Top

Published in:

Open Access 01-01-2022 | Primary Immunodeficiency | Original Article

Analysis of incidence and risk factors of the multidrug resistant gastrointestinal tract infection in children and adolescents undergoing allogeneic and autologous hematopoietic cell transplantation: a nationwide study

Authors: Małgorzata Salamonowicz-Bodzioch, Jowita Frączkiewicz, Krzysztof Czyżewski, Olga Zając-Spychała, Ewa Gorczyńska, Grażyna Wróbel, Bernarda Kazanowska, Dorota Sęga-Pondel, Jadwiga Węcławek-Tompol, Marek Ussowicz, Krzysztof Kałwak, Mariusz Wysocki, Magdalena Dziedzic, Jacek Wachowiak, Agnieszka Zaucha-Prażmo, Jerzy Kowalczyk, Jolanta Goździk, Jan Styczyński

Published in: Annals of Hematology | Issue 1/2022

Abstract

The aim of this multi-center study was to evaluate the incidence, clinical course, and risk factors for bacterial multidrug-resistant (MDR) gastrointestinal tract infections (GTI) among children undergoing allogeneic and autologous hematopoietic cell transplantation. A total number of 175 pediatric patients (aged 1–18 years), transplanted between January 2018 and December 2019, who were tested for bacterial colonization/infection were enrolled into this multi-center analysis. Episodes of MDR GTI occurred in 77/175 (44%) patients. In multivariate analysis for higher GTI incidence, the following factors were significant: matched-unrelated donor (MUD) transplantation, HLA mismatch, presence of graft-versus-host disease (GVHD), and gut GVHD. The most common GTI were Clostridium difficile (CDI), multidrug-resistant Enterobacteriaceae (Klebsiella pneumoniae, Escherichia coli extended-spectrum β-lactamase), and Enterococcus HLAR (high-level aminoglycoside-resistant). No MDR GTI–attributed deaths were reported. MDR GTI is a frequent complication after HCT among children, causes prolonged hospitalization, but rarely contributes to death. We identified risk factors of MDR GTI development in children, with focus on GVHD and unrelated donor and HLA mismatch. We conclude that the presence of Clostridiales plays an important anti-inflammatory homeostatic role and decreases incidence of GVHD or alleviate its course.

Available only for authorised users

Satlin MJ, Walsh TJ (2017) Multidrug-resistant Enterobacteriaceae, Pseudomonas aeruginosa, and vancomycin-resistant Enterococcus: three major threats to hematopoietic stem cell transplant recipients. Transpl Infect Dis 19(6):https://doi.org/10.1111/tid.12762

Zinter MS, Dvorak CC, Auletta JJ (2020) How we treat fever and hypotension in pediatric hematopoietic cell transplant patients. Front Oncol 16(10):581447. https://doi.org/10.3389/fonc.2020.581447CrossRef

Shono Y, van den Brink MRM (2018) Gut microbiota injury in allogeneic haematopoietic stem cell transplantation. Nat Rev Cancer 18(5):283–295. https://doi.org/10.1038/nrc.2018.10CrossRefPubMedPubMedCentral

Holler E, Butzhammer P, Schmid K, Hundsrucker C, Koestler J, Peter K, Zhu W, Sporrer D, Hehlgans T, Kreutz M, Holler B, Wolff D, Edinger M, Andreesen R, Levine JE, Ferrara JL, Gessner A, Spang R, Oefner PJ (2014) Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant 20(5):640–645. https://doi.org/10.1016/j.bbmt.2014.01.030CrossRefPubMedPubMedCentral

Bhatt AS, Freeman SS, Herrera AF, Pedamallu CS, Gevers D, Duke F, Jung J, Michaud M, Walker BJ, Young S, Earl AM, Kostic AD, Ojesina AI, Hasserjian R, Ballen KK, Chen YB, Hobbs G, Antin JH, Soiffer RJ, Baden LR, Garrett WS, Hornick JL, Marty FM, Meyerson M (2013) Sequence-based discovery of Bradyrhizobium enterica in cord colitis syndrome. N Engl J Med 369(6):517–528. https://doi.org/10.1056/NEJMoa1211115CrossRefPubMedPubMedCentral

Salamonowicz-Bodzioch M, Frączkiewicz J, Czyżewski K, Zając-Spychała O, Gorczyńska E, Panasiuk A, Ussowicz M, Kałwak K, Szmit Z, Wróbel G, Kazanowska B, Chybicka A, Ukielska-Hoffmann B, Wendycz-Domalewska D, Wysocki M, Dziedzic M, Wachowiak J, Zaucha-Prażmo A, Kowalczyk J, Goździk J, Styczyński J (2021) Prospective analysis of BKV hemorrhagic cystitis in children and adolescents undergoing hematopoietic cell transplantation. Ann Hematol. https://doi.org/10.1007/s00277-021-04454-7CrossRefPubMedPubMedCentral

Salamonowicz M, Ociepa T, Frączkiewicz J, Szmydki-Baran A, Matysiak M, Czyżewski K, Wysocki M, Gałązka P, Zalas-Więcek P, Irga-Jaworska N, Drożyńska E, Zając-Spychała O, Wachowiak J, Gryniewicz-Kwiatkowska O, Czajńska-Deptuła A, Dembowska-Bagińska B, Chełmecka-Wiktorczyk L, Balwierz W, Bartnik M, Zielezińska K, Urasiński T, Tomaszewska R, Szczepański T, Płonowski M, Krawczuk-Rybak M, Pierlejewski F, Młynarski W, Gamrot-Pyka Z, Woszczyk M, Małas Z, Badowska W, Urbanek-Dądela A, Karolczyk G, Stolpa W, Sobol-Milejska G, Zaucha-Prażmo A, Kowalczyk J, Goździk J, Gorczyńska E, Jermakow K, Król A, Chybicka A, Ussowicz M, Kałwak K, Styczyński J (2018) Incidence, course, and outcome of Clostridium difficile infection in children with hematological malignancies or undergoing hematopoietic stem cell transplantation. Eur J Clin Microbiol Infect Dis 37(9):1805–1812. https://doi.org/10.1007/s10096-018-3316-5CrossRefPubMedPubMedCentral

Styczyński J, Gil L (2008) EBMT Paediatric Diseases Working Party. Prevention of infectious complications in pediatric HSCT. Bone Marrow Transplant 42(Suppl 2):S77-81. https://doi.org/10.1038/bmt.2008.289CrossRefPubMed

Centers for Disease Control and Prevention; Infectious Disease Society of America; American Society of Blood and Marrow Transplantation (2000) Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep. 49(RR-10):1–125, CE1–7. Erratum in: MMWR Recomm Rep. 2004 53(19):396

10.

O'Brien SN, Blijlevens NM, Mahfouz TH, Anaissie EJ . Infections in patients with hematological cancer: recent developments. Hematology Am Soc Hematol Educ Program 2003; 438–472https://doi.org/10.1182/asheducation-2003.1.438

11.

Boyle N, Magaret A, Stednick Z, Morrison A, Butler-Wu S, Zerr D, Rogers K, Podczervinski S, Cheng A, Wald A (2015) Pergam SA (2015) Evaluating risk factors for Clostridium difficile infection in adult and pediatric hematopoietic cell transplant recipients. Antimicrob Resist Infect Control 4:41. https://doi.org/10.1186/s13756-015-0081-4CrossRefPubMedPubMedCentral

12.

Cózar-Listó A, Ramos-Martinez A (2016) Cobo J (2016) Clostridium Difficile infection in special high-risk populations. Infect Dis Ther 5(3):253–269. https://doi.org/10.1007/s40121-016-0124-zCrossRef

13.

Alonso CD, Treadway SB, Hanna DB, Huff CA, Neofytos D, Carroll KC (2012) Marr KA (2012) Epidemiology and outcomes of Clostridium difficile infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 54(8):1053–1063. https://doi.org/10.1093/cid/cir1035CrossRefPubMedPubMedCentral

14.

Balletto E, Mikulska M (2015) Bacterial infections in hematopoietic stem cell transplant recipients. Mediterr J Hematol Infect Dis 7(1):e2015045. https://doi.org/10.4084/MJHID.2015.045CrossRefPubMedPubMedCentral

15.

Patriarca F, Cigana C, Massimo D, Lazzarotto D, Geromin A, Isola M, Battista ML, Medeot M, Cerno M, Sperotto A, Candoni A, Crapis M, Sartor A, Scarparo C, Bassetti M, Fanin R (2017) Risk factors and outcomes of infections by multidrug-resistant gram-negative bacteria in patients undergoing hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 23(2):333–339. doi: https://doi.org/10.1016/j.bbmt.2016.11.005 Erratum in: Biol Blood Marrow Transplant. 2017 Jun;23(6):1040

16.

Gudiol C, Calatayud L, Garcia-Vidal C, Lora-Tamayo J, Cisnal M, Duarte R, Arnan M, Marin M, Carratala J, Gudiol F (2010) Bacteraemia due to extended-spectrum beta-lactamase-producing escherichia coli (esbl-ec) in cancer patients: clinical features, risk factors, molecular epidemiology and outcome. J Antimicrob Chemother 65(2):333–341. https://doi.org/10.1093/jac/dkp411CrossRefPubMed

17.

Chong Y, Yakushiji H, Ito Y, Kamimura T (2011) Clinical impact of fluoroquinolone prophylaxis in neutropenic patients with hematological malignancies. Int J Infect Dis 15(4):e277–e281. https://doi.org/10.1016/j.ijid.2010.12.010CrossRefPubMed

18.

Mikulska M, Viscoli C, Orasch C, Livermore DM, Averbuch D, Cordonnier C, Akova M 2014 Fourth European Conference on Infections in Leukemia Group ajvoEEIELN, Esgich/Escmid Aetiology and resistance in bacteraemias among adult and paediatric haematology and cancer patients. J Infect 68(4):321–31. doi: https://doi.org/10.1016/j.jinf.2013.12.006

19.

ECDC (2012) European centre for disease prevention and control. Antimicrobial resistance surveillance in europe. Annual report of the European antimicrobial resistance surveillance network (ears-net). Stockholm: Ecdc; available at: Http://ecdc.Europa.Eu/en/publications/publications/antimicrobial-resistance-surveillance-europe-2012.Pdf 2013

20.

Gavriilaki E, Sakellari I, Chatzikonstantinou T, Mallouri D, Batsis I, Katsifa E, Papadimitriou S, Panteliadou A, Baldoumi E, Demosthenous C, Bousiou Z, Constantinou V, Sotiropoulos D, Anagnostopoulos A (2021) Risk factors and outcomes of Klebsiella pneumoniae infection before and after allogeneic hematopoietic cell transplantation. Front Med (Lausanne) 7:608165. https://doi.org/10.3389/fmed.2020.608165CrossRef

21.

Simms-Waldrip TR, Sunkersett G, Coughlin LA, Savani MR, Arana C, Kim J, Kim M, Zhan X, Greenberg DE, Xie Y, Davies SM, Koh AY (2017) Antibiotic-induced depletion of anti-inflammatory clostridia is associated with the development of graft-versus-host disease in pediatric stem cell transplantation patients. Biol Blood Marrow Transplant 23(5):820–829. https://doi.org/10.1016/j.bbmt.2017.02.004CrossRefPubMed

22.

Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, Fukuda S, Saito T, Narushima S, Hase K, Kim S, Fritz JV, Wilmes P, Ueha S, Matsushima K, Ohno H, Olle B, Sakaguchi S, Taniguchi T, Morita H, Hattori M, Honda K (2013) Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500(7461):232–236. https://doi.org/10.1038/nature12331CrossRefPubMed

23.

Tanoue T, Honda K (2012) Induction of Treg cells in the mouse colonic mucosa: a central mechanism to maintain host-microbiota homeostasis. Semin Immunol 24(1):50–57. https://doi.org/10.1016/j.smim.2011.11.009CrossRefPubMed

24.

Narushima S, Sugiura Y, Oshima K, Atarashi K, Hattori M, Suematsu M, Honda K (2014) Characterization of the 17 strains of regulatory T cell-inducing human-derived Clostridia. Gut Microbes 5(3):333–339. https://doi.org/10.4161/gmic.28572CrossRefPubMedPubMedCentral

25.

Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, Rudensky AY (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504(7480):451–455. https://doi.org/10.1038/nature12726CrossRefPubMedPubMedCentral

26.

Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M, Fukuda NN, Murakami S, Miyauchi E, Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T, Clarke JM, Topping DL, Tomita M, Hori S, Ohara O, Morita T, Koseki H, Kikuchi J, Honda K, Hase K, Ohno H (2013) Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504(7480):446–450. https://doi.org/10.1038/nature12721CrossRefPubMed

27.

Jenq RR, Taur Y, Devlin SM, Ponce DM, Goldberg JD, Ahr KF, Littmann ER, Ling L, Gobourne AC, Miller LC, Docampo MD, Peled JU, Arpaia N, Cross JR, Peets TK, Lumish MA, Shono Y, Dudakov JA, Poeck H, Hanash AM, Barker JN, Perales MA, Giralt SA, Pamer EG, van den Brink MR (2015) Intestinal blautia is associated with reduced death from graft-versus-host disease. Biol Blood Marrow Transplant 21(8):1373–1383. https://doi.org/10.1016/j.bbmt.2015.04.016CrossRefPubMedPubMedCentral

28.

Kinnebrew MA, Lee YJ, Jenq RR, Lipuma L, Littmann ER, Gobourne A, No D, van den Brink M, Pamer EG, Taur Y (2014) Early clostridium difficile infection during allogeneic hematopoietic stem cell transplantation. PLoS ONE 9(3):e90158. https://doi.org/10.1371/journal.pone.0090158CrossRefPubMedPubMedCentral

29.

Willems L, Porcher R, Lafaurie M, Casin I, Robin M, Xhaard A, Andreoli AL, Rodriguez-Otero P, Dhedin N, Socie G, Ribaud P, Peffault de Latour R (2012) Clostridium difficile infection after allogeneic hematopoietic stem cell transplantation: Incidence, risk factors, and outcome. Biol Blood Marrow Transplant 18(8):1295–301. https://doi.org/10.1016/j.bbmt.2012.02.010CrossRefPubMed

30.

Tuncer HH, Rana N, Milani C, Darko A, Al-Homsi SA (2012) Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. World J Gastroenterol 18(16):1851–1860. https://doi.org/10.3748/wjg.v18.i16.1851CrossRefPubMedPubMedCentral

31.

Arango JI, Restrepo A, Schneider DL, Callander NS, Ochoa-Bayona JL, Restrepo MI, Bradshaw P, Patterson J, Freytes CO (2006) Incidence of Clostridium difficile-associated diarrhea before and after autologous peripheral blood stem cell transplantation for lymphoma and multiple myeloma. Bone Marrow Transplant 37(5):517–521. https://doi.org/10.1038/sj.bmt.1705269CrossRefPubMed

32.

Tomblyn M, Gordon L, Singhal S, Tallman M, Williams S, Winter J, Mehta J (2002) Rarity of toxigenic Clostridium difficile infections after hematopoietic stem cell transplantation: implications for symptomatic management of diarrhea. Bone Marrow Transplant 30(8):517–519. https://doi.org/10.1038/sj.bmt.1703703CrossRefPubMed

33.

Lee JH, Lim GY, Im SA, Chung NG, Hahn ST (2008) Gastrointestinal complications following hematopoietic stem cell transplantation in children. Korean J Radiol 9(5):449–457. https://doi.org/10.3348/kjr.2008.9.5.449CrossRefPubMedPubMedCentral

34.

Benya EC, Sivit CJ, Quinones RR (1993) Abdominal complications after bone marrow transplantation in children: sonographic and CT findings. AJR Am J Roentgenol 161(5):1023–1027. https://doi.org/10.2214/ajr.161.5.8273603CrossRefPubMed

35.

Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad, II, Rolston KV, Young JA, Wingard JR, Infectious Diseases Society of A. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011 52(4):427–31. doi: https://doi.org/10.1093/cid/ciq147

36.

Oliveira AL, de Souza M, Carvalho-Dias VM et al (2007) Epidemiology of bacteremia and factors associated with multidrug-resistant gram negative bacteremia in hematopoietic stem cell transplant recipients. Bone Marrow Transplant 39(12):775–781. https://doi.org/10.1038/sj.bmt.1705677CrossRefPubMed

37.

Mikulska M, Del Bono V, Raiola AM et al (2009) Blood stream infections in allogeneic hematopoietic stem cell transplant recipients: reemergence of Gram-negative rods and increasing antibiotic resistance. Biol Blood Marrow Transplant 15(1):47–53. https://doi.org/10.1016/j.bbmt.2008.10.024CrossRefPubMed

38.

Poutsiaka DD, Price LL, Ucuzian A, Chan GW, Miller KB, Snydman DR (2007) Blood stream infection after hematopoietic stem cell transplantation is associated with increased mortality. Bone Marrow Transplant 40(1):63–70. https://doi.org/10.1038/sj.bmt.1705690CrossRefPubMed

39.

Macesis N, Morrissey CO, Cheng AC, Spencer A, Peleg AY (2014) Changing microbial epidemiology in hematopoietic stem cell transplant recipients: increasing resistance over a 9-year period. Transplant Infect Dis 16(6):887–896. https://doi.org/10.1111/tid.12298CrossRef

Title: Analysis of incidence and risk factors of the multidrug resistant gastrointestinal tract infection in children and adolescents undergoing allogeneic and autologous hematopoietic cell transplantation: a nationwide study
Authors: Małgorzata Salamonowicz-Bodzioch
Jowita Frączkiewicz
Krzysztof Czyżewski
Olga Zając-Spychała
Ewa Gorczyńska
Grażyna Wróbel
Bernarda Kazanowska
Dorota Sęga-Pondel
Jadwiga Węcławek-Tompol
Marek Ussowicz
Krzysztof Kałwak
Mariusz Wysocki
Magdalena Dziedzic
Jacek Wachowiak
Agnieszka Zaucha-Prażmo
Jerzy Kowalczyk
Jolanta Goździk
Jan Styczyński
Publication date: 01-01-2022
Publisher: Springer Berlin Heidelberg
Keywords: Primary Immunodeficiency
Graft-Versus-Host Disease
Clostridioides Difficile
Graft-Versus-Host Disease
Stem Cell Transplantation
Stem Cell Transplantion
Stem Cell Transplantation
Published in: Annals of Hematology / Issue 1/2022
Print ISSN: 0939-5555
Electronic ISSN: 1432-0584
DOI: https://doi.org/10.1007/s00277-021-04681-y

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2022

Characterization of molecular genetics and clinicopathology in thymic MALT lymphoma

Cytomegalovirus reactivation in patients under immunosuppressive treatment for autoimmune haemolytic anaemia

Vemurafenib as bridging therapy of hairy cell leukemia in a Jehovah’s Witness patient

Aggressive lymphoma, hemophagocytic lymphohistiocytosis, and G6PD crisis: a lytic cocktail

Ruxolitinib in the management of steroid-resistant/-dependent acute and chronic graft-versus-host disease: results of routine practice in an academic centre

Non-transfusion-dependent thalassemia in Italy: less blues, no role of reds

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage