Apa_042.tex

Severe adverse reactions to Infliximab therapy are common in young
children with inflammatory bowel disease
K-L Kolho (kaija-leena.kolho@helsinki.fi)1, T Ruuska2, E Savilahti1
1.Hospital for Children and Adolescents, University of Helsinki, Box 281, FIN-00029 HYKS, Helsinki, Finland2.Department of Pediatrics, Tampere University Hospital, Box 2000, FIN-33014, Tampere, Finland Keywords
Abstract
Adverse effect, Crohn´s disease, TNF-alpha Since 2000 we have introduced 141 Infliximab infusions to 23 children with severe inflammatory bowel disease. A total of seven severe adverse reactions occurred in 26% (6 of 23) of the children.
Correspondence
K-L Kolho, Hospital for Children and
Four reactions were acute (anaphylaxis n = 2; allergic reaction n = 2) and 3/4 of these children Adolescents, Box 281, FIN-00029, Finland.
were younger than 10 years of age. Two children developed an abscess and one child had Tel: +358-9-471 74787 | Fax: +358-9-471 72599 septicaemia and brain lesions related to progressive multifocal leucoencephalopathy.
Conclusion: adverse reactions to Infliximab infusions are common. Young children seem to be prone to severe Received
allergic reactions although they are on azathioprine and conventional glucocorticoid therapy.
15 May 2006; revised 30 June 2006; accepted 11July 2006 Infliximab, a monoclonal human-murine chimeric antibody tating no medication. Five children (5 of 23; 22%) did not to tumour necrosis factor-␣ (TNF-␣) has been a break- respond to the Infliximab infusion, and the therapy was dis- through in the therapy of severe inflammatory bowel dis- continued soon. Six children had received 10 or more In- ease (IBD) refractory to conventional treatment. Infliximab fliximab infusions. The only child with UC experienced no blocks both soluble and membrane-bound TNF-␣ thus re- adverse events during her seven Infliximab infusions.
ducing inflammation (1). In children with refractory Crohn’s Major adverse reactions occurred in 6 of 23 children (26%; disease, Infliximab therapy benefits the majority but about children no. 1–4 and 8–9 in Table 2). The time interval to one third of treated patients show no improvement (2). In the preceding infusion was within 1–2 months in all children those responsive, the effect of Infliximab is often transitory (3). Side effects are relatively common, ranging from 5% to Severe acute reactions occurred in 4 children (4 of 23; 17% of paediatric patients (2–6) and hamper the use of this 17%; children no. 1–3 and 8 in Table 2). The majority of these children were younger than 10 years of age (3 of 4; We have used Infliximab infusions in our paediatric pa- number of children ≤10 years of age in this study n = 3). All tients since year 2000 for treatment of severe Crohn’s these children were on glucocorticoid therapy (Prednisolone disease that is not responding to conventional treatment 20 mg daily n = 1; 2.5 mg Prednisolone on alternate days regimens with steroids, azathioprine, antibiotics or enteral n = 1; Budesonide 9 mg and 6 mg on alternate days n = feeding. We did a retrospective chart review in all our pa- 1; Budesonide 6 mg daily n = 1;) and two of these children tients with IBD who had received one or more Infliximab were on azathioprine. The youngest child (2.7 years of age) infusions in Helsinki and Tampere university hospital that had received 20 mg Prednisolone (2 mg/kg) 2–3 hour prior comprise the two major referral centres for the diagnostics to infusion and she had been on azathioprine for 6 months.
and treatment of paediatric IBD with catchment area of 56% The 2-year-old child, who had a severe acute reaction af- of the paediatric population in Finland (a population base of ter her second infusion, had two abscesses necessitating revi- 2.9 million). We traced 23 children, 22 of them with Crohn’s sion under anaesthesia within 1 week after her first infusion.
disease and 1 child with ulcerative colitis treated with Inflix- There was no bacterial growth. An 11-year-old boy had an abscess within 4 weeks in his buttock that needed surgical The demographic data of the patients are presented in revision. None of the 23 children developed an opportunistic Table 1. Infliximab infusions were initiated with a regular dose of 5 mg/kg. Five children received infusion with lower The most severe adverse reactions occurred in a 16-year- dose of 3–4 mg/kg. The majority of patients were on azathio- old boy who after the second Infliximab infusion developed prine and on oral glucocorticoids (Prednisolone or Budes- severe septicaemia necessitating treatment in the intensive onide) at the time of their first infusion (Table 1).
care unit. His clinical condition deteriorated, and 3 months The 23 children with IBD treated with Infliximab infu- later, MRI examination revealed changes related to progres- sions received a total of 141 infusions during this 5-year pe- sive multifocal leucoenkephalopathy. There were no specific riod. Four children experienced a minor reaction (4 of 23; findings in biopsy and no infective agent was found. The neu- 17%; children no. 4–7 in Table 2) during infusion necessi- rological symptoms vanished and brain lesions disappeared C 2006 The Author(s)/Journal Compilation C 2006 Foundation Acta Pædiatrica/Acta Pædiatrica 2007 96, pp. 128–134
Table 1 Demographic data on the paediatric patients with inflammatory bowel
sidered secondary to the formation of antibodies directed disease treated with Infliximab infusions at our hospitals against Infliximab (11). In the study by Miele et al. (9), morethan one third of the child patients developed human an- tichimeric antibodies (HACA) during the course of repeatedinfusions (9). To avoid the development of HACA, azathio- prine on regular doses may show a preventive effect and is thus recommended in patients receiving Infliximab (11). The Crohn´s disease n = 22Ulcerative colitis n =1 majority of allergic reactions occur during the first four in- Therapy at the time of first infusion (no. of patients) fusions (6,10). Among our patients, the most severe anaphy- laxis occurred during the seventh infusion (a girl of 6 years of age). It is remarkable that anaphylaxis and severe urticaria occurred although the children were concomitantly on glu- cocorticoids. One child had received a Prednisolone dose of2 mg/kg 2–3 h before infusion, but this did not prevent the completely within 6 months after discontinuation of the In- development of severe urticaria during infusion. This partic- ular patient had received immunosuppressive medication for Acute infusion reactions during Infliximab infusion are more than 4 months, a time interval considered to reduce the relatively common, the frequency estimated from 4–5% (5,7) risk for infusions reactions (10). Others have reported that to 12–16% (2,6,8) and 23% (8) per number of patients immunosuppressive therapy does not exclude severe infu- treated. A total of 35% of our patients experienced an acute reaction during Infliximab infusion, and 50% of these acute The incidence of serious infections in all patients treated events were anaphylaxis or severe urticaria, the majority of with Infliximab is estimated to reach 8% in adults (7). In them (3 of 4) occurring in children under 10 years of age.
this study, 8.7% of the children (2 children) developed ster- It is remarkable that each child under 10 years of age expe- ile abscesses within 2–4 weeks of the infusion and 1 child rienced an acute adverse reaction. To our knowledge, there presented with severe septicaemia. No other infections were are no reports addressing the safety of Infliximab infusion in the very young children. In paediatric studies on Inflix- Infliximab may cause neural changes suggestive of multi- imab, the age of children has been over 10 years (2,8,10).
ple sclerosis or other demyelinating processes as described In the large recent multi-centre study in paediatric pa- in a 19-year-old girl with Crohn’s disease. Fortunately, these tients (6), severe reactions were rare (anaphylaxis 2 of 243) changes seem to recover after the Infliximab therapy is dis- but the age of the patients with adverse reactions was not continued (12). Our patient was a 16-year-old boy with ex- tremely aggressive Crohn’s disease not responding to any Infliximab is a recombinant chimeric antibody including of the treatments. His brain lesions related to progressive antigens originating from mouse. Infusion reactions are con- multifocal leucoenkephalopathy with corresponding neural Table 2 Adverse reactions to Infliximab infusions in 23 children with inflammatory bowel disease
Diagnosis Therapy at the time of adverse reaction Abscess at the infusion site and in the leg (2 weeks Mesalazine 500 mg × 2 Budesonide 6 mg∗ Mesalazine 500 mg × 3 Azathioprine 25 mg × Dizziness and nausea (2nd infusion)Abscess in the buttock (4 weeks after 2nd infusion) Flu mild (1st infusion)Vertigo (2nd infusion) tiredness (3rd infusion) Azathioprine 25 mg × 2 Mesalazine 500 mg × Low blood pressure (3rd infusion) with no subjective Prednisolone 20 mg × 1 Azathioprine 50 mg × Difficulties to breath, chest pain (1st infusion) Prednisolone 2.5 mg on alternate days Azathioprine 5 Severe septicaemia (after 2nd infusion)Multifocal leucoencephalopathy ∗Azathioprine not tolerated.
∗∗Infliximab dose 3.5 mg/kg.
C 2006 The Author(s)/Journal Compilation C 2006 Foundation Acta Pædiatrica/Acta Pædiatrica 2007 96, pp. 128–134
symptoms developed within 3 months after introduction of (Remicade) in severe Pediatric Crohn disease. J Pediatr Infliximab therapy. Within 6 months after discontinuation Gastroenterol Nutr 2003; 36: 632–6.
of Infliximab therapy, his brain MRI was completely normal 5. Stephens MC, Shepanski MA, Mamula P, Markowitz JE, Brown KA, Baldassano RN. Safety and steroid-sparing and he presented no neurological symptoms.
experience using infliximab for Crohn´s disease at a pediatric In conclusion, adverse reactions to Infliximab infusions inflammatory disease center. Am J Gastroenterol 2003; 98: are common. The majority of reactions are mild and enable continuation of the therapy. However, young children seem 6. Jacobstein DA, Markowitz JE, Kirschner BS, Cohen G, Stanley to be prone to severe adverse reactions although they are on A, Gold BD, et al. Premedication and infusion reactions with azathioprine and conventional glucocorticoid therapy. It is infliximab: results from a pediatric inflammatory bowel disease advisable that this therapy should be limited to specialized consortium. Inflamm Bowel Dis 2005; 442–6.
7. Colombel J-F, Loftus EV Jr, Tremaine WJ, Egan LJ, Harmsen WS, Schleck CD, et al. The safety profile of infliximab in Ms Sari Honkanen is thanked for her excellent assistance patients with Crohn´s disease: the Mayo clinic experience in in gathering the data. The Finnish Cultural Foundation and 500 patients. Gastroenterology 2004; 126: 19–31.
the Finnish Pediatric Research Foundation supported this 8. Lamireau Th, C ´ezard J-P, Dabadie A, Goulet O, Lachauz A, Turck D, et al. Efficacy and tolerance of infliximab in childrenand adolescents with Crohn´s disease. Inflamm Bowel Dis 9. Miele E, Markowitz JE, Mamula P, Baldassano RN. Human 1. Scallon BJ, Moore MA, Trinh H, Knight DM, Ghrayeb J.
antichimeric antibody in children and young adults with Chimeric anti-TNF-alpha monoclonal antibody cA2 binds inflammatory bowel disease receiving infliximab. J Pediatr recombinant transmembrane TNF-alpha and activates immune Gastroenterol Nutr 2004; 38: 502–8.
effector functions. Cytokine 1995; 7: 251–9.
10. Crandall WV, Mackner LM. Infusion reactions to infliximab in 2. Wewer V, Riis L, Vind I, Husby S, Munkholm P, Paerregaard children and adolescents: frequency, outcome and a predictive A. Infliximab dependency in a national cohort of children with model. Aliment Pharmacol Ther 2003; 17: 75–84.
Crohn´s disease. J Pediatr Gastroenterol Nutr 2006; 42: 40–5.
11. Baert F, Noman M, Vermeire S, Van Assche G, D´Haens G, 3. Friesen CA, Calabro C, Christenson K, Carpenter E, Welchert Carbonez A, et al. Influence of immunogenicity on the E, Daniel JF, et al. Safety of infliximab treatment in pediatric long-term efficacy of infliximab in Crohn’ disease. NEJM 2003; patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2004; 39: 265–9.
12. Thomas CW Jr, Weinshenker BG, Sandborn WJ.
4. Cezard J-P, Nouaili N, Talbotec C, Hugot J-P, Gobert J-G, Demyelination during anti-tumor necrosis factor alpha therapy Schmitz J, et al. A prospective study of the efficacy and with infliximab for Crohn´s disease. Inflamm Bowel Dis 2004; tolerance of a chimeric antibody to tumor necrosis factors Identification of a novel compound heterozygote SCO2 mutation in
cytochrome c oxidase deficient fatal infantile cardioencephalomyopathy
M Knuf1∗, J Faber (jorg.faber@childrens.harvard.edu)1∗, R G Huth1, P Freisinger2, F Zepp1, C Kampmann1
1. Children’s Hospital, Johannes Gutenberg-University, Mainz, Germany
2. Children’s Hospital and Metabolic Disease Centre, University of Technology Munich, Germany Keywords
Abstract
Cardioencephalomyopathy, Mitochondrial disorder, Fatal infantile cardioencephalomyopathy (OMIM No. 604377) is a disorder of the mitochondrial respiratory chain and is characterised by neonatal progressive muscular hypotonia and Correspondence
cardiomyopathy because of severe Cytochrome c oxidase deficiency. Here we report a novel Joerg Faber, Children’s Hospital Boston,Karp Research Facilities 8006b, mutation in the Cytochrome c oxidase assembly gene SCO2 in an infant with fatal infantile 1 Blackfan Circle, MA 02115, Boston, USA.
cardioencephalomyopathy despite normal initial metabolic screening.
Tel: +1 617 919 2505 | Fax:+1 617 730 0934 |Email: jorg.faber@childrens.harvard.edu Conclusion: In newborns with unexplained muscular hypotonia and cardiomyopathy genetic testing of mitochon- drial respiratory chain disorders might be helpful to establish a final diagnosis and guide treatment decisions.
Received
15 February 2006; accepted 14 June 2006
∗MK and JF contributed equally to the work.
Cytochrome c oxidase (COX) is a multimeric enzyme of the COX deficiency constitutes around 1/3 (1). COX deficiency inner mitochondrial membrane and catalyses the reduction presents with a wide range of multi-system symptoms. Sev- of molecular oxygen by reduced cytochrome c, the terminal eral pathogenic mutations have been reported in the three step in the respiratory chain. The incidence of respiratory mitochondrial-encoded COX subunits and in genes involved chain disorders is 1 in 10 000 newborns of which isolated in the assembly of the COX holoenzyme (2).
C 2006 The Author(s)/Journal Compilation C 2006 Foundation Acta Pædiatrica/Acta Pædiatrica 2007 96, pp. 128–134

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