Scientific Letter
Bone marrow toxicity secondary to a primary Epstein–Barr infection in a patient with Crohn's disease on thiopurines treatment
Toxicidad medular secundaria a primoinfección por virus de Epstein-Barr en paciente con enfermedad de Crohn en tratamiento con tiopurínicos
C. Ruiz Hernández, D. Sánchez Hernández, V. Vila Miravet, S. Pinillos Pisón, J. Martin de Carpi
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Sección de Gastroenterología, Hepatología y Nutrición Pediátrica, Unidad para el Cuidado Integral de la Enfermedad Inflamatoria Intestinal Pediátrica, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
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Ruiz Hernández, D. Sánchez Hernández, V. Vila Miravet, S. Pinillos Pisón, J. Martin de Carpi" "autores" => array:5 [ 0 => array:2 [ "nombre" => "C." "apellidos" => "Ruiz Hernández" ] 1 => array:2 [ "nombre" => "D." "apellidos" => "Sánchez Hernández" ] 2 => array:2 [ "nombre" => "V." "apellidos" => "Vila Miravet" ] 3 => array:2 [ "nombre" => "S." "apellidos" => "Pinillos Pisón" ] 4 => array:4 [ "nombre" => "J." "apellidos" => "Martin de Carpi" "email" => array:1 [ 0 => "javiermartin@hsjdbcn.org" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Sección de Gastroenterología, Hepatología y Nutrición Pediátrica, Unidad para el Cuidado Integral de la Enfermedad Inflamatoria Intestinal Pediátrica, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Toxicidad medular secundaria a primoinfección por virus de Epstein-Barr en paciente con enfermedad de Crohn en tratamiento con tiopurínicos" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The efficacy of thiopurine immunosuppressants in the treatment of inflammatory bowel disease (IBD) has been demonstrated, and thiopurines are the most commonly used drugs to maintain remission induced by exclusive enteral nutrition or steroids in paediatric patients with Crohn's (EC) disease. Their long-term use may facilitate the development of opportunistic infections by viruses such as Epstein–Barr virus (EBV). Thiopurine blocking of regulatory T cells enhances the cytotoxicity of EBV, leading to B-cell lymphoproliferation. In immunosuppressed patients, the manifestation of EBV may range from an infectious mononucleosis to a haemophagocytic lymphohistiocytosis (HLH).<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">We present the case of a 14-year-old male patient with CD in clinical and laboratory remission following combined treatment with infliximab (IFX) and azathioprine (AZA) since diagnosis. In order to reduce the risk associated with dual immunosuppression, IFX was discontinued 10 months after initiating treatment, and the patient developed a high fever, odynophagia, submandibular lymphadenopathy and splenomegaly. Laboratory analysis revealed pancytopaenia and elevated levels of transaminases, triglycerides and ferritin (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Intravenous empirical antibiotic therapy was initiated due to the presence of febrile neutropaenia (500 cells/mm<span class="elsevierStyleSup">3</span>) and was suspended after 72<span class="elsevierStyleHsp" style=""></span>h following a negative blood culture and a positive Paul-Bunnell test. Epstein–Barr virus was detected by polymerase chain reaction (quantitative PCR), with a viral load of 7650 copies/mL. An incipient HLH in association with primary infection by EBV (initial test was negative at the time of CD diagnosis) was suspected, leading to discontinuation of AZA and initiation of empirical antiviral treatment with ganciclovir. At 72<span class="elsevierStyleHsp" style=""></span>h, the clinical manifestations had improved, with a reduction in lymphadenopathy, improvement of pancytopaenia and a decrease in the viral load. Ganciclovir treatment was discontinued on the fifth day, when the patient had been afebrile for 48<span class="elsevierStyleHsp" style=""></span>h. The patient was discharged seven days after admission after ruling out HLH, as he did not meet the full laboratory criteria<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">2</span></a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Thirty-two days following the diagnosis of primary infection by EBV, the viral load was undetectable and monotherapy with IFX was resumed on an outpatient basis, and at present, 20 months after discontinuation of AZA, the patient remains in clinical and laboratory remission and has not developed any complications from the medication.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">It is known that children with IBD have certain characteristics that increase the risk of opportunistic infection (immunosuppressive treatment, malnutrition…). There are cases of infection by EBV with a fatal outcome in patients with CD during treatment with AZA. Biank et al.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">3</span></a> described four cases of HLH secondary to primary infection with EBV in EC. N’Guyen et al.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">4</span></a> reported a case of primary infection by EBV in which the patient was receiving treatment with AZA for EC and developed infectious mononucleosis, HLH and a B cell lymphoproliferative disorder. Francolla et al.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">5</span></a> published the first paediatric case of HLH secondary to EBV in EC during treatment with IFX and AZA. While there is no evidence of the beneficial effect of discontinuing immunosuppressants therapy in these cases, the European Crohn's and Colitis Organization (ECCO) recommends that, in patients that develop severe infection by EBV during treatment with thiopurines, antiviral therapy should be combined with the discontinuation of immunosuppressant therapy, which could lead to the spontaneous improvement of the process without any other intervention.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">6</span></a> This consensus document states that EBV IgG screening should be considered before initiation of immunomodulator therapy with thiopurines.</p><p id="par0020" class="elsevierStylePara elsevierViewall">In our case, the early diagnosis and management with antiviral therapy and discontinuation of thiopurine treatment probably prevented the development of a haemophagocytic lymphohistiocytosis, which has the potential to become fatal.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Ruiz Hernández C, Sánchez Hernández D, Vila Miravet V, Pinillos Pisón S, Martin de Carpi J. Toxicidad medular secundaria a primoinfección por virus de Epstein-Barr en paciente con enfermedad de Crohn en tratamiento con tiopurínicos. An Pediatr (Barc). 2015;83:134–135.</p>" ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from the Histiocyte Society HLH-2004." "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleBold">5 of the following 8 criteria must be met:</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>1. Fever<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>38.5<span class="elsevierStyleHsp" style=""></span>°C \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>2. Splenomegaly \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>3. Cytopaenias (affecting at least 2 or 3 lineages in the peripheral blood) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Haemoglobin<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>9<span class="elsevierStyleHsp" style=""></span>g/dL (in infants younger than 4 weeks, haemoglobin<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>g/dL) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Platelets<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">3</span>/mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Neutrophils<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>0<span class="elsevierStyleSup">3</span>/mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>4. Hypertriglyceridaemia (fasting triglycerides, >265<span class="elsevierStyleHsp" style=""></span>mg/dL) and/or hypofibrinogenaemia (<150<span class="elsevierStyleHsp" style=""></span>mg/dL) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>5. Haemophagocytosis in bone marrow, spleen, lymph nodes or liver \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab869313.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Diagnostic criteria for haemophagocytic lymphohistiocytosis.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Parameter \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Before antiviral treatment \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">After antiviral treatment \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Leukocytes (neutrophils) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3000 cells/μL (600 cells/μL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6000 cells/μL (1200 cells/μL) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Haemoglobin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9.8<span class="elsevierStyleHsp" style=""></span>g/L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11<span class="elsevierStyleHsp" style=""></span>g/L \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Platelets \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">114 000 cells/μL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">123 000 cells/μL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Triglycerides \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">187<span class="elsevierStyleHsp" style=""></span>mg/dL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">193<span class="elsevierStyleHsp" style=""></span>mg/dL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Ferritin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.572<span class="elsevierStyleHsp" style=""></span>μg/L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">730<span class="elsevierStyleHsp" style=""></span>μg/L \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">ALT/AST \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">135/178<span class="elsevierStyleHsp" style=""></span>IU/L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">140/122<span class="elsevierStyleHsp" style=""></span>IU/l \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">PT/fibrinogen \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">66.7%/2.7<span class="elsevierStyleHsp" style=""></span>g/l \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">75.9%/2.8<span class="elsevierStyleHsp" style=""></span>g/l \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">EBV PCR (copies) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7650<span class="elsevierStyleHsp" style=""></span>copies/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1095<span class="elsevierStyleHsp" style=""></span>copies/mL \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab869312.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Laboratory parameters of the patient.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:6 [ 0 => array:3 [ "identificador" => "bib0035" "etiqueta" => "1" "referencia" => array:1 [ 0 => 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 8 | 10 | 18 |
| 2024 October | 49 | 35 | 84 |
| 2024 September | 46 | 32 | 78 |
| 2024 August | 63 | 74 | 137 |
| 2024 July | 51 | 45 | 96 |
| 2024 June | 61 | 30 | 91 |
| 2024 May | 51 | 39 | 90 |
| 2024 April | 54 | 37 | 91 |
| 2024 March | 51 | 23 | 74 |
| 2024 February | 44 | 28 | 72 |
| 2024 January | 41 | 24 | 65 |
| 2023 December | 29 | 25 | 54 |
| 2023 November | 32 | 21 | 53 |
| 2023 October | 38 | 26 | 64 |
| 2023 September | 28 | 27 | 55 |
| 2023 August | 36 | 21 | 57 |
| 2023 July | 31 | 32 | 63 |
| 2023 June | 35 | 24 | 59 |
| 2023 May | 35 | 22 | 57 |
| 2023 April | 22 | 14 | 36 |
| 2023 March | 42 | 30 | 72 |
| 2023 February | 32 | 11 | 43 |
| 2023 January | 17 | 23 | 40 |
| 2022 December | 34 | 28 | 62 |
| 2022 November | 28 | 29 | 57 |
| 2022 October | 36 | 38 | 74 |
| 2022 September | 24 | 28 | 52 |
| 2022 August | 27 | 55 | 82 |
| 2022 July | 25 | 38 | 63 |
| 2022 June | 30 | 34 | 64 |
| 2022 May | 23 | 32 | 55 |
| 2022 April | 30 | 48 | 78 |
| 2022 March | 40 | 39 | 79 |
| 2022 February | 32 | 32 | 64 |
| 2022 January | 31 | 32 | 63 |
| 2021 December | 32 | 52 | 84 |
| 2021 November | 36 | 55 | 91 |
| 2021 October | 51 | 55 | 106 |
| 2021 September | 30 | 42 | 72 |
| 2021 August | 25 | 36 | 61 |
| 2021 July | 34 | 34 | 68 |
| 2021 June | 34 | 46 | 80 |
| 2021 May | 25 | 35 | 60 |
| 2021 April | 59 | 72 | 131 |
| 2021 March | 46 | 40 | 86 |
| 2021 February | 29 | 31 | 60 |
| 2021 January | 38 | 22 | 60 |
| 2020 December | 41 | 23 | 64 |
| 2020 November | 30 | 17 | 47 |
| 2020 October | 21 | 21 | 42 |
| 2020 September | 17 | 18 | 35 |
| 2020 August | 18 | 20 | 38 |
| 2020 July | 18 | 20 | 38 |
| 2020 June | 19 | 11 | 30 |
| 2020 May | 37 | 19 | 56 |
| 2020 April | 15 | 20 | 35 |
| 2020 March | 23 | 23 | 46 |
| 2020 February | 31 | 15 | 46 |
| 2020 January | 27 | 15 | 42 |
| 2019 December | 26 | 29 | 55 |
| 2019 November | 17 | 11 | 28 |
| 2019 October | 28 | 16 | 44 |
| 2019 September | 22 | 15 | 37 |
| 2019 August | 30 | 23 | 53 |
| 2019 July | 31 | 39 | 70 |
| 2019 June | 27 | 16 | 43 |
| 2019 May | 31 | 57 | 88 |
| 2019 April | 33 | 32 | 65 |
| 2019 March | 34 | 23 | 57 |
| 2019 February | 40 | 46 | 86 |
| 2019 January | 26 | 16 | 42 |
| 2018 December | 46 | 41 | 87 |
| 2018 November | 75 | 22 | 97 |
| 2018 October | 86 | 21 | 107 |
| 2018 September | 37 | 15 | 52 |
| 2018 August | 1 | 0 | 1 |
| 2018 July | 3 | 0 | 3 |
| 2018 June | 4 | 0 | 4 |
| 2018 May | 6 | 0 | 6 |
| 2018 April | 15 | 0 | 15 |
| 2018 March | 33 | 0 | 33 |
| 2018 February | 6 | 0 | 6 |
| 2018 January | 20 | 0 | 20 |
| 2017 December | 11 | 0 | 11 |
| 2017 November | 12 | 0 | 12 |
| 2017 October | 9 | 0 | 9 |
| 2017 September | 19 | 0 | 19 |
| 2017 August | 14 | 0 | 14 |
| 2017 July | 32 | 1 | 33 |
| 2017 June | 25 | 9 | 34 |
| 2017 May | 19 | 5 | 24 |
| 2017 April | 78 | 6 | 84 |
| 2017 March | 5 | 2 | 7 |
| 2017 February | 12 | 5 | 17 |
| 2017 January | 4 | 6 | 10 |
| 2016 December | 29 | 8 | 37 |
| 2016 November | 39 | 11 | 50 |
| 2016 October | 46 | 6 | 52 |
| 2016 September | 34 | 5 | 39 |
| 2016 August | 25 | 5 | 30 |
| 2016 July | 9 | 6 | 15 |
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