumonitis. One other patient was reconverted to tacrolimus because of the recurrence of his primary kidney disease (granulomatosis with polyangiitis). Primary endpoint At month 12 after transplantation, there was no statistically significant difference with regard to eGFR between the tacrolimus and everolimus group: 53 vs. 56 ml/min per 1.73 m2 , respectively (p = 0.52). The difference at month 12 was 3 ml/min per 1.73 m2 . In the tacrolimus group an average decrease of Δ = -1 ml/min in eGFR occurred over the course of 9 months, whereas in the everolimus group an increase of Δ = 2 ml/min occurred during this same period. Median protein/creatinine ratios were significantly different between the everolimus and tacrolimus group: 18.7 vs. 11.8 mg/mmol, respectively (U = 212.5; p = 0.005; table 4). Secondary outcomes The outcome parameters are listed in table 4. At baseline, no significant differences between efficacy parameters were found. Differences per group between month 3 and month 12 are shown in Supplementary table 2. At month 12 there was a significant difference in haemoglobin concentration in favour of the tacrolimus Figure 2. Cumulative survival curve of non-rejectors Table 1. Baseline characteristics Tacrolimus group (n = 30) Everolimus group (n = 30) Age at time of transplant (years) 56 (11) 51 (15) Gender - Male/female 25 (83%) / 5 (17%) 19 (63%) / 11 (37%) Ethnicity - White 26 (87%) 25 (83%) - Black 1 (3%) 2 (7%) - Asian 0 2 (7%) - Other 3 (10%) 1 (3%) BMI (kg/m2 ) 27.2 (3.6) 26.7 (3.5) Number of kidney transplantation - 1st 30 (100%) 26 (87%) - 2nd 0 4 (13%) Primary kidney disease - Hypertensive nephropathy 8 (27%) 5 (17%) - Diabetic nephropathy 5 (17%) 4 (13%) - Polycystic kidney disease 5 (17%) 4 (13%) - Glomerulonephritis 4 (13%) 9 (30%) - Reflux disease / Chronic pyelonephritis 3 (10%) 2 (7%) - Other 2 (7%) 4 (13%) - Unknown 3 (10%) 2 (7%) Donor type Living-related/Living-unrelated 10 (33%) / 20 (67%) 14 (47%) / 16 (53%) - PRA % (< 15% / ≥ 15%) 30 (100%) / 0 (0%) 27 (90%) / 3 (10%) - Peak PRA % (< 15% / ≥ 15%) 29 (97%) / 1 (3%) 25 (83%) / 5 (17%) - HLA mismatches 3.4 (1.2) 3.5 (1.5) Data represents mean (SD) or n (%). PRA = panel reactive antibodies. 19 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine Bouamar et al. Conversion from tacrolimus to everolimus. Table 2. Incidence of biopsy-proven acute rejection Tacrolimus group Everolimus group (n = 30) (n = 30) Borderline 0 (0.0%) 0 (0.0%) Type 1 - 1A 0 (0.0%) 2 (6.7%) - 1B 0 (0.0%) 2 (6.7%) Type 2 - 2A 1 (3.3%) 2 (6.7%) - 2B 0 (0.0%) 1 (3.3%) Type 3 1 (3.3%) 0 (0.0%) ABMR 0 (0.0%) 1 (3.3%) Mixed ACR and ABMR 0 (0.0%) 1 (3.3%) Total 2 (6.7%) 9 (30.0%) ABMR = antibody mediated rejection; ACR = acute cellular rejection. Table 3. Adverse events Event Tacrolimus group (n = 30) Everolimus group (n = 30) p Blood or lymphatic system 11 28 0.12 - Leucopenia 8 19 - Anaemia 2 5 - Thrombocytopenia 0 2 - Other 1 2 Bleeding and thrombotic events 4 3 0.45 - Thrombotic event 2 2 - Bleeding 2 1 Malignancy 1 1 > 0.99 Cardiac 4 6 > 0.99 - Cardiac decompensation 1 3 - Other 3 3 Gastrointestinal 18 13 0.07 - Diarrhoea 8 4 - Other 10 9 Oral ulcer 0 9 0.01 Opportunistic infection 5 13 0.35 - Cytomegalovirus 2 4 - Herpes simplex virus 2 4 vervolg Table 3. Adverse events Event Tacrolimus group (n = 30) Everolimus group (n = 30) p - BK viraemia 1 3 - Epstein-Barr virus 0 2 Other infection 34 44 0.73 - Respiratory tract infection 11 18 - Urinary tract infection 9 6 - Gastroenteritis 8 4 - Other 6 16 Locomotor system disorder 17 13 0.11 Metabolism or nutrition 8 9 0.81 - Liver enzyme abnormality 1 5 - Dysregulation of preexisting DM 5 3 - Post-transplant DM 2 1 Nervous system 6 12 0.65 - Headache 2 4 - Tremor 1 3 - Other 3 5 Skin-related disorders 3 14 0.08 - Maculopapular rash 0 8 - Other 3 6 Tacrolimus-induced nephrotoxicity 2 0 0.17 Urological complication 5 2 0.13 Wound-related problem 2 2 > 0.99 Other 24 33 > 0.99 Allergic reaction 0 1 > 0.99 Other laboratory abnormality 19 17 0.20 - Hypovitaminosis D 6 6 - Iron deficiency 5 5 - Hypercalcaemia 4 1 - Hypophosphataemia 1 3 - Other 3 2 (Peripheral) oedema 4 18 0.04 Total 167 238 DM = diabetes mellitus. 20 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine Bouamar et al. Conversion from tacrolimus to everolimus. group. When adjusted for gender and baseline haemoglobin, the difference between groups remained statistically significantly different (p < 0.001). Total cholesterol level and LDL cholesterol were significantly lower in the tacrolimus group at month 12. All other outcome parameters were not significantly different between the two groups (table 4). Medication dosages and changes are listed in Supplementary table 3. There were no significant changes in medication usage between groups at month 12. Increased use of antihypertensive and lipid-lowering drugs as compared with baseline was observed in both groups. There were no statistically significant changes in the use of glucose-lowering drugs. DISCUSSION Conversion from tacrolimus to everolimus-based immunosuppression three months after transplantation with complete and early withdrawal of glucocorticoids is not safe in living-donor kidney transplant recipients. Conversion results in an unacceptably high risk of acute rejection. Moreover, a considerable number of patients discontinued everolimus because of side effects. The results of this trial differ from other randomised trials that studied early conversion from a CNI-based to an everolimus-based immunosuppressive regimen.14,15 The investigators of the ZEUS trial concluded that early conversion (month 4.5 after transplantation) Table 4. Outcome parameters Month 12 n Tacrolimus group n Everolimus group p (CI) / p (U)* Body weight (kg) 25 86.8 (67.5; 109.2) 26 82.4 (53; 143.5) 0.11 (239.0) BMI (kg/m2 ) 26 (6) 26 (7) 0.73 (-2.89; 4.13) Blood pressure Systolic/diastolic (mmHg) 25 138 (15) / 81 (11) 25 132 (13) / 79 (9) 0.17 (-2.41; 13.37) / 0.58 (-4.19; 7.39) Kidney function Creatinine (µmol/l) 29 121 (66; 190) 29 108 (58; 238) 0.20 (338.5) eGFR (ml/min per 1.73 m2 ) 29 53 (13) 29 56 (18) 0.52 (-11.07; 5.69) Protein/creatinine ratio 29 11.8 (2.0; 59.6) 27 18.7 (5.7; 296.1) 0.01 (212.5) Glucose metabolism Glucose (mmol/l) 27 6.2 (3.9; 16.8) 27 5.4 (4.0; 8.8) 0.14 (279.5) HbA1c (mmol/mol) 20 42.0 (3.6; 93.0) 17 40.0 (31.0; 46.0) 0.21 (129.0) Lipids Cholesterol, total (mmol/l) 25 4.2 (1.0) 24 5.0 (1.2) 0.01 (-1.44; -0.21) Triglycerides (mmol/l) 25 1.5 (0.6; 3.9) 24 1.7 (0.5; 7.0) 0.29 (247.5) HDL-cholesterol (mmol/l) 25 1.3 (0.3) 24 1.4 (0.5) 0.43 (-0.33; 0.14) LDL-cholesterol (mmol/l) 25 2.4 (0.8) 24 3.0 (0.9) 0.02 (-1.06; -0.85) Haematology Haemoglobin (mmol/l) 27 8.7 (0.7) 29 7.8 (1.0) <0.001 0="" 47="" 1="" 41="" mcv="" fl="" 27="" 86="" 5="" 29="" 85="" 20="" -0="" 96="" 4="" 52="" thrombocytes="" 10="" 9="" l="" 230="" 129="" 806="" 231="" 124="" 436="" 90="" 384="" leucocytes="" 6="" 8="" 3="" 14="" 2="" 17="" 75="" 372="" data="" represents="" mean="" sd="" and="" p="" confidence="" interval="" of="" the="" difference="" or="" median="" range="" u="" egfr="" gfr="" corpuscular="" volume="" 21="" january="" 2018="" vol="" 76="" no="" netherlands="" journal="" medicine="" from="" cyclosporine="" to="" everolimus="" resulted="" in="" improved="" kidney="" function="" without="" compromising="" efficacy="" safety="" dutch="" multi-centre="" mecano="" trial="" renal="" transplant="" recipients="" were="" converted="" mycophenolate="" sodium="" prednisolone-based="" immunosuppression="" prednisolone="" combination="" therapy="" at="" month="" after="" transplantation="" conversion="" everolimus-based="" better="" preservation="" histology="" compared="" with="" patients="" who="" treated="" prednisolonebased="" 15="" elevate="" 715="" de="" novo="" randomised="" 10-14="" weeks="" convert="" n="" remain="" on="" standard="" cni="" tacrolimus="" mycophenolic="" acid="" glucocorticoids="" 16="" there="" was="" primary="" endpoint="" estimated="" change="" randomisation="" 12="" post-transplant="" line="" observations="" made="" present="" incidence="" bpar="" arm="" 7="" comparable="" that="" remained="" but="" significantly="" higher="" continued="" tacrolimusbased="" a="" major="" between="" study="" previous="" investigations="" is="" complete="" cessation="" we="" chose="" eliminate="" both="" groups="" because="" double="" immunosuppressive="" consisting="" mofetil="" onwards="" practice="" our="" centre="" zeus="" trials="" maintained="" mg="" an="" equivalent="" glucocorticoid="" another="" type="" control="" group="" either="" whereas="" all="" baseline="" reported="" here="" which="" considered="" more="" potent="" high="" rates="" acute="" rejection="" also="" observed="" other="" 18-20="" central="" experienced="" episode="" first="" year="" had="" similar="" design="" as="" except="" performed="" early="" 19="" drop="" out="" 30="" stopped="" 26="" toxicity="" most="" cases="" these="" typical="" side="" effects="" associated="" use="" mtor="" inhibitor="" such="" oedema="" exanthema="" management="" left="" attending="" physician="" effort="" keep="" their="" assigned="" treatment="" general="" if="" possible="" dose="" reduction="" any="" concomitant="" medication="" co-trimoxazole="" valganciclovir="" calcium="" channel="" blockers="" withdrawn="" reduced="" this="" cause="" symptoms="" oral="" ulcers="" often="" managed="" topical="" steroids="" however="" several="" requested="" refused="" further="" when="" troublesome="" occurred="" dropout="" rate="" everolimus-related="" consistent="" results="" switch="" studies="" big="" discontinuation="" -32="" 14-16="" investigators="" 43="" accounted="" for="" 25="" 13="" reasons="" respectively="" indicating="" physicians="" less="" inclined="" back="" even="" failing="" willingness="" treating="" period="" adverse="" events="" may="" contribute="" greatly="" differences="" two="" obviously="" only="" included="" limited="" number="" not="" powered="" detect="" think="" it="" unlikely="" would="" have="" been="" detected="" planned="" 194="" benefit="" terms="" has="" previously="" 7-9="" likely="" offset="" by="" risk="" on-treatment="" analysis="" supplementary="" table="" showed="" switched="" vs="" those="" 66="" 53="" ml="" min="" thus="" proportion="" seem="" whether="" persists="" over="" time="" remains="" be="" determined="" note="" long-term="" follow-up="" found="" develop="" donor-specific="" anti-hla="" antibodies="" factor="" chronic="" furthermore="" are="" reliable="" biomarkers="" can="" assist="" clinicians="" identifying="" will="" do="" well="" 22="" bouamar="" et="" al="" limitations="" ended="" prematurely="" small="" available="" therefore="" lacks="" power="" significant="" increases="" probability="" detecting="" chance="" statistical="" error="" feel="" random="" second="" population="" primarily="" consisted="" caucasian="" males="" making="" generalisable="" patient="" populations="" still="" african="" american="" high-immunological="" advisable="" 23="" finally="" mentioned="" above="" many="" centres="" publication="" very="" important="" 24="" publications="" provide="" information="" researchers="" considering="" embark="" goals="" designs="" systematic="" reviews="" meta-analysis="" balanced="" representation="" literature="" positive="" negative="" outcome="" crucial="" summary="" everolimusbased="" compete="" withdrawal="" three="" months="" living-donor="" unacceptably="" addition="" causing="" considerable="" based="" findings="" strategy="" should="" safe="" cannot="" recommended="" acknowledgements="" authors="" grateful="" research="" nurses="" mrs="" m="" j="" boer="" -verschragen="" ms="" cadogan="" leeuw="" -van="" weenen="" valuable="" contribution="" clinical="" like="" thank="" i="" buijt="" her="" help="" analyses="" professor="" h="" boersma="" dr="" r="" hen="" b="" hilbrands="" serving="" monitoring="" board="" received="" grant="" 017006041="" organization="" scientific="" nwo="" shuker="" ip11="" 44="" foundation="" nierstichting="" nederland="" full="" access="" responsibility="" contents="" decision="" submit="" disclosures="" prof="" t="" van="" gelder="" lecture="" fees="" chiesi="" pharmaceuticals="" astellas="" pharma="" v="" consulting="" novartis="" roche="" teva="" sandoz="" d="" hesselink="" support="" bristol-myers="" squibb="" msd="" conflicts="" interest="" disclose="" funding="" investigator-initiated="" financially="" supported="" arnhem="" producer="" certican="" role="" collection="" interpretation="" writing="" report="" final="" references="" sandwijk="" bemelman="" fj="" ten="" berge="" ijm="" drugs="" solid="" organ="" neth="" med="" 2013="" 71:281-9="" shipkova="" da="" holt="" dw="" therapeutic="" drug="" everolimus:="" consensus="" ther="" monit="" 2016="" 38:143-69="" witzke="" o="" sommerer="" c="" arns="" w="" transplantation:="" what="" optimal="" rev="" orlando="" 30:3-12="" ventura-aguiar="" campistol="" jm="" diekmann="" f="" inhibitors="" adult="" expert="" opin="" saf="" 15:303-19="" holdaas="" rostaing="" seron="" calcineurin="" s="" multicenter="" 24-month="" 2011="" 92:410-8="" budde="" k="" rath="" outcomes="" following="" late="" randomized="" apollo="" clin="" nephrol="" 2015="" 83:11-21="" becker="" calcineurin-inhibitorfree="" regimen="" de-novo="" transplants:="" open-label="" controlled="" lancet="" 377:837-47="" lehner="" five-year="" am="" 15:119-28="" posttransplant:="" 3-year="" 2012="" 12:1528-40="" haas="" sis="" racusen="" lc="" banff="" meeting="" report:="" inclusion="" c4d-negative="" antibody-mediated="" antibody-associated="" arterial="" lesions="" 2014="" 14:272-83="" 11="" levey="" coresh="" greene="" using="" standardized="" serum="" creatinine="" values="" modification="" diet="" disease="" equation="" estimating="" glomerular="" filtration="" ann="" intern="" 2006="" 145:247-54="" vafadari="" mm="" weimar="" baan="" cc="" inhibitory="" effect="" p38="" mitogen-activated="" protein="" kinase="" signaling="" measured="" whole-blood="" phosphospecific="" flow="" cytometry="" 93:1245-51="" bouzas="" tutor="" jc="" determination="" blood="" concentrations="" liver="" sirolimus="" antibody="" conjugated="" magnetic="" immunoassay="" acmia="" lab="" 57:403-6="" zeier="" recipients:="" transpl="" int="" 27:1192-204="" fijter="" jw="" kers="" alternative="" weaning="" associates="" beneficial="" function:="" randomized-controlled="" 2017="" 17:1020-30="" yen="" inhibitor-="" 17:1853-67="" webster="" ac="" woodroffe="" rc="" taylor="" rs="" chapman="" jr="" craig="" versus="" meta-regression="" bmj="" 2005="" 331:810="" 18="" mjornstedt="" schwartz="" sorensen="" von="" zur="" muhlen="" years="" 28:42-51="" ss="" 12:2744-53="" chadban="" sj="" eris="" kanellis="" dual="" care="" 27:302-11="" liefeldt="" brakemeier="" glander="" hla="" cohort="" comparing="" 12:1192-8="" brunet="" barcelona="" biomarker-based="" 38="" suppl="" :s1-20="" higgins="" fishman="" ja="" disparities="" ethnic="" minorities:="" facts="" solutions="" 6:2556-62="" ups="" downs="" importance="" reporting="" 2007="" 65:3-4="" smits="" pilot="" studies:="" one="" swallow="" does="" make="" summer="" 2003="" 61:270-2="" appendix="" s1="" characteristics="" group:="" non-rejectors="" rejectors="" ci="" bmi="" kg="" m2="" 78="" -2="" pressure="" systolic="" mmhg="" 136="" 138="" 88="" -15="" diastolic="" 65="" 110="" 80="" 70="" 101="" 71="" 82="" mol="" 114="" 32="" 145="" 35="" 03="" -57="" -4="" per="" 73="" 77="" 04="" 59="" ratio="" mmol="" 54="" 68="" glucose="" metabolism="" 83="" hba1c="" 40="" 39="" 62="" 33="" 46="" 58="" lipids="" cholesterol="" total="" 67="" triglycerides="" 02="" hdl-cholesterol="" 00="" 60="" 91="" 95="" 42="" ldl-cholesterol="" 79="" haematology="" haemoglobin="" -1="" 271="" 237="" 63="" -26="" day="" 87="" predose="" concentration="" ng="" 50="" 34="" non="" whole="" reconverted="" reason="" last="" before="" reintroduction="" s2="" changes="" -3="" -5="" -25="" -47="" 93="" 377="" 61="" -6="" -37="" -36="" 280="" 295="" 48="" 49="" 36="" 01="" 28="" 128="" 56="" 227="" -9="" -18="" 217="" -30="" -16="" -44="" s3="" dosages="" 69="" 72="" -="" 45="" mmf="mycophenolate" 1367="" 706="" 1283="" 520="" 1092="" 438="" 966="" 325="" mpa="mycophenolic" antihypertensive="" decreased="" same="" 57="" increased="" glucose-lowering="" lipid-lowering="" re-converted="" measurement="" missing="" s4="" 112="" 130="" 81="" 125="" 31="" 99="" -22="" 126="" 09="" 108="" 267="" 171="" 64="" 146="" 122="" zuiden="" communications="" rights="" reserved="" original="" article="" simethicone="" improves="" bowel="" capsule="" endoscopy="" visualisation="" quality="" krijbolder1="" grooteman1="" bogers2="" jong1="" department="" gastroenterology="" hepatology="" radboud="" university="" medical="" center="" nijmegen="" bernhoven="" hospital="" uden="" corresponding="" author:="" mskrijbolder="" gmail="" com="" abstract="" background:="" sbce="" diagnostic="" tool="" small-bowel="" diseases="" its="" hampered="" intraluminal="" gas="" evaluated="" added="" value="" anti-foaming="" agent="" preparation="" polyethylene="" glycol="" peg="" methods:="" retrospective="" single-blind="" prior="" peg-s="" ingested="" additional="" assessed="" four-point="" scale="" faecal="" contamination="" means="" survey="" agents="" sample="" hospitals="" performing="" results:="" proximal="" segment="" distal="" amount="" transit="" times="" hours="" yield="" frequency="" low="" conclusion:="" improving="" reducing="" keywords="" introduction="" proven="" play="" diagnosis="" obscure="" gastrointestinal="" bleeding="" crohn="" 1-4="" unfortunately="" impaired="" due="" intestinal="" juice="" air="" bubbles="" food="" residue="" lower="" completion="" examination="" caused="" delayed="" gastric="" might="" improve="" thereby="" 5-7="" since="" 2000="" lot="" carried="" order="" define="" including="" prokinetics="" purgatives="" mainly="" shortening="" while="" few="" seen="" improvement="" cleansing="" somewhat="" contradictory="" 12-17="" despite="" much="" regarding="" reached="" regimens="" used="" lead="" krijbolder="" heterogeneity="" moreover="" widely="" accepted="" measuring="" method="" definition="" adequate="" impeding="" standardisation="" effective="" aim="" evaluate="" hypothesise="" alone="" secondary="" materials="" methods="" single-blinded="" prospectively="" collected="" underwent="" until="" december="" exclusion="" criteria="" contraindications="" swallowing="" difficulties="" known="" suspected="" fistulas="" stenosis="" presence="" implantable="" cardioverter="" defibrillator="" motility="" severe="" diverticulosis="" pregnancy="" age="" than="" cohorts="" records="" november="" liquid="" litres="" clear="" evening="" followed="" overnight="" fast="" march="" they="" suspension="" containing="" lefax="" bayer="" germany="" tap="" water="" minutes="" took="" iron="" supplements="" asked="" temporarily="" stop="" seven="" days="" pillcam="" sb="" given="" imaging="" israel="" allowed="" drink="" liquids="" eat="" light="" meal="" images="" battery="" ran="" reviewed="" rapid="" medtronic="" united="" states="" assessment="" thirteen="" videos="" evaluation="" interobserver="" variability="" agreement="" discrepancies="" 51="" investigator="" disagreement="" discussed="" video="" blinded="" limiting="" mucosal="" visibility="" every="" grading="" scale:="" grade="" 0:="" 1:="" little="" 2:="" some="" leading="" moderate="" 3:="" substantial="" classified="" separately="" part="" defined="" hour="" duodenal="" bulb="" image="" began="" caecal="" explanatory="" could="" explain="" signs="" did="" show="" abnormalities="" randomly="" selected="selected" perform="" spread="" regions="" mix="" regional="" teaching="" peripheral="" obtain="" brochures="" consulted="" departments="" contacted="" telephone="" focused="" descriptive="" statistics="" expressed="" deviation="" categorical="" variables="" chi-square="" test="" unpaired="" t-test="" p-value="" 05="" statistically="" spss="" software="" version="" ibm="" armonk="" ny="" usa="" analysed="" excluded="" empty="" men="" gender="" indications="" anaemia="" inflammatory="" ibd="inflammatory" polyps="" indication="" polyposis="" syndrome="" diagnosed="" listed="" difficulty="" serious="" during="" differ="" definitive="" established="" male="" female="" 0-1="" 2-3="" see="" section="" definitions="" 0-3="" academic="" specific="" routinely="" located="" region="" evaluates="" adding="" mucosa="" increase="" fasting="" review="" 13-17="" proved="" children="" influenced="" debris="" juices="" reduce="" possibly="" obtained="" rosa="" demonstrated="" leads="" entire="" fluid="" contrast="" comparison="" seems="" decrease="" investigated="" useful="" assessing="" factors="" context="" led="" importantly="" litre="" 300="" hypothesis="" rather="" fluids="" expected="" reduces="" surface="" tension="" neither="" nor="" finding="" longer="" 12-14="" knowledge="" although="" causes="" hence="" explanation="" underpowered="" overall="" explained="" fact="" become="" instrument="" flexible="" undergoing="" underlying="" pathology="" guidelines="" reach="" emphasises="" costs="" units="" foam="" oesophagogastro-="" duodenoscopy="" colonoscopy="" suggest="" consider="" limits="" allocated="" purgative="" hand="" assessors="" evaluating="" relatively="" enough="" limitation="" subjective="" validated="" ge="" recent="" proposed="" questioned="" quantitative="" e="" counting="" closely="" related="" daily="" conclusion="" demonstrates="" date="" standardised="" potential="" good="" profile="" recommend="" future="" focus="" stricter="" investigate="" declare="declare" conflict="" financial="" yw="" chang="" dk="" endosc="" 49:16-20="" carey="" ej="" leighton="" heigh="" ri="" single-center="" experience="" 260="" consecutive="" gastroenterol="" 102:89-95="" tukey="" pleskow="" legnani="" cheifetz="" moss="" utility="" 2009="" 104:2734-9="" yang="" d-h="" keum="" jeen="" yt="" disease:="" current="" status="" res="" pract="" 2016:8236367="" tuyl="" sac="" den="" ouden="" stolk="" mfj="" kuipers="" endoscopy:="" prospective="" 39:1037-40="" viazis="" sgouros="" papaxoinis="" gastrointest="" 2004="" 60:534-8="" wei="" z-z="" lu="" gao="" y-j="" hu="" y-b="" xiao="" s-d="" mosapride="" hepatol="" 22:1605-8="" park="" sc="" seo="" ys="" dig="" dis="" sci="" 56:1769-75="" belsey="" crosta="" epstein="" meta-analysis:="" curr="" 28:1883-90="" dai="" gubler="" hengstler="" meyenberger="" bauerfeind="" 61:28-31="" hooks="" 3rd="" rutland="" tj="" di="" palma="" lubiprostone="" decreases="" visualization="" double-blind="" placebo-controlled="" 70:942-6="" spada="" riccioni="" me="" familiari="" plus="" 2010="" 42:365-70="" fang="" y="" chen="" zhang="" zhejiang="" univ="" 10:46-51="" combined="" 2008="" 103:77-82="" h-y="" simeticone="" 38:836-40="" bjf="" barbosa="" magalhaes="" rebelo="" moreira="" mj="" cotter="" world="" 5:67-73="" albert="" gobel="" c-m="" lesske="" lotterer="" nietsch="" fleig="" 59:487-91="" enns="" ra="" hookey="" armstrong="" 152:497-514="" adler="" sn="" baltes="" barbaro="" cellier="" charton="" jp="" device-assisted="" enteroscopy="" small-="" disorders="" :="" european="" society="" esge="" guideline="" 352-76="" wu="" cao="" liao="" huang="" endoscopic="" scand="" 46:227-35="" oliva="" cucchiara="" paediatric="" 46:51-5="" papamichael="" karatzas="" theodoropoulos="" kyriakos="" archavlis="" mantzaris="" gj="" adjunct="" non-crohn="" q="" publ="" hell="" soc="" 28:464-8="" iddan="" g="" meron="" glukhovsky="" swain="" wireless="" nature="" 405:417="" klein="" gizbar="" bourke="" ahlenstiel="" computed="" score="" 28:564-9="" goyal="" goel="" mcgwin="" weber="" system="" assess="" search="" holy="" grail="" open="" 2:e183-6="" hurry="" up="" quiet="" emergency="" ter="" avest1="" onnes1="" der="" vaart2="" land2="" leeuwarden="" operations="" faculty="" economics="" business="" groningen="" teravestewoud="" hotmail="" introduction:="" ed="" crowding="" contemporary="" problem="" multiple="multiple" involve="" lengthy="" implementation="" process="" meanwhile="" identify="" simple="" strategies="" focussing="" optimising="" efficiency="" resources="" adopted="" now="" careful="" inflow="" throughput="" outflow="" 823="" visiting="" large="" looked="" detail="" longest="" average="" peaks="" beyond="" midday="" surge="" arrivals="" handled="" adequately="" distinctive="" pattern="" backlog="" building="" morning="" maximum="" bed="" capacity="" yet="" consequences="" timing="" internal="" efforts="" performance="" integral="" approach="" prevent="" situation="" identified="" need="" services="" outstrips="" forms="" universal="" eds="" various="" shown="" bad="" satisfaction="" actually="" places="" risk:="" complication="" mortality="" 3-5="" multifactorial="" spanning="" healthcare="" delivery="" contributing="" categorised="" increasing="" inappropriate="" decreasing="" personnel="" diminishing="" lack="" in-hospital="" beds="" linden="" week="" couple="" sharp="" ambulance="" bans="" declared="" administrators="" response="" resulting="" transport="" itself="" affect="" provided="" realised="" example="" identification="" non-urgent="" setting="" collaboration="" practitioners="" temporary="" ban="" shorter="" result="" minimising="" needed="" tests="" instance="" creating="" observation="" wards="" evidence="" around="" interventions="" requires="" mutual="" adjustment="" parties="" involved="" you="" burden="" avest="" objective="" examine="" patterns="" measure="" 671-bed="" northern="" cardiac="" vascular="" surgery="" annual="" census="" 000="" size="" acquisition="" retrospectively="" electronic="" chart="" presentation="" mirador="" recorded="" arrival="" unique="" triage="" category="" according="" manchester="" referral="" practitioner="" ems="" self-referral="" destination="" discharge="" hospitalisation="" calculated="" stratified="" relation="" convenience="" busiest="" studied="" each="" cumulative="" arriving="" being="" triaged="" discharged="" plots="" constructed="" microsoft="" excel="" corp="" seattle="" ethics="" exempt="" local="" ethical="" committee="" protocol="" nwmo2017="" 225="" attended="" majority="" referred="" service="" urgency="" 1-2="" highest="" categories="" 5-point="" discovered="" characteristic="" input="" course="" figure="" peaked="" later="" pm="" too="" night="" tightly="" follows="" new="" consequence="" nearly="" start="" arrive="" gradually="" fills="" then="" sudden="" rise="" moment="" again="" horizontal="" distance="" curves="" equilibrium="" slightly="" created="" countless="" decades="" alleviate="" concentrate="" uncontrolled="" usually="" perceived="" why="" measures="" hard="" individual="" highly="" demographic="" socioeconomic="" availability="" western="" countries="" face="" ageing="" people="" getting="" older="" resultant="" comorbidities="" live="" independently="" instead="" institutions="" problems="" length="" stay="" hospitalised="" government="" policy="" steady="" decline="" five="" presenting="" complex="" unable="" address="" tend="" urgent="" complaints="" self-referring="" sprains="" re-visits="" never="" re-direct="" short="" involves="" determine="" how="" mandatory="" contracted="" assistants="" specialists="" shifts="" scheduled="" output="" indicates="" becomes="" filling="" prospect="" starting="" right="" speed="" processes="" avoid="" counterintuitive="" accepting="" accumulation="" searched="" explaining="" slower="" mornings="" speculate="" shift="" just="" require="" immediate="" handed="" next="" wait="" doctor="" maximal="" absolute="" afternoon="" nurse="" busy="" ward="" receive="" admitted="" 3-4="" 4-5="" 5-6="" 6-7="" 7-8="" 8-9="" 9-10="" 10-11="" 11-12="" 12-13="" 13-14="" 14-15="" 15-16="" 16-17="" 17-18="" 18-19="" 19-20="" 20-21="" 21-22="" 22-23="" 23-24="" hourly="" hr="" legend:="" vertical="" axis="" hourly-average="" represent="" long="" 0:00="" 3:00="" 6:00="" 9:00="" 12:00="" 15:00="" 18:00="" 21:00="" triages="" discharges="" cum="" nr="" leaving="" represented="" thick="" dark="" gray="" grey="" schedule="" sufficient="" able="" treat="" promptly="" providers="" deliver="" relies="" completeness="" accurateness="" registration="" solely="" stated="" optimisation="" take="" place="" consideration="" possibilities="" though="" national="" generalised="" across="" staffing="" vary="" shortcomings="" demonstrate="" critical="" unexpected="" rescheduling="" site-specific="" accomplished="" quickly="" always="" costly="" instituted="" college="" acep="" statement="" revised="" approved="" directors="" february="" pines="" hilton="" alkemade="" aj="" international="" perspectives="" acad="" emerg="" 18:1358-70="" bernstein="" sl="" aronsky="" duseja="" task="" force="" clinically="" oriented="" 16:1-10="" lin="" fu="" associations="" length-of-stay="" publicly="" quality-of-care="" 24:246-50="" reznek="" ma="" murray="" youngren="" mn="" door-to-imaging="" stroke="" adversely="" affected="" 48:49-54="" reijnen="" derlett="" rw="" managers="" experiences="" 6:41="" goslings="" gorzeman="" offeringa-klooster="" berdowski="" brandbrief="" regionale="" spoedzorg="" rek="" er="" uit="" 19-5-2016="" jarvis="" pr="" exp="" 30:63-8="" boyle="" departments:="" guidance="" cem="" emphases="" system-wide="" 32:92="" griffey="" rt="" learned="" decade="" 22:985-7="" jayaprakash="" sullivan="" bey="" ahmed="" lotfipour="" perspective="" west="" 10:233-9="" gaakeer="" mi="" brand="" cl="" gips="" landelijke="" ontwikkelingen="" nederlandse="" seh="" aantallen="" en="" herkomst="" pati="" nten="" periode="" 2012-2015="" ned="" tijdschr="" geneeskd="" 160:d970="" schull="" kiss="" szalai="" low-complexity="" waiting="" 49:257-64="" thijssen="" wa="" kraaijvanger="" barten="" dg="" boerma="" giesen="" wensing="" impact="" well-developed="" netherlands:="" bmc="" health="" serv="" 16:149="" case="" glucarpidase="" methotrexate="" intoxication:="" boelens1="" math="" t2="" vlaar1="" bouman1="" intensive="" pharmacy="" pharmacology="" amsterdam="" email:="" vlaar="" amc="" uva="" nl="" high-dose="" mtx="" induced="" injury="" sustained="" systemic="" levels="" 39-year-old="" man="" lymphoblastic="" t-cell="" lymphoma="" unit="" elevated="" prolonged="" supportive="" complemented="" novel="" rapidly="" lowered="" extracellular="" series="" negatively="" leucovorin="" rescue="" lastly="" carries="" elucidates="" theoretical="" suggests="" exposure="" administration="" reverse="" intracellular="" aimed="" shortly="" direct="" toxic="" uptake="" into="" cells="" chemotherapeutic="" oncological="" disrupts="" cell="" repair="" proliferation="" inhibition="" folate="" through="" dihydrofolate="" reductase="" enzyme="" malignant="" healthy="" folates="" cofactors="" dna="" rna="" synthesis="" generally="" data-mce-fragment="1"> 500-1000 mg/m2 , is therefore followed by administration of leucovorin to counteract the effects of MTX on healthy cells. Leucovorin itself is a reduced folate, bypassing the inhibition of MTX and reducing its cytotoxic effects. High-dose MTX therapy carries the risk of acute kidney injury (AKI) by precipitation of MTX in the renal tubules.1 Volume depletion and acidic urine are major risk factors for What was known on this topic? Methotrexate (MTX) toxicity is a rare, but serious complication of high-dose MTX therapy often compounded by reduced clearance due to direct nephrotoxicity. Glucarpidase effectively and rapidly reduces extracellular MTX levels almost completely, but has no effect on intracellular levels. What does this add? Despite largely positive observational studies showing fast and significant effects on plasma MTX levels, there are several issues associated with glucarpidase. First, there are no randomised controlled studies that show a beneficial effect on clinical outcome compared with conservative therapy. Secondly, there are serious concerns about the efficacy of leucovorin therapy after glucarpidase administration. And lastly, glucarpidase therapy in recommended dosages carries a significant financial burden. For these reasons glucarpidase is not recommended for the treatment of MTX toxicity until further randomised studies show improved outcome. 37 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine Boelens et al. Glucarpidase treatment for methotrexate intoxication. MTX precipitation. Therefore, hyperhydration and urine alkalinisation are vital parts of MTX treatment protocols. MTX-induced AKI has the potential to induce a vicious circle in which delayed clearance maintains high systemic MTX levels, in turn causing further kidney injury. Sustained high systemic levels of MTX may lead to myelosuppression, hepatic and pulmonary toxicity, neurotoxicity and Stevens-Johnson syndrome. Toxicity plasma concentration thresholds vary based on the organ system, but it has been reported there is a greater risk for toxicity with plasma levels greater than 10 µM at 24 hours. Empirically developed nomograms are often used 24 to 36 hours post infusion to determine if patients are at high risk for MTX toxicity and to pharmacokinetically guide leucovorin rescue therapy based on the MTX serum concentrations and the time post MTX infusion.1 Here we describe a case of MTX intoxication in which standard supportive therapy was complemented by glucarpidase, a relatively novel treatment for MTX intoxication. We then review the available evidence to support this treatment. C A S E R E P O R T A 39-year-old male with a history of Crohn’s disease was admitted to our ICU with increased serum creatinine (from 66 to 398 µmol/l) and MTX levels (23 µmol/l) 70 hours after high-dose (5 g/m2 ) MTX for acute lymphoblastic T-cell lymphoma, despite preventive measures including leucovorin, intravenous hydration and urine alkalisation. Leucovorin therapy was intensified based on treatment protocols as described in the HOVON 100 ALL trial,3 while vigorous hydration and urine alkalisation were continued. Because of progressive renal failure under maximum supportive therapy, addition of glucarpidase was considered at admission. Glucarpidase was ordered from Clinigen Healthcare Ltd. in the United Kingdom and was delivered to our hospital the next day. Eighty-five hours after initiation of MTX treatment, serum MTX levels had decreased to 12 µmol/l. Glucarpidase was administered in a single dose of 50 IU/kg and within one hour the serum MTX level had decreased to 0.10 µmol/l (figure 1). In the days after glucarpidase treatment a small, but significant rise in serum MTX levels to a maximum of 0.63 µmol/l was noted. Creatinine levels remained elevated (figure 1). In the following days, the patient received two sessions of haemodialysis with a minimal effect on the serum MTX level at a sieving coefficient of 0.08. The patient was discharged to the general ward. His renal function improved in the following weeks and after one month his estimated glomerular filtration rate (eGFR) had normalised to pre-toxicity levels. Four months later a PET-CT scan showed complete remission. D I S C U S S I O N MTX intoxication is a life-threatening complication of high-dose MTX. Its incidence has decreased after the introduction of MTX treatment protocols that include screening for third space fluid collections such as ascites and pleural fluid, intensive hydration and alkalinisation, and leucovorin therapy. Once this complication occurs, however, it still carries a high risk for severe morbidity and mortality. The goal is to treat the effects that have already occurred and to minimise further toxicity. Our patient received glucarpidase in addition to intensified leucovorin rescue treatment, hyperhydration and urine alkalisation, and recovered. Extracorporeal techniques such as haemofiltration and haemodialysis have been used to enhance MTX clearance. Evidence for the efficacy of these techniques is mostly limited to case reports with varying efficacy.4-13 High-flux haemodialysis is thought to be most effective in removing MTX. With all extracorporeal techniques a significant rebound effect necessitating multiple treatments often occurs.14 The risks of these techniques are haemodynamic instability and introduction of invasive catheters in patients prone to infection and bleeding diathesis. Recently, glucarpidase has come under attention as an alternative to extracorporeal techniques. Glucarpidase, or Voraxaze™, is a carboxypeptidase that can eliminate extracellular MTX by hydrolysing its terminal carboxylglutamate residue, producing inactive metabolites such as 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA).15 Four Figure 1. MTX serum concentrations and creatinine levels during the course of treatment 38 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine Boelens et al. Glucarpidase treatment for methotrexate intoxication. case series reported an important reduction in extracellular MTX levels in adult patients after a single dose of glucarpidase.16-19 Widemann et al. performed a pooled analysis of efficacy data from these four multicentre, single arm, compassionate use clinical trials using protocols from 1993-2007.20 This analysis showed that glucarpidase can rapidly and safely reduce extracellular MTX levels by a median of 99% and a clinically important reduction in 59% of patients. Side effects of glucarpidase treatment, while difficult to distinguish in patients with symptoms of MTX toxicity, were rare and self-limiting in all of the case series. Paraesthesia and flushing were most often reported. The effects of glucarpidase on intracellular concentrations of MTX are less clear. It is known that with sufficiently high MTX concentrations over time MTX is polyglutamated intracellularly.21,22 The polyglutamation process prohibits these MTX molecules from leaving the cell and increases their affinity for the target enzymes involved in reducing folates. MTX toxicity therefore is concentration and time dependent. The rate and extent at which glucarpidase reduces extracellular MTX levels compared with extracorporeal techniques preventing further polyglutamation might be its main advantage. Also, by reducing systemic MTX levels further precipitation in the renal tubules might be prevented. Glucarpidase, however, does not directly affect the intracellular concentration of MTX. Because MTX and leucovorin compete for a common uptake path into the cell, proportionally higher concentrations of leucovorin are required to achieve rescue in the presence of MTX.1 Plasma MTX concentrations should always be monitored closely and leucovorin therapy intensified and continued until MTX serum levels have decreased to non-toxic levels and there are no signs of ongoing toxicity. Reducing extracellular MTX levels might enhance leucovorin uptake into the cell. However, leucovorin also competes with MTX as a substrate for glucarpidase, although with a lower affinity. This effect decreases the exposure to leucovorin for up to 26 hours after administration of glucarpidase. A reduction of the efficacy of leucovorin therapy by glucarpidase poses a serious risk. This concern was raised in the withdrawal report for glucarpidase at the European Medicines Agency (EMA).23 Given the lack of evidence of the effect of glucarpidase on intracellular levels of MTX and the possible negative effect it has on leucovorin rescue therapy, it is unfortunate that none of the case series compared the results of glucarpidase treatment to patients receiving standard supportive care in clinically relevant outcome parameters such as mortality or time to return to normal kidney function. In fact, despite glucarpidase treatment, mortality in one case series was as high as 23%.18 In our patient renal function returned to near baseline levels more than one month after glucarpidase therapy. Glucarpidase is currently not registered on the European market and only available directly from the manufacturer. Orders are generally delivered within 24 hours within the Netherlands, but this still causes a delay in initiation of treatment. At the time of application to the EMA, no dose-finding study had been performed to determine optimal dosage. A dose of 50 U/kg is recommended by the manufacturer; however, the proposed dose is not justified by clinical data and it is not shown that repeated use of glucarpidase is beneficial. Animal studies suggest that lower doses might have the same results.23 In two of the case series some patients received lower doses of glucarpidase. Unfortunately, the decrease in MTX levels was not reported separately for these patients.17,18 In a normal adult of 70 kg, treatment with 3500 units can cost up to 60,000 euro. A lower recommended dose could help to reduce the cost of treatment considerably. CONCLUSION MTX toxicity is a rare, but serious complication of high-dose MTX therapy. Supportive measures include first and foremost intensified leucovorin therapy together with hydration and urine alkalisation to maximise renal clearance. Glucarpidase is a relatively new agent that can rapidly and safely reduce extracellular MTX to non-toxic levels. However, glucarpidase does not reduce intracellular MTX levels and might reduce efficacy of leucovorin therapy. To date there is no randomised controlled trial comparing it with standard supportive measures on clinically relevant outcome parameters and treatment with glucarpidase carries a significant financial burden. Because of these issues, we cannot recommend the use of glucarpidase in the treatment of MTX toxicity. There are no randomised clinical data to support the use in severe cases and theoretical evidence suggests that glucarpidase administration is unable to reverse high intracellular MTX concentrations after prolonged exposure to high MTX levels. Glucarpidase might be able to prevent irreversible MTX uptake into cells and limit direct effects of high MTX levels on kidney function. New randomised controlled studies should therefore be aimed at early administration of glucarpidase in patients with high levels shortly after administration of MTX. A recent meta-analysis of the observational data showed that administration of glucarpidase within 96 hours of MTX dosage reduced the development of severe toxicity.20 New studies should also include different treatment regimens for glucarpidase, since earlier studies suggest that a much lower dosage might be just as effective 39 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine Boelens et al. Glucarpidase treatment for methotrexate intoxication. and could possibly reduce any deleterious side effects and cost of treatment. DISCLOSURES All authors declare no conflict of interest. No funding or financial support was received. REFERENCES 1. Howard SC, McCormick J, Pui CH, Buddington RK, Harvey RD. Preventing and Managing Toxicities of High-Dose Methotrexate. Oncologist. 2016;21:1471-82. 2. Cavone JL, Yang D, Wang A. Glucarpidase Intervention for Delayed Methotrexate Clearance. Ann Pharmacother. 2014;48:897-907. 3. HOVON/EORTC. Clofarabine added to prephase and consolidation therapy in acute lymphoblastic leukemia in adults 2014 [cited 2017 Mar 1]. Available from: http://hovon.nl/studies/studies-per-ziektebeeld/all. html?getfile=1&studie=69&studieveld=26. 4. Diskin CJ, Stokes TJ, Dansby LM, Radcliff L, Carter TB. Removal of methotrexate by peritoneal dialysis and hemodialysis in a single patient with end-stage renal disease. Am J Med Sci. 2006;332:156-8. 5. Escobosa Sanchez OM, Herrero Hernandez A, Ortega Acosta MJ, Camacho Alonso J, Milano Manso G, Acha Garcia T. Clearance of methotrexate by means of hemofiltration in a patient with osteosarcoma. Clin Transl Oncol. 2006;8:379-80. 6. Murashima M, Adamski J, Milone MC, Shaw L, Tsai DE, Bloom RD. Methotrexate clearance by high-flux hemodialysis and peritoneal dialysis: a case report. Am J Kidney Dis. 2009;53:871-4. 7. Vilay AM, Mueller BA, Haines H, Alten JA, Askenazi DJ. Treatment of methotrexate intoxication with various modalities of continuous extracorporeal therapy and glucarpidase. Pharmacotherapy. 2010;30:111. 8. Grafft C, Gunderson H, Langman L, Farmer JC, Leung N. High-dose continuous venovenous hemofiltration combined with charcoal hemoperfusion for methotrexate removal. NDT Plus. 2011;4:87-9. 9. Mutsando H, Fahim M, Gill DS, et al. High dose methotrexate and extended hours high-flux hemodialysis for the treatment of primary central nervous system lymphoma in a patient with end stage renal disease. Am J Blood Res. 2012;2:66-70. 10. Abdelsalam MS, Althaf MM, Alfurayh O, Maghfoor I. The utility of online haemodiafiltration in methotrexate poisoning. BMJ Case Rep. 2014;2014. 11. Bertram A, Ivanyi P, Hafer C, et al. High cut-off dialysis as a salvage therapy option in high-dose methotrexate chemotherapy? Ann Hematol. 2014;93:1053-5. 12. Connors NJ, Sise ME, Nelson LS, Hoffman RS, Smith SW. Methotrexate toxicity treated with continuous venovenous hemofiltration, leucovorin and glucarpidase. Clin Kidney J. 2014;7:590-2. 13. AWu CC, Huang CF, Shen LJ, Wu FL. Successful Elimination of Methotrexate by Continuous Veno-venous Haemofiltration in a Psoriatic Patient with Methotrexate Intoxication. Acta Derm Venereol. 2015;95:626-7. 14. Widemann BC, Balis FM, Kempf-Bielack B, et al. High-dose methotrexateinduced nephrotoxicity in patients with osteosarcoma. Cancer. 2004;100:2222-32. 15. Fermiano M, Bergsbaken J, Kolesar JM. Glucarpidase for the management of elevated methotrexate levels in patients with impaired renal function. Am J Health Syst Pharm. 2014;71:793-8. 16. Krause AS, Weihrauch MR, Bode U, et al. Carboxypeptidase-G2 rescue in cancer patients with delayed methotrexate elimination after high-dose methotrexate therapy. Leuk Lymphoma. 2002;43:2139-43. 17. Buchen S, Ngampolo D, Melton RG, et al. Carboxypeptidase G2 rescue in patients with methotrexate intoxication and renal failure. Br J Cancer. 2005;92:480-7. 18. Schwartz S, Borner K, Muller K, et al. Glucarpidase (carboxypeptidase g2) intervention in adult and elderly cancer patients with renal dysfunction and delayed methotrexate elimination after high-dose methotrexate therapy. Oncologist. 2007;12:1299-308. 19. Widemann BC, Balis FM, Kim A, et al. Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome. J Clin Oncol. 2010;28:3979-86. 20. Widemann BC, Schwartz S, Jayaprakash N, et al. Efficacy of glucarpidase (carboxypeptidase g2) in patients with acute kidney injury after high-dose methotrexate therapy. Pharmacotherapy. 2014;34:427-39. 21. Jolivet J, Chabner BA. Intracellular pharmacokinetics of methotrexate polyglutamates in human breast cancer cells. Selective retention and less dissociable binding of 4-NH2-10-CH3-pteroylglutamate4 and 4-NH2-10-CH3-pteroylglutamate5 to dihydrofolate reductase. J Clin Invest. 1983;72:773-8. 22. Treon SP, Chabner BA. Concepts in use of high-dose methotrexate therapy. Clin Chem. 1996;42:1322-9. 23. European Medicines Agency. Withdrawal Assessment Report for Voraxaze 2008 [cited 2016 Nov 18]. Available from: http://www.ema.europa.eu/ docs/en_GB/document_library/Application_withdrawal_assessment_ report/2010/01/WC500068409.pdf. 40 JANUARY 2018, VOL. 76, NO. 1 © Van Zuiden Communications B.V. All rights reserved. The Netherlands Journal of Medicine CASE REPORT Fulminant presentation of oral mucosal leishmaniasis as severe stomatitis and periodontitis M.H.T. de Ruiter1 *, C. Stijnis2 , J.W. Nolte1 , A. Bart3 , S.L. Croonen4 , J. de Lange1 , M.P. Grobusch2 Departments of 1 Oral and Maxillofacial Surgery, 2 Infectious Diseases, Division of Internal Medicine, Center of Tropical Medicine and Travel Medicine, 3 Medical Microbiology, Parasitology Section, 4 Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands,*corresponding author: email: m.h.deruiter@amc.uva.nl ABSTRACT This case report shows an atypical presentation of mucosal leishmaniasis infantum in the oral cavity resulting in severe stomatitis and periodontitis. The patient was immunocompromised because of rheumatoid arthritis for which he used prednisone and methotrexate. He was treated with intravenous liposomal amphotericin B and recovered within four weeks. K E Y W O R D S Leishmaniasis, mucosal, oral, periodontitis, stomatitis, Leishmania infantum INTRODUCTION Mucosal leishmaniasis (ML) is a chronic infection that affects the upper respiratory tract or oral mucosa and is caused by the protozoan parasites of the genus Leishmania. Leishmaniasis is found worldwide and is considered to be endemic in approximately 90 countries. It has an estimated prevalence of 12 million infected individuals worldwide, with a global incidence of 1.5-2 million new cases per year. Leishmaniasis is responsible for approximately 80,000 deaths yearly.1 There are three main clinical forms of leishmaniasis: visceral leishmaniasis (VL), cutaneous leishmaniasis (CL) and ML. Exclusive involvement of the mucosa is not a novelty,2 but a fulminant course, as described here, with severe stomatitis and periodontitis, is noteworthy in our opinion. CASE REPORT The dentist referred a 40-year-old male because of severe stomatitis (figure 1). Inflammatory symptoms had been present for several months, in the absence of fever. His medical history included rheumatoid arthritis for which he used prednisone and methotrexate. The patient originated from Morocco, which he had visited seven months prior to his initial presentation and on several occasions earlier, but he had been living continuously in the Netherlands for most of his life. On physical examination, no signs of abdominal pain were present, and abdominal ultrasound yielded no hepatosplenomegaly. What was known on this topic? Leishmaniasis is an endemic disease in many countries and appears in three main forms: Visceral leishmaniasis, cutaneous leishmaniasis and mucocutaneous leishmaniasis. Exclusive involvement of the mucosa is unusual, especially when it presents as severe stomatitis and periodontitis. What does this add? This fulminant case demonstrates a rare, disabling and disfiguring but treatable isolated oral manifestation of mucosal leishmaniasis in an immunocompromised patient, highlighting the importance of a good pathological/microbiological work-up in patients with stomatitis and periodontitis under immunosuppressive therapy. 41 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine De Ruiter et al. Mucosal leishmaniasis presenting as severe stomatitis and periodontitis. Except for CRP (10 mg/l) and a leucocytosis (13.9 x 109/l) with neutrophilia (11.0 x 109//l), full blood count and biochemistry were inconspicuous. HIV, hepatitis B/C, Epstein-Barr virus and cytomegalovirus serology were negative. We considered a diagnosis of severe periodontitis and stomatitis combined with superficial candidiasis. Anti-fungal therapy was prescribed in combination with oral hygienist treatment, but due to the lack of clinical improvement, eventually all his maxillary teeth had to be removed. On day 7, there were no signs of early healing; instead, the clinical manifestation had worsened. A palatal biopsy was taken, which was indicative of leishmaniasis in view of a deep penetrating ulcerative process. The inflammatory infiltrate consisted mainly of lymphocytes and histiocytes and showed focal small granulomas; numerous histiocytes contained large numbers of intracytoplasmic bodies suggestive of Leishmania spp. amastigotes (figure 2). Parasitological diagnosis by microscopy of a direct smear of a biopsy showed numerous Leishmania parasites, and mini-exon repeat PCR according to Marfurt et al. was positive.3 Culture was negative, while serological testing by RK39 and DAT tests proved positive. Sequence analysis of the mini-exon repeat PCR product indicated that the parasites belonged to the L. donovani complex. Therefore, a PCR and sequence analysis for the cpb gene was performed, according to Hide et al., showing Leishmania infantum to be the causative species.4 The patient was admitted and treated with intravenous liposomal amphotericin B (3 mg/kg every 24 hours for 10 days). Methotrexate was temporarily stopped. Within 14 days, the palate showed significant improvement and returned to normal within four weeks. A biopsy after three months showed no presence of Leishmania spp. amastigotes; the PCR was also negative. Without his former therapy, his rheumatoid arthritis exacerbated. Therefore, methotrexate was re-introduced after the PCR from the last biopsy was negative. The patient was rehabilitated with a full dental prosthesis, and he has been followed up for two years with no signs of recurrence. DISCUSSION This case highlights the diagnostic difficulties in patients with exclusively mucosal lesions at an atypical location. Based upon the clinical manifestation, this patient is to be considered as having suffered from ML. It is most often caused by parasites of the Viannia subgenus and is considered to be a haematogenous or lymphatic dissemination of amastigotes from a CL lesion to the naso-oropharyngeal mucosa.5 However, the patient described above did not have a previous or concomitant episode of cutaneous leishmaniasis. ML is mostly caused by reactivation of the disease months or even years after onset of a primary CL, although in some cases there is no history of a cutaneous lesion. Less than 5% of patients suffering from the cutaneous form will develop mucosal metastatic disease.2 In the Old World, ML can be diagnosed as a sole entity or concomitantly with VL. L. infantum is known for causing VL and spreads through the mononuclear phagocyte system. This patient did not have any fever or other symptoms of VL suggestive of visceralisation. Furthermore, bacterial (super)infection occurs frequently in VL under immunosuppressive therapy,6 which could explain the severe periodontitis and stomatitis of the maxilla in this case. The absence of other clinical symptoms is exceptional. In this patient an Old World species, L. infantum, is causing solitary ML, which is unusual. The mucosal manifestation due Figure 1. The mucosa of the maxilla showing severe inflammation and ulceration Figure 2. Detail of palatal inflammatory infiltrate showing large numbers of Leishmania bodies (arrows), mostly located in histiocytes. Haemotoxylin & eosin stain, x630 42 JANUARY 2018, VOL. 76, NO. 1 The Netherlands Journal of Medicine De Ruiter et al. Mucosal leishmaniasis presenting as severe stomatitis and periodontitis. to Old World species is not often described in patients with L. infantum.7,8 At present, liposomal amphotericin B appears to be the preferred choice of treatment, because of its short treating period and less adverse effects in comparison with, for example, stibogluconate (Pentostam).2,9 Because of the multicultural population in the Netherlands, an increasing incidence is reported, with an estimated 20-30 patients being diagnosed with CL and 5-10 patients with VL every year.10,11 Furthermore, a solitary ML is extremely rarely encountered in Western Europe. In southern Europe leishmaniasis is suggested to be a latent public health threat, because of a high prevalence of asymptomatic human carriers of L. infantum. 12 This is demonstrated by the increase of co-infections with human immunodeficiency virus and leishmaniasis, with leishmaniasis becoming the third most frequent opportunistic parasitic disease after toxoplasmosis and cryptosporidiosis.8,13 In order to facilitate a favourable patient outcome, it is important to consider isolated ML if the history of possible exposure warrants to include this rare condition in the differential diagnosis. REFERENCES 1. Murray HW, Berman JD, Davies CR, Saravia NG. Advances in leishmaniasis. Lancet. 2005;366:1561-77. 2. Amato VS, Tuon FF, Siqueira AM, Nicodemo AC, Neto VA. Treatment of mucosal leishmaniasis in Latin America: systematic review. Am J Trop Med Hyg. 2007;77:266-74. 3. Marfurt J, Nasereddin A, Niederwieser I, Jaffe CL, Beck HP, Felger I. Identification and differentiation of Leishmania species in clinical samples by PCR amplification of the miniexon sequence and subsequent restriction fragment length polymorphism analysis. J Clin Microbiol. 2003;41:3147-53. 4. Hide M, Bras-Goncalves R, Banuls AL. Specific cpb copies within the Leishmania donovani complex: evolutionary interpretations and potential clinical implications in humans. Parasitology. 2007;134:379-89. 5. Herwaldt BL. Leishmaniasis. Lancet. 1999;354:1191-9. 6. Andrade TM, Carvalho EM, Rocha H. Bacterial infections in patients with visceral leishmaniasis. J Infect Dis. 1990;162:1354-9. 7. Faucher B, Pomares C, Fourcade S, et al. Mucosal Leishmania infantum leishmaniasis: specific pattern in a multicentre survey and historical cases. J Infect. 2011;63:76-82. 8. Alvar J, Velez ID, Bern C, et al. Leishmaniasis worldwide and global estimates of its incidence. PLoS One. 2012;7:e35671. 9. Palumbo E. Treatment strategies for mucocutaneous leishmaniasis. J Glob Infect Dis. 2010;2:147-50. 10. Zeegelaar JE, Steketee WH, van Thiel PP, Wetsteyn JC, Kager PA, Faber WR. Changing pattern of imported cutaneous leishmaniasis in the Netherlands. Clin Exp Dermatol. 2005;30:1-5. 11. Bart A, van Thiel PP, de Vries HJ, Hodiamont CJ, Van Gool T. Imported leishmaniasis in the Netherlands from 2005 to 2012: epidemiology, diagnostic techniques and sequence-based species typing from 195 patients. Euro Surveill. 2013;18:20544. 12. Ready PD. Leishmaniasis emergence in Europe. Euro Surveill. 2010;15:19505. 13. Desjeux P, Alvar J. Leishmania/HIV co-infections: epidemiology in Europe. Ann Trop Med Parasitol. 2003;97 Suppl 1:3-15. 43 JANUARY 2018, VOL. 76, NO. 1 © Van Zuiden Communications B.V. All rights reserved. The Netherlands Journal of Medicine PHOTO QUIZ Pancytopenia in a young girl with skin lesions S.K. Bhavya, N.P. Prakash, T.M. Anoop, N. Rakul* Department of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, India, *corresponding author: email: rakulnambiar@yahoo.com CASE REPORT A 14-year-old-girl presented with complaints of being easily fatigued and bleeding gums of two weeks’ duration. She had a history of seizures in childhood. Physical examination demonstrated papular lesions on the nose, and cheeks consistent with facial angiofibromas (figure 1) There were ash-leaf hypomelanotic macules on the limbs (figure 2). No oral or periungual fibromas were seen. Examination of the cardiovascular and respiratory system was unremarkable. Her blood investigations revealed a haemoglobin of 4.59 mmol/l, elevated leucocyte count 4.93 x 109/l with 78% abnormal cells and thrombocytopenia 1.6 x 109/l. Bone marrow showed immature cells having irregular nuclei with folding and invagination (figure 3). The immature cells were peroxidase positive. Magnetic resonance imaging of the brain revealed subependymal nodules in the lateral ventricle (figure 4). W H A T I S T H E H A E M A T O L O G I C A L C O N D I T I O N C A U S I N G PA N C Y T O P E N I A A N D W H A T I S T H E S Y N D R O M E I N T H I S PATIENT? See page 44 for the answer to this photo quiz. Figure 1. Papular lesions on the nose, and cheeks consistent with facial angiofibromas Figure 4. Magnetic resonance imaging of the brain demonstrated subependymal nodules in the lateral ventricle Figure 2. Ash-leaf hypomelanotic macules on limbs Figure 3. Bone marrow showed immature cells having irregular nuclei with folding and invagination 44 JANUARY 2018, VOL. 76, NO. 1 © Van Zuiden Communications B.V. All rights reserved. The Netherlands Journal of Medicine DIAGNOSIS The haematological condition is acute myeloid leukaemia and the syndrome in this patient is tuberous sclerosis. Tuberous sclerosis is an inherited neurocutaneous syndrome characterised by multiple benign hamartomas involving brain, eyes, heart, lung, liver, kidney, and skin.1 It has an autosomal dominant pattern of inheritance with an approximate incidence of 1 in 5000 to 10,000 live births.2 Tuberous sclerosis can be diagnosed clinically using the criteria from the International Tuberous Sclerosis Complex Consensus Conference.3 Patients with tuberous sclerosis are at an increased risk of developing malignant tumours involving kidneys, brain, and soft tissues.4 The risk of malignancy in tuberous sclerosis is approximately 18-fold higher than in the normal population. Downregulation of tuberous sclerosis complex 2 expression has been demonstrated in acute myeloid leukaemia.5 REFERENCES 1. Schwartz RA, Fernández G, Kotulska K, Jóźwiak S. Tuberous sclerosis complex: advances in diagnosis, genetics, and management. J Am Acad Dermatol. 2007;57:189. 2. Hallett L, Foster T, Liu Z, et al. Burden of disease and unmet needs in tuberous sclerosis complex with neurological manifestations: systematic review. Curr Med Res Opin. 2011;27:1571. 3. Northrup H, Krueger DA, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49:243. 4. Al-Saleem T, Wessner LL, Scheithauer BW, et al. Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex. Cancer. 1998;83:2208. 5. Xu Z, Wang M, Wang L, et al. Aberrant expression of TSC2 gene in the newly diagnosed acute leukemia. Leuk Res. 2009;33:891-7. ANSWER TO PHOTO QUIZ (PAGE 43) PANCYTOPENIA IN A YOUNG GIRL WITH SKIN LESIONS 45 JANUARY 2018, VOL. 76, NO. 1 © Van Zuiden Communications B.V. All rights reserved. The Netherlands Journal of Medicine PHOTO QUIZ From dentist to internist J. Hanssen*, F. Toonen Department of Internal Medicine, Alrijne Hospital, Leiderdorp, the Netherlands, *corresponding author: email: jljhanssen@gmail.com CASE REPORT A 64-year-old man was referred by his dentist because of remarkably enlarged and vulnerable gums. His chief complaints were nausea, weight loss and haematemesis because of gum bleeding for the last 5 weeks. He has a past medical history of retroperitoneal fibrosis, hypothyroidism and a myelodysplastic syndrome type refractory cytopenia with multi-lineage dysplasia since 2013 for which he received no treatment. His only medication was levothyroxine 75 µg once daily. He does not smoke. Physical examination revealed a fever, marked gingival enlargement (figure 1), a 2 cm submandibular lymph node on his left side and several haematomas on both legs. WHAT IS YOUR DIAGNOSIS? See page 46 for the answer to this photo quiz. Figure 1. Marked gingival enlargement 46 JANUARY 2018, VOL. 76, NO. 1 © Van Zuiden Communications B.V. All rights reserved. The Netherlands Journal of Medicine DIAGNOSIS The complete blood count showed a haemoglobin of 4.8 mmol/l, thrombocytes of 11 mmol/l and leucocytes of 8.2 mmol/l. The peripheral blood smear revealed 80% leukaemic blasts, tear drop cells and fragmentocytes. Clotting times and fibrinogen levels were normal. A transformation of his myelodysplastic syndrome into an acute myeloid leukaemia was suspected. This was confirmed by bone marrow which showed 71% blasts with strong positive myeloperoxidase staining and immunophenotyping revealing predominantly myelocytic blasts fitting an acute myeloblastic leukaemia. Tumour cytogenetic and molecular analysis showed a normal male karyotype and no mutations. Gingival enlargement can be a sign or even a presenting symptom of acute leukaemia, especially when there is a prominent monocytic component.1 It is not unusual that a dentist is the one who refers the patient to an internist for further analysis. An observational study showed that up to 66.7% of patients with acute monocytic leukaemia have gingival infiltrates or hyperplasia. Followed by 18.5% in patients with acute myelomonocytic and 3.7% with myeloblastic leukemia.2 For unknown reasons it seems that acute lymphocytic leukaemia rarely causes gingival enlargement.3 Hyperplasia can be due to direct infiltration of leukaemic cells. In that case it is called a myeloid sarcoma or chloroma. Sometimes, however, cytology only shows a reactive pattern without infiltration.4 A histological biopsy was not performed in our patient. There is probably a tooth-associated factor in the pathogenesis since leukaemic gum invasion is not seen in people who are edentulous.2 Gingival hyperplasia is also a fairly well-known side effect of certain drugs. It has been well described with calcium antagonists, cyclosporine and antiepileptic drugs.5 More recently also vemurafenib has been identified.6 Furthermore it can be a manifestation of an autoimmune disease, namely granulomatosis with polyangiitis, Crohn’s disease, tuberculosis and sarcoidosis.7 The obvious therapy is treating the underlying disease or abstaining from the responsible drug. The patient participated in the European Organisation for Research and Treatment of Cancer (ORTC) 1301 trial and was initially only treated with two cycles of decitabine. Because there was progression of disease under this regimen he was switched to an intensive therapy according to the Hemato-Oncology Adult Netherlands (HOVON) 103 trial. After two cycles of cytarabine, remission was achieved and he was referred to an academic hospital for an allogenic bone marrow transplantation which was successful. With this, his gingival enlargement also improved back to normal. REFERENCES 1. Hasan S, Khan NI, Reddy LB. Leukemic gingival enlargement: Report of a rare case with review of literature. Int J App Basic Med Res. 2015;5:65-7. 2. Dreizen S, McCredie KB, Keating MJ, et al. Malignant gingival and skin “infiltrates” in adult leukemia. Oral Surg Oral Med Oral Pathol. 1983;55:572-9. 3. M.C. Haytac, et al. Severe Alveolar Bone loss and Gingival hyperplasia as Initial Manifestation of Burkitt Cell Type Acute Lymphoblastic Leukemia. J Periodontol. 2003;74:547-51. 4. Arul ASKJ, Verma S, Ahmed S, et al. A clinical and fine needle aspiration cytology study of gingiva in acute leukemia. Dent Res J . 2012;9:80-5. 5. Marshall R, Bartold M. A clinical review of drug-induced gingival overgrowths 1999. Aust Dent J. 1999;44:219-32. 6. Mangold AR, Bryce A, Sekulic A. Vemurafenib-associated gingival hyperplasia in patient with metastatic melanoma. J Am Acad Dermatol. 2014;71:e205-6. 7. Agrawal AA. Gingival enlargements: Differential diagnosis and review of literature. World J Clin Cases. 2015;3:779-88. ANSWER TO PHOTO QUIZ (PAGE 45) FROM DENTIST TO INTERNIST 47 JANUARY 2018, VOL. 76, NO. 1 © Van Zuiden Communications B.V. All rights reserved. The Netherlands Journal of Medicine PHOTO QUIZ Fever, abdominal erythema and subcutaneous emphysema M.L. van Schaik, P.H.P. Groeneveld* Department of Internal Medicine, Isala Clinics, Zwolle, the Netherlands, *corresponding author: email: p.h.p.groeneveld@isala.nl CASE REPORT A 72-year-old male presented with fever and abdominal erythema (figure 1). His medical history included an aortic graft stent (open procedure) in 2009 because of an abdominal aortic aneurysm and a myocardial infarction in 2006. Four days earlier the general practitioner started amoxicillin/clavulanic acid because of a fever, abdominal erythema and suspicion of erysipelas. At presentation signs of septic shock including high fever, high inflammation parameters and hypotension not responding to fluid resuscitation were present but he only experienced mild abdominal pain. During palpation of the abdominal erythema an underlying infiltrate was discovered and crepitus was found, suggesting the presence of subcutaneous emphysema. WHAT IS YOUR DIAGNOSIS? See page 48 for the answer to this photo quiz. Figure 1. Abdominal erythema 48 JANUARY 2018, VOL. 76, NO. 1 © Van Zuiden Communications B.V. All rights reserved. The Netherlands Journal of Medicine DIAGNOSIS Erysipelas was considered a possible diagnosis by the general practitioner. However, there were signs that make this diagnosis less likely. Although erysipelas can develop in any area of the skin, it is typically found on the lower extremities. One study showed that 77% (48 out of 62 patients) of erysipelas cases involved the lower extremities, 13% involved the upper extremities and in only 3% of cases the lower abdomen was affected.1 There was no sign of a portal of entry, which is found in most cases,2 and the patient developed sepsis-induced hypotension after four days of adequate antibiotic treatment. These findings led us to reconsider the diagnosis. On physical examination an infiltrate was palpable underlying the erythema, and during palpation crepitus was observed that suggested subcutaneous emphysema. Bowel sounds were hyperactive, but the patient did not vomit or experience nausea. A few days later a more detailed medical history was taken and revealed the patient had vomited in the days before presentation. An ultrasound confirmed presence of a fluid collection localised under the possible infiltrate, but was otherwise inconclusive. The surgical department was consulted because necrotising fasciitis was the diagnosis to be ruled out. The erythema, fever, subcutaneous emphysema and septic shock could all be signs of necrotising fasciitis, but the absence of ‘disproportionate pain’ was atypical.3 The CT scan of the abdomen showed an incarcerated herniation of the intestine (figure 2). The presence of (free) air suggested intestinal perforation. The patient was immediately transferred to the operating room where two perforations of the transverse colon inside of the hernia sac were found. Ten centimetres/four inches of the transverse colon were resected. Contents of the large intestine were only found inside the hernia sac and in the subcutis. The antibiotic treatment given on the ICU consisted of piperacillin/tazobactam as well as fluconazole, which was later switched to anidulafungin because of a positive ascites culture for Candida albicans. The ascites culture also showed Enterobacter cloacae, Morganella morganii, E. coli and Klebsiella pneumoniae. Of these bacteria only Morganella morganii was found in the blood cultures collected at presentation. Because of the condition of the patient, primary anastomosis was postponed and performed during a second procedure three days later. Eleven days after initial presentation the patient could leave the ICU. An incisional hernia is the most probable cause of the herniation and incarceration that developed in this patient. It is estimated that 10-15% of patients undergoing a laparotomy incision eventually develop incisional herniation, 60% of these patients are asymptomatic.4 Research suggests perioperative factors play a role in the development of incisional hernias, for example wound infection and the suture technique.5 Incisional hernia repairs are performed in 6 to 15% of cases because of strangulation or obstruction.6 Risk factors for strangulation are a narrow diameter of the hernia sac neck and increasing intraabdominal pressure caused by other abdominal pathology, including intraabdominal sepsis.7 Treatment of an incarcerated hernia consists of immediate surgical intervention, using the open approach when there is the suspicion of strangulation and the need of bowel resection.8 Subcutaneous emphysema, or crepitus on palpation, which is associated with necrotising fasciitis, is actually a late sign of this disease (developing during the third and last stage) along with skin necrosis with discoloration and skin anaesthesia.9 In this case it turned out to be a sign of ‘free’ air due to perforation. REFERENCES 1. Koutkia P, Mylonakis E, Boyce J. Cellulitis: evaluation of possible predisposing factors in hospitalized patients. Diagn Microbiol Infect Dis. 1999;34:325-7. 2. Raff AB, Kroshinsky D. Cellulitis. JAMA. 2016;316:325. ANSWER TO PHOTO QUIZ (PAGE 47) FEVER, ABDOMINAL ERYTHEMA AND SUBCUTANEOUS EMPHYSEMA Figure 2. Abdominal CT in axial view showing herniation of the intestine with presence of free air suggesting perforation 49 JANUARY 2018, VOL. 76, NO. 1 © Van Zuiden Communications B.V. All rights reserved. The Netherlands Journal of Medicine 3. Leiblein M, Marzi I, Sander AL, Barker JH, Ebert F, Frank J. Necrotizing fasciitis: treatment concepts and clinical results. Eur J Trauma Emerg Surg. 2017 May 8. [Epub ahead of print] 4. Kingsnorth A, LeBlanc K. Hernias: Inguinal and incisional. Lancet. 2003;362:1561-71. 5. Burger JWA, Lange JF, Halm JA, Kleinrensink GJ, Jeekel H. Incisional hernia: Early complication of abdominal surgery. World J Surg. 2005;29:1608-13. 6. Sanders DL, Kingsnorth AN. The modern management of incisional hernias. BMJ. 2012 May 9;344:e2843. 7. Yang X-F, Liu J-L. Acute incarcerated external abdominal hernia. Ann Transl Med. 2014;2:110. 8. Birindelli A, Sartelli M, Di Saverio S, et al. 2017 update of the WSES guidelines for emergency repair of complicated abdominal wall hernias. World J Emerg Surg [Internet]. 2017;12:37. Available from: http://wjes. biomedcentral.com/articles/10.1186/1749-7922-8-50 9. Wang YS, Wong CH, Tay YK. Staging of necrotizing fasciitis based on the evolving cutaneous features. Int J Dermatol. 2007;46:1036-41.