Mamoun Elawad

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

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Publications (31)94.93 Total impact

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    ABSTRACT: 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.
    Journal of Crohn's & colitis. 09/2014;
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    ABSTRACT: Clostridium difficile is an important nosocomial pathogen and the leading cause of antibiotic-associated diarrhoea. Multi-locus 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 characterise host immunity to CF5 and M68, two genetically well-defined RT017 strains. Both strains engaged with host Toll-like receptors (TLR)-2/6, TLR2-CD14 and 5 to a similar extent in a model cell-line. Despite this, CF5 mediated significantly greater dendritic cell (DC) IL-12/IL-27/IL-10 immunity compared to M68. Both strains elicited similar IL-1β mRNA levels and yet, only M68 caused a marked increase in secretory IL-1β. CF5 co-cultured-DC cytokine milieu drove an equipotent Th1/Th17 whilst M68 promoted greater Th17 immunity. Human gastrointestinal ex-vivo cytokine responses to both strains were characterised. Taken together, our data suggests 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;
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    ABSTRACT: 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.
    Journal of Medical Genetics 08/2014; · 5.70 Impact Factor
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    ABSTRACT: 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).
    Alimentary Pharmacology & Therapeutics 06/2014; · 4.55 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; · 2.18 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; · 5.12 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
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    ABSTRACT: Food protein induced gastrointestinal allergies are difficult to characterise due to the delayed nature of this allergy and absence of simple diagnostic tests. Diagnosis is based on an allergy focused history which can be challenging and often yields ambiguous results. We therefore set out to describe a group of children with this delayed type allergy, to provide an overview on typical profile, symptoms and management strategies. This retrospective analysis was performed at Great Ormond Street Children's Hospital. Medical notes were included from 2002 -- 2009 where a documented medical diagnosis of food protein induced gastrointestinal allergies was confirmed by an elimination diet with resolution of symptoms, followed by reintroduction with reoccurrence of symptoms. Age of onset of symptoms, diagnosis, current elimination diets and food elimination at time of diagnosis and co-morbidities were collected and parents were phoned again at the time of data collection to ascertain current allergy status. Data from 437 children were analysis. The majority (67.7%) of children had an atopic family history and 41.5% had atopic dermatitis at an early age. The most common diagnosis included, non-IgE mediated gastrointestinal food allergy (n = 189) and allergic enterocolitis (n = 154) with symptoms of: vomiting (57.8%), back-arching and screaming (50%), constipation (44.6%), diarrhoea (81%), abdominal pain (89.9%), abdominal bloating (73.9%) and rectal bleeding (38.5%). The majority of patients were initially managed with a milk, soy, egg and wheat free diet (41.7%). At a median age of 8 years, 24.7% of children still required to eliminate some of the food allergens. This large retrospective study on children with food induced gastrointestinal allergies highlights the variety of symptoms and treatment modalities used in these children. However, further prospective studies are required in this area of food allergy.
    World Allergy Organization Journal 08/2013; 6(1):13.
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    ABSTRACT: X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in SH2D1A. In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant clinical phenotype. Among 25 symptomatic patients diagnosed with XIAP deficiency, we identified 17 patients who initially presented with manifestations other than HLH. These included Crohn-like bowel disease (n=6), severe infectious mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1), periodic fever (n=1), fistulating skin abscesses (n=1) and severe Giardia enteritis (n=1). Subsequent manifestations included celiac-like disease, antibody deficiency, splenomegaly and partial HLH. Screening by flow cytometry identified 14 of 17 patients in our cohort. However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations.
    Clinical Immunology 07/2013; 149(1):133-141. · 3.77 Impact Factor
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    ABSTRACT: Clostridium difficile infection (CDI) is the leading cause of hospital and community-acquired antibiotic-associated diarrhoea and currently represents a significant health burden. Although the role and contribution of C. difficile toxins to disease pathogenesis is being increasingly understood, at present other facets of C. difficile-host interactions, in particular, bacterial-driven effects on host immunity remain less studied. Using an ex-vivo model of infection, we report that the human gastrointestinal mucosa elicits a rapid and significant cytokine response to C. difficile. Marked increase in IFN-γ with modest increase in IL-22 and IL-17A was noted. Significant increase in IL-8 suggested potential for neutrophil influx while presence of IL-12, IL-23, IL-1β and IL-6 was indicative of a cytokine milieu that may modulate subsequent T cell immunity. Majority of C. difficile-driven effects on murine bone-marrow-derived dendritic cell (BMDC) activation were toxin-independent; the toxins were however responsible for BMDC inflammasome activation. In contrast, human monocyte-derived DCs (mDCs) released IL-1β even in the absence of toxins suggesting host-specific mediation. Infected DC-T cell crosstalk revealed the ability of R20291 and 630 WT strains to elicit a differential DC IL-12 family cytokine milieu which culminated in significantly greater Th1 immunity in response to R20291. Interestingly, both strains induced a similar Th17 response. Elicitation of mucosal IFN-γ/IL-17A and Th1/Th17 immunity to C. difficile indicates a central role for this dual cytokine axis in establishing antimicrobial immunity to CDI.
    PLoS ONE 01/2013; 8(7):e69846. · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: Inherited deficiencies of IL-10 or IL-10 receptor (IL-10R) lead to immune dysregulation with life-threatening early-onset enterocolitis. OBJECTIVES: We sought to gather clinical data of IL-10/IL-10R-deficient patients and devise guidelines for diagnosis and management, including hematopoietic stem cell transplantation (HSCT). METHODS: We enrolled 40 patients with early-onset enterocolitis and screened for mutations in IL10/IL10R using genetic studies, functional studies, or both of the IL-10 signaling pathway. Medical records of IL-10/IL-10R-deficient patients were reviewed and compiled. RESULTS: Of 40 patients, we identified 7 with novel mutations, predominantly in consanguineous families with more than 1 affected member. IL-10/IL-10R-deficient patients had intractable enterocolitis, perianal disease, and fistula formation. HSCT was carried out in 2 patients with IL-10 deficiency and 1 patient with IL-10R α chain deficiency and proved to be an effective therapy, leading to rapid improvement of clinical symptoms and quality of life. CONCLUSION: Because the defect in patients with IL-10/IL-10R deficiency resides in hematopoietic lineage cells and their colitis is resistant to standard immunosuppressive therapy, HSCT should be considered early as a potentially curative therapeutic option.
    The Journal of allergy and clinical immunology 11/2012; · 12.05 Impact Factor
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    ABSTRACT: Inflammatory bowel disease (IBD) is a chronic inflammatory disease characterized by abdominal pain, bloody diarrhoea, and malabsorption leading to weight loss. It is considered the result of inadequate control of an excessive reaction of the immune system to the resident flora of the gut. Like other primary immunodeficiencies, IL-10 and IL-10 receptor (IL10R) deficiency present with IBD and demonstrate the sensitivity of the intestine to any changes of the immune system. Both IL-10 and IL10R deficiency cause severe early-onset enterocolitis and can be successfully treated by hematopoietic stem cell transplantation (HSCT).
    Current Allergy and Asthma Reports 08/2012; 12(5):373-9. · 2.75 Impact Factor
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    ABSTRACT: To assess and compare the pattern of reflux in a selected population of infants with cow's milk (CM) allergy (CMA) and suspected gastroesophageal reflux disease (GERD) while on dietary exclusion and following challenge with CM. Seventeen children (median age: 14 months) with a proven diagnosis of CMA and suspected GERD underwent 48-hour multichannel intraluminal impedance-pH monitoring. For the first 24 hours, the infants were kept on amino acid-based formula, and for the subsequent 24 hours, they were challenged with CM. The total reflux episodes and the number of weakly acidic episodes were higher during CM challenge compared with the amino acid-based formula period [total reflux episodes: 105 (58-127.5) vs 65 (39-87.5), P < .001; weakly acidic episodes: 53 (38.5-60.5) vs 19 (13-26.5), P < .001; median (25th-75th)]. No differences were found for either acid or weakly alkaline episodes (not significant). The number of weakly acidic episodes reaching the proximal, mid, and distal esophagus was higher during CM challenge (P < .001). No differences were found in either acid exposure time or number of long-lasting episodes (not significant). In children with CMA and suspected GERD, CM exposure increases the number of weakly acidic reflux episodes. CM challenge during 48-hour multichannel intraluminal impedance-pH monitoring identifies a subgroup of patients with allergen-induced reflux, and in selected cases of children with CMA in whom GERD is suspected, its use could be considered as part of diagnostic work-up.
    The Journal of pediatrics 04/2012; 161(3):476-481.e1. · 4.02 Impact Factor
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    ABSTRACT: Lower threshold and widening indications for paediatric gastrointestinal endoscopy have resulted in a significant increase in the numbers of endoscopic procedures performed in infants. Despite this, knowledge of gastrointestinal mucosal findings in this age group is limited and data on the clinical usefulness of endoscopy are lacking. All of the children younger than 1 year referred to a single tertiary paediatric gastroenterology unit during the period June 1987 to August 2007 who underwent gastrointestinal endoscopy were identified and the clinical indications and histological outcomes were reviewed. A total of 933 gastroesophageal duodenoscopies and 439 colonoscopies were performed in 1024 cases in a total of 823 infants. In order of frequency, clinical indications were diarrhoea (51%), failure to thrive (41.2%), symptoms of reflux (27.1%), and rectal bleeding (8.5%). Mucosal biopsies were insufficient for assessment in only 2.4% of cases. Mucosal histology was normal in 33.8%, whereas histological abnormalities were identified in 63.8%. Specific histological diagnoses included microvillous inclusion disease, autoimmune enteropathy, graft-versus-host disease post-bone marrow transplantation, tufting enteropathy, and disaccharidase deficiency. There was only 1 colonic perforation complicating endoscopy in a total of 889 cases for which relevant information was available (0.1%). In two-thirds of cases, histological abnormalities were detected that influenced management following endoscopic examination and mucosal biopsy in infants. Endoscopy with biopsies is a greatly informative test with low failure and complication rates in the first year of life.
    Journal of pediatric gastroenterology and nutrition 12/2011; 55(1):62-5. · 2.18 Impact Factor
  • Digestive and Liver Disease - DIG LIVER DIS. 01/2011; 43.
  • Digestive and Liver Disease - DIG LIVER DIS. 01/2011; 43.
  • The Lancet 10/2010; 376(9748):1272. · 39.06 Impact Factor
  • F. Kiparissi, M. Elawad, K. Lindley
    Journal of Crohn s and Colitis Supplements 09/2009; 3(1):22-22.
  • F. Kiparissi, C. Ong, M. Elawad
    Journal of Crohn's and Colitis Supplements. 01/2009; 3(1):13-14.
  • F. Kiparissi, A. Kader, M. Elawad
    Journal of Crohn's and Colitis Supplements. 01/2009; 3(1):14-14.