M. Elawad

Great Ormond Street Hospital for Children NHS Foundation Trust, Londinium, England, United Kingdom

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Publications (47)208.52 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim: The role of adalimumab in medically refractory ulcerative colitis (UC) in children remains to be defined. The aim of this study was to describe 11 cases of paediatric patients who received adalimumab as a second-line anti-TNF-α treatment for paediatric UC. Methods: A retrospective review of all patients with UC who received adalimumab between April 2008 and October 2013 at our hospital was conducted. Clinical efficacy and safety were assessed. Results: Eleven patients (three boys, eight girls) with a median age of 13.8 years (5.7-16.6 years) were included. All patients had been previously treated with infliximab. Six patients achieved and maintained clinical remission, with a median duration of treatment of 25 months. One patient was successfully weaned off adalimumab after 26 months of therapy. Treatment was unsuccessful in four out of 11 patients (36%) who underwent colectomy 4-13 months (median 7 months) from the first adalimumab dose. The remaining patient developed extensive rash and was switched to alternative therapy. Conclusion: In this case series, our experience shows that there is a role for adalimumab as a combination therapy in a subgroup of children with refractory UC.
    European journal of gastroenterology & hepatology 10/2015; DOI:10.1097/MEG.0000000000000470 · 2.25 Impact Factor
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    ABSTRACT: Gastrointestinal food allergy (GIFA) occurs in 2 to 4 % of children, the majority of whom are infants (<1 year of age). Although endoscopy is considered the gold standard for diagnosing GIFA, it is invasive and requires general anaesthesia. Therefore, we aimed to investigate whether in infants with GIFA, gastrointestinal symptoms predict histological findings in order to help optimise the care pathway for such patients. All infants <1 year of age over a 20 year period who underwent an endoscopic procedure gastroscopy or colonoscopy for GIFA were evaluated for the study. Symptoms at presentation were reviewed and compared with mucosal biopsy histological findings, which were initially broadly classified for study purposes as "Normal" or "Abnormal" (defined as the presence of any mucosal inflammation by the reporting pathologist at the time of biopsy). Of a total of 1319 cases, 544 fitted the inclusion criteria. 62 % of mucosal biopsy series in this group were reported as abnormal. Infants presenting with diarrhoea, rectal (PR) bleeding, irritability and urticaria in any combination had a probability >85 % (OR > 5.67) of having abnormal histological findings compared to those without. Those with isolated PR bleeding or diarrhoea were associated with 74 % and 68 % probability (OR: 2.85 and 2.13) of an abnormal biopsy, respectively. Conversely, children presenting with faltering growth or reflux/vomiting showed any abnormal mucosal histology in only 50.8 % and 45.3 % (OR: 1.04 and 0.82) respectively. Food allergy may occur in very young children and is difficult to diagnose. Since endoscopy in infants has significant risks, stratification of decision-making may be aided by symptoms. At least one mucosal biopsy demonstrated an abnormal finding in around half of cases in this selected population. Infants presenting with diarrhoea, PR bleeding, urticaria and irritability are most likely to demonstrate abnormal histological findings.
    BMC Clinical Pathology 06/2015; 15(1):12. DOI:10.1186/s12907-015-0012-6
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    ABSTRACT: X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was originally described in male patients with X-linked lymphoproliferative syndrome type 2 (XLP2). Recent observations have highlighted a critical role of XIAP for the regulation of NOD2 signaling and are probably the molecular basis for increasingly recognized further immune dysregulatory symptoms of XIAP deficient patients, such as inflammatory bowel disease (IBD). We describe a large Caucasian family in which IBD and erythema nodosum (EN) also manifested in female carriers of XIAP mutations. Clinical data and laboratory findings including flow cytometric analysis of XIAP protein expression and sequencing of the BIRC4 gene. NOD2 signaling was investigated by determination of TNFα production in monocytes upon L18-MDP stimulation in vitro. The BIRC4 nonsense mutation p.P225SfsX226 was identified as the genetic cause of XIAP deficiency in our family. Surprisingly, clinical symptoms were not restricted to male patients, but also occurred in several female carriers. The most severely affected carrier demonstrated random X-inactivation, leading to a significant expression of mutated XIAP protein in monocytes, and consequently to impaired NOD2 responses in vitro. Our report provides further evidence that clinical symptoms of XIAP deficiency are not restricted to male patients. Random X-inactivation may be associated with EN and mild IBD also in female carriers of BIRC4 mutations. Analysis of the X-inactivation pattern reflected by XIAP protein expression can identify such carriers and the analysis of NOD2 signaling by flow cytometry can confirm the functional significance. XIAP expression patterns should be investigated in female patients with a family history of EN and/or IBD.
    Journal of Clinical Immunology 05/2015; 35(5). DOI:10.1007/s10875-015-0166-0 · 3.18 Impact Factor
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    ABSTRACT: Eosinophilic gastrointestinal disease (EGID) and inflammatory bowel disease (IBD) are two distinct disorders that share some clinical manifestations but have different diagnostic criteria. In this article, we reviewed the clinical data of three children with EGID who later developed IBD. This study is a retrospective case note review that was conducted between 2007 and 2012. EGID seems to precede IBD in some subsets of children in whom the diagnosis of IBD may take a few years to fully develop.
    European Journal of Gastroenterology & Hepatology 10/2014; 27(1). DOI:10.1097/MEG.0000000000000230 · 2.25 Impact Factor
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    ABSTRACT: Background: Management of refractory inflammatory bowel disease (IBD) in children is challenging and once response to conventional medical therapy deviates from the expected, options are often limited. Sirolimus is commonly used in post-transplantation management and is used sparsely as rescue therapy in refractory Crohn's disease. In the present study, we report the efficacy of sirolimus as an adjuvant immunosuppressive therapy in a retrospective case review of a selected group of IBD children who were refractory to the conventional treatments. Methods: Medical records of children with refractory IBD unresponsive to conventional therapy and started on sirolimus between 2006 and 2012 were retrospectively reviewed. Clinical response, through Pediatric Ulcerative Colitis Activity Index (PUCAI) and Pediatric Crohn's Disease Activity Index (PCDAI), as well as intestinal inflammation, through specific histological scores, was evaluated. Results: The records of 14 patients were analyzed. Eleven of them had ulcerative colitis (UC) and 3 Crohn's disease (CD); mean age at diagnosis was 9.1 years (standard deviation 3.8). Of UC patients, 5 (45%) achieved clinical remission and 2 (18%) showed clinical response. All CD patients went into clinical remission. Mucosal healing was achieved by 5 children (45%) with UC and 2 (67%) with CD patients. One child with ulcerative colitis was weaned off adalimumab, while 2 children with CD were weaned off prednisolone and methotrexate successfully. Conclusion: Our data provide evidence that sirolimus seems to be effective as rescue therapy in a subgroup of children with severe IBD refractory to conventional therapies by inducing both clinical remission and mucosal healing.
    Journal of Crohn s and Colitis 09/2014; 8(12). DOI:10.1016/j.crohns.2014.08.014 · 6.23 Impact Factor
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    ABSTRACT: Clostridium difficile is an important nosocomial pathogen and the leading cause of antibiotic-associated diarrhea. Multilocus sequence typing indicates that C. difficile strains belong to five distinct genetic clades encompassing several PCR ribotypes (RT). Since their emergence in 2003, hypervirulent RT027 strains have been a major focus of research; in contrast, our current understanding of RT017-mediated disease pathogenesis lags far behind. In this study, we aimed to characterize host immunity to CF5 and M68, two genetically well-defined RT017 strains. Both strains engaged with host Toll-like receptor 2/6 (TLR2/6), TLR2-CD14, and TLR5 to similar extents in a model cell line. Despite this, CF5 mediated significantly greater dendritic cell (DC) interleukin-12 (IL-12), IL-27, and IL-10 immunity than M68. Both strains elicited similar IL-1β mRNA levels, and yet only M68 caused a marked increase in secretory IL-1β. A CF5 cocultured-DC cytokine milieu drove an equipotent Th1 and Th17 response, while M68 promoted greater Th17 immunity. Human gastrointestinal ex vivo cytokine responses to both strains were characterized. Taken together, our data suggest that C. difficile strains mediate overlapping and yet distinct mucosal and DC/T cell immunity. Finally, toxin-driven IL-1β release supports the hypothesis that this cytokine axis is a likely target for therapeutic intervention for C. difficile infection.
    Infection and Immunity 09/2014; 82(12). DOI:10.1128/IAI.02605-14 · 3.73 Impact Factor
  • Journal of Crohn s and Colitis 09/2014; 8:S405. DOI:10.1016/S1873-9946(14)50045-1 · 6.23 Impact Factor
  • Journal of Crohn s and Colitis 09/2014; 8:S414. DOI:10.1016/S1873-9946(14)50075-X · 6.23 Impact Factor
  • Journal of Crohn s and Colitis 09/2014; 8:S435-S436. DOI:10.1016/S1873-9946(14)50144-4 · 6.23 Impact Factor
  • Journal of Crohn s and Colitis 09/2014; 8:S405. DOI:10.1016/S1873-9946(14)50043-8 · 6.23 Impact Factor
  • Journal of Crohn s and Colitis 09/2014; 8:S404-S405. DOI:10.1016/S1873-9946(14)50042-6 · 6.23 Impact Factor
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    ABSTRACT: Background Multiple monogenetic conditions with partially overlapping phenotypes can present with inflammatory bowel disease (IBD)-like intestinal inflammation. With novel genotype-specific therapies emerging, establishing a molecular diagnosis is becoming increasingly important. Design We have introduced targeted next-generation sequencing (NGS) technology as a prospective screening tool in children with very early onset IBD (VEOIBD). We evaluated the coverage of 40 VEOIBD genes in two separate cohorts undergoing targeted gene panel sequencing (TGPS) (n=25) and whole exome sequencing (WES) (n=20). Results TGPS revealed causative mutations in four genes (IL10RA, EPCAM, TTC37 and SKIV2L) discovered unexpected phenotypes and directly influenced clinical decision making by supporting as well as avoiding haematopoietic stem cell transplantation. TGPS resulted in significantly higher median coverage when compared with WES, fewer coverage deficiencies and improved variant detection across established VEOIBD genes. Conclusions Excluding or confirming known VEOIBD genotypes should be considered early in the disease course in all cases of therapy-refractory VEOIBD, as it can have a direct impact on patient management. To combine both described NGS technologies would compensate for the limitations of WES for disease-specific application while offering the opportunity for novel gene discovery in the research setting.
    Journal of Medical Genetics 08/2014; DOI:10.1136/jmedgenet-2014-102624 · 6.34 Impact Factor
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    ABSTRACT: Background Aprepitant (Emend, Merck Sharp & Dohme Ltd, Haarlem, the Netherlands), a neurokinin-1 receptor antagonist, prevents vomiting in a range of conditions. No data are available on its use in children with cyclical vomiting syndrome (CVS). Aim We investigated the efficacy of aprepitant as prophylactic treatment or acute intervention in CVS children refractory to conventional therapies. Methods Forty-one children (median age: 8 years) fulfilling NASPGHAN criteria treated acutely (RegA) or prophylactically (RegP) with aprepitant were retrospectively reviewed. Primary outcome was the clinical response (decrease in frequency and intensity of CVS episodes). Secondary outcomes were: number of CVS episodes/ year, number of hospital admissions/year, CVS episode duration, number of vomits/h, symptom-free interval length (days), and school attendance percentage. The follow-up period was 18-60 months. Results Sixteen children received RegP and 25 RegA. One child on RegP stopped treatment due to severe migraine. At 12-months on intention-to-treat analysis, 13 children on RegP (81%) achieved either complete (3/16, 19%) or partial (10/16, 62%) clinical response. On RegA, 19 children (76%) had either complete (3/25, 12%) or partial (16/25, 64%) response (P = 0.8 vs. RegP). In both RegP and RegA, there was a significant decrease in CVS episodes/year, hospital admission number/year, CVS episode length, number of vomits/h, as well as an increase in symptom-free interval duration and school attendance percentage. Side effects were reported only in RegP (5/16, 31%) including hiccough (3/16, 19%), asthenia/fatigue (2/16, 12.5%), increased appetite (2/16, 12.5%), mild headache (1/16, 6%) and severe migraine (1/16, 6%). Conclusion Aprepitant appears effective for both acute and prophylactic management of paediatric cyclical vomiting syndrome refractory to conventional therapies.
    Alimentary Pharmacology & Therapeutics 06/2014; 40(3). DOI:10.1111/apt.12822 · 5.73 Impact Factor
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    ABSTRACT: The presence of extraintestinal manifestations (EIM) in children with gastrointestinal (GI) food allergy (GIFA) is highly debated. In this study we assessed the prevalence of EIM in GIFA children and investigated whether their presence is helpful in the allergy-focused history taking process. The medical records of all children with a proven diagnosis of GIFA were reviewed along with those of children diagnosed with inflammatory bowel disease (IBD) as controls. Data regarding age at onset, age at diagnosis, atopic family history, atopic co-morbidities, GI symptoms and EIM was recorded. Data from 436 GIFA and 74 IBD children was included in the analysis. EIM were documented in 368 GIFA children, including fatigue (53.0%), allergic shiners (49.1%), mouth ulcers (39.0%), joint pain/hypermobility (35.8%), poor sleep (34.4%), night sweats (34.4%), headache (22.7%) and bed wetting (17.7%). The proportion of patients with EIM was higher in the GIFA group compared to the IBD group [368/436 (84.4%) vs 40/74 (54.1%); p < 0.001]. Segregating the GIFA group into children with and without atopic comorbidities, both atopic (276/30; 89.9%) and non-atopic (93/130; 71.5%) children showed higher proportion of EIM than IBD children [(40/74; 54.1%), p < 0.01 and p < 0.05, respectively]. Gastrointestinal food allergies are commonly associated with a wide range of EIM, which appear to represent important and specific clinical features of this group of conditions. Their recognition in an allergy-focused history taking might play an important role for both diagnosis and management.
    Journal of pediatric gastroenterology and nutrition 04/2014; 59(2). DOI:10.1097/MPG.0000000000000391 · 2.63 Impact Factor
  • Journal of Crohn s and Colitis 02/2014; 8:S297. DOI:10.1016/S1873-9946(14)60670-X · 6.23 Impact Factor
  • Journal of Crohn s and Colitis 02/2014; 8:S111. DOI:10.1016/S1873-9946(14)60240-3 · 6.23 Impact Factor
  • Biology of Blood and Marrow Transplantation 02/2014; 20(2):S89-S90. DOI:10.1016/j.bbmt.2013.12.113 · 3.40 Impact Factor
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    ABSTRACT: Early-onset inflammatory bowel disease starting within the first months of life could be due to a particular genetic defect. We set up the GENetically determined ImmUne-mediated enteropathieS (GENIUS) network and collected infants with a proven defect of the IL10 axis for accurate phenotyping of disease presentation and evolution. Ten patients with early-onset inflammatory bowel disease with confirmed mutations in IL10, IL10RA, or IL10RB genes were characterized on clinical, endoscopic-histological, immunobiological, and radiological findings. Functional assays to confirm defective responses to IL10 were performed on peripheral blood mononuclear cells. A functional defect in IL10 signaling was confirmed in all IL10R patients tested. Disease started with severe diarrhea within the first 12 weeks in all patients. All infants showed Crohn's disease-like ulcerations limited to the colon with marked perianal inflammation (fissures, abscess, and fistula); disease progression to the small bowel occurred in only 1 patient. Four of the 10 patients had granulomata on histology, and all patients showed Crohn's disease-like mesenteric infiltration on imaging. Disease pattern was indistinguishable between IL10R alpha or beta chain or IL10 defects; autoimmunity was not observed. Mutations in IL10 were more frequently associated with bacterial and viral infections. Patients responded partially to treatment with steroids or anti-tumor necrosis factor drugs, whereas hematopoietic stem cell transplantation proved efficacious. The importance of the IL10 pathway within the colonic mucosa is highlighted by the development of severe colitis within a few weeks in infants with mutations in IL10, IL10RA, or IL10RB. Immunosuppression failed to correct the defect in this pathway, which seems to be a key to controlling inflammation in the colon.
    Inflammatory Bowel Diseases 11/2013; 19(13). DOI:10.1097/01.MIB.0000435439.22484.d3 · 4.46 Impact Factor
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    ABSTRACT: Very early onset inflammatory bowel disease (VEO - IBD) results in chronic intractable and therapy resistant inflammation of the gut and severe growth failure. The pervasive nature of the disorder often requires lengthy hospital admission. Despite underlying genetic heterogeneity, clinical presentation is often homogeneous. The differential diagnosis of VEO-IBD includes monogenic conditions with defects in epithelial barrier function, T/B lymphocyte selection and activation and innate and adaptive immune response as well as conditions leading to neutropenia and defective phagocyte killing and hyper- and autoinflammation. We have implemented a next generation sequencing approach to expedite the diagnosis of VEO-IBD patients, by screening 40 genes associated with the disorder. Coverage of the panel overall is 99% at 30x or greater. Thus far 5 positive controls and 6 VEO-IBD patients have been screened. All control mutations were detected and the pathogenic mutation in 1 previously undiagnosed patient has been identified. The subject presented with severe intractable inflammation of the large and small bowel and was diagnosed with autoimmune enterocolitis. Despite lack of diagnosis and due to the severity of the condition the subject has undergone experimental haematopoietic stem cell transplant (HCST), which has a mortality rate of 20%. Subsequent molecular analysis, showed the patient to be a compound heterozygote for mutations in TTC37 (c.2018G>A p.Gly673Asp and c.2808G>A p.Trp936*), associated with tricho-hepato-enteric syndrome (THES), a very rare disease (1/1,000,000 births). The phenotype of this patient is unlike the characteristic features reported in other cases; thus NGS has enabled a diagnosis of a) a rare disorder not characterised by phenotype alone and b) a genetic test which until now has not been offered clinically. Due to the rarity of THES, it is currently unknown whether HCST is optimal treatment for the condition. Identifying the molecular basis of VEO-IBD has the potential to profoundly affect patient management; e.g. patients with mutations in IL10 can be successfully treated with HCST. In addition 42 primary immune deficiency genes are also captured with the same panel and analysis can be extended to these genes, offering a comprehensive molecular approach to this complex group of patients. We aim to introduce this extensive genetic screening early on in patient management, to guide medical intervention at the earliest opportunity.
    American Society of Human Genetics, Boston, USA; 10/2013

Publication Stats

196 Citations
208.52 Total Impact Points


  • 2006–2015
    • Great Ormond Street Hospital for Children NHS Foundation Trust
      • Department of Gastroenterology
      Londinium, England, United Kingdom
  • 2014
    • Institute for Child Health Policy (ICHP)
      اورموند بيتش، فلوريدا, Florida, United States
  • 2012
    • University College London
      • Division of Infection and Immunity
      Londinium, England, United Kingdom
  • 2009
    • University of Helsinki
      • The Hospital for Children and Adolescents
      Helsinki, Uusimaa, Finland