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1. Outcomes following SARS-CoV-2 infection in patients with primary and secondary immunodeficiency in the UK

Author: Katie Townsend, Evon Boules, Rachael O’Brien, Sai Murng, Smita Y. Patel, Helen Baxendale, Siraj A. Misbah, Ariharan Anantharachagan, Aarnoud Huissoon, Richard Herriot, Andrew R. Gennery, Kenneth F Baker, David M. Lowe, Lucy Leeman, Suzanne Elcombe, Alex G. Richter, Grant Hayman, Philip D Bright, Moira Thomas, Sarah Goddard, Magdalena Dziadzio, Prashantha M. Vaitla, Sameer Bahal, Betsy Cleave, Dylan James Mac Lochlainn, Elizabeth McDermott, Malini Bhole, Anna Shrimpton, Sujoy Khan, Nisha Verma, William H. Bermingham, Sinisa Savic, Anthony Williams, Gururaj Arumugakani, Lavanya Diwakar, Elizabeth Drewe, James Laffan, Lucy Cliffe, Catherine Stroud, Stephen Jolles, A Herwadkar, Siobhan O. Burns, Adrian M Shields, Shanti Mahabir, Scott Hackett, Sofia Grigoriadou, Sarah Johnston, John Dempster, Hadeil Morsi, Peter Lane, Sadia Noorani, Arthur Price, Tasneem Rahman, Fatima Dhalla, Christopher J A Duncan, Lisa Devlin, Harichandrana Ghanta, Fiona Moghaddas, Charu Chopra, Suranjith Senevirantne, Shuayb Elkhalifa, and Rashmi Jain
Subjects: medicine.medical_specialty, inborn errors of immunity, hypogammaglobulinemia, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunology, AcademicSubjects/MED00730, secondary immunodeficiencies, Antibodies, Monoclonal, Humanized, Antibodies, Viral, Dexamethasone, Secondary immunodeficiency, AcademicSubjects/MED00160, Internal medicine, Medicine, Immunology and Allergy, Humans, In patient, COVID-19 Serotherapy, business.industry, SARS-CoV-2, Immunization, Passive, Immunologic Deficiency Syndromes, COVID-19, lymphopenia, Antibodies, Neutralizing, United Kingdom, COVID-19 Drug Treatment, Drug Combinations, business, AcademicSubjects/MED00010, AcademicSubjects/MED00690, Research Article, primary immunodeficiencies
Abstract: Purpose To define the burden of morbidity and mortality arising from COVID-19 in individuals with primary (PID) and secondary immunodeficiency (SID) in the United Kingdom. Methods In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. Anonymised demographic data, pre-SARS-CoV-2 infection lymphocyte counts, co-morbidities, targeted treatments and outcomes were collected. Three groups were analysed in further detail: individuals with common variable immunodeficiency (CVID), individuals with any PID, including CVID, receiving immunoglobulin replacement therapy (IgRT) and individuals with secondary immunodeficiency. Results A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID, had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Conclusion Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count and the presence of co-morbidities are additional risk factors for poor outcome in this cohort.
Published: 2023

2. Vitamin D status of children with paediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (PIMS-TS)

Author: Suma Uday, Barnaby R. Scholefield, Angeline Darren, Syed Habib Ali, Ashish Chikermane, Deepthi Jyothish, Hari Krishnan Kanthimathinathan, Kavitha Masilamani, Scott Hackett, Meissa Osman, Steven B. Welch, and Eslam Al-Abadi
Subjects: Male, medicine.medical_specialty, Paediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2, medicine.medical_treatment, Population, Medicine (miscellaneous), 030209 endocrinology & metabolism, medicine.disease_cause, Gastroenterology, Multisystem Inflammatory Syndrome in Children, vitamin D deficiency, 03 medical and health sciences, 0302 clinical medicine, Immune system, Internal medicine, medicine, Vitamin D and neurology, Humans, Paediatric intensive care unit, Severe acute respiratory syndrome coronavirus 2, 030212 general & internal medicine, Vitamin D, Child, education, education.field_of_study, Vitamin D deficiency, Nutrition and Dietetics, Coronavirus disease 2019, biology, SARS-CoV-2, business.industry, COVID-19, Full Papers, Immune dysregulation, medicine.disease, Systemic Inflammatory Response Syndrome, Cytokine, Child, Preschool, Cohort, biology.protein, Antibody, business, Human and Clinical Nutrition
Abstract: Coronavirus disease 2019 (COVID-19) has caused mild illness in children, until the emergence of the novel hyperinflammatory condition paediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PIMS-TS). PIMS-TS is thought to be a post-SARS-CoV-2 immune dysregulation with excessive inflammatory cytokine release. We studied 25 hydroxyvitamin D (25OHD) concentrations in children with PIMS-TS, admitted to a tertiary paediatric hospital in the UK, due to its postulated role in cytokine regulation and immune response. Eighteen children (median (range) age 8·9 (0·3-14·6) years, male = 10) met the case definition. The majority were of Black, Asian and Minority Ethnic (BAME) origin (89 %, 16/18). Positive SARS-CoV-2 IgG antibodies were present in 94 % (17/18) and RNA by PCR in 6 % (1/18). Seventy-eight percentage of the cohort were vitamin D deficient (< 30 nmol/l). The mean 25OHD concentration was significantly lower when compared with the population mean from the 2015/16 National Diet and Nutrition Survey (children aged 4–10 years) (24 v. 54 nmol/l (95 % CI −38·6, −19·7); P < 0·001). The paediatric intensive care unit (PICU) group had lower mean 25OHD concentrations compared with the non-PICU group, but this was not statistically significant (19·5 v. 31·9 nmol/l; P = 0·11). The higher susceptibility of BAME children to PIMS-TS and also vitamin D deficiency merits contemplation. Whilst any link between vitamin D deficiency and the severity of COVID-19 and related conditions including PIMS-TS requires further evidence, public health measures to improve vitamin D status of the UK BAME population have been long overdue.
Published: 2021

3. Achieving equitable management of allergic disorders and primary immunodeficiency in a Black, Asian and Minority Ethnic population

Author: Adam T. Fox, Scott Hackett, Mamidipudi Thirumala Krishna, and Claire Bethune
Subjects: Primary Immunodeficiency Diseases, Immunology, Population, Ethnic group, MEDLINE, Black People, State Medicine, Asian People, Environmental health, Hypersensitivity, Humans, Immunology and Allergy, Medicine, Minority Health, Healthcare Disparities, education, Minority Groups, education.field_of_study, Health Equity, Delivery of Health Care, Integrated, business.industry, Health Status Disparities, medicine.disease, Culturally Competent Care, United Kingdom, Race Factors, Primary immunodeficiency, business
Published: 2020

4. Paediatric Inflammatory Multisystem Syndrome: Temporally Associated with SARS-CoV-2 (PIMS-TS): Cardiac Features, Management and Short-Term Outcomes at a UK Tertiary Paediatric Hospital

Author: Scott Hackett, Tristan Ramcharan, Barnaby R. Scholefield, Chui Yi Lai, Alex G. Richter, Hari Krishnan Kanthimathinathan, Oscar Nolan, Ashish Chikermane, Eslam Al-Abadi, Deepthi Jyothish, Nanda Prabhu, Raghu Krishnamurthy, and Steven B. Welch
Subjects: Male, medicine.medical_specialty, Heart Diseases, Pneumonia, Viral, MIS-C, 030204 cardiovascular system & hematology, Mucocutaneous Lymph Node Syndrome, Ventricular Function, Left, 03 medical and health sciences, Betacoronavirus, 0302 clinical medicine, 030225 pediatrics, Internal medicine, Troponin I, medicine, Humans, Vasoconstrictor Agents, Pediatrics, Perinatology, and Child Health, Child, Pandemics, Retrospective Studies, Ejection fraction, business.industry, SARS-CoV-2, COVID-19, Immunoglobulins, Intravenous, Retrospective cohort study, Stroke Volume, Stroke volume, Vascular surgery, medicine.disease, Hospitals, Pediatric, Patient Discharge, Systemic Inflammatory Response Syndrome, United Kingdom, Cardiac surgery, Treatment Outcome, Hyper-inflammatory, Echocardiography, Pediatrics, Perinatology and Child Health, Cohort, Kawasaki, Kawasaki disease, Original Article, Female, Cardiology and Cardiovascular Medicine, business, Coronavirus Infections, PIMS-TS
Abstract: Children were relatively spared during COVID-19 pandemic. However, the recently reported hyperinflammatory syndrome with overlapping features of Kawasaki disease and toxic shock syndrome-"Paediatric Inflammatory Multisystem Syndrome-temporally associated with SARS-CoV-2" (PIMS-TS) has caused concern. We describe cardiac findings and short-term outcomes in children with PIMS-TS at a tertiary children's hospital. Single-center observational study of children with PIMS-TS from 10th April to 9th May 2020. Data on ECG and echocardiogram were retrospectively analyzed along with demographics, clinical features and blood parameters. Fifteen children with median age of 8.8 (IQR 6.4-11.2) years were included, all were from African/Afro-Caribbean, South Asian, Mixed or other minority ethnic groups. All showed raised inflammatory/cardiac markers (CRP, ferritin, Troponin I, CK and pro-BNP). Transient valve regurgitation was present in 10 patients (67%). Left Ventricular ejection fraction was reduced in 12 (80%), fractional shortening in 8 (53%) with resolution in all but 2. Fourteen (93%) had coronary artery abnormalities, with normalization in 6. ECG abnormalities were present in 9 (60%) which normalized in 6 by discharge. Ten (67%) needed inotropes and/or vasopressors. None needed extracorporeal life support. Improvement in cardiac biochemical markers was closely followed by improvement in ECG/echocardiogram. All patients were discharged alive and twelve (80%) have been reviewed since. Our entire cohort with PIMS-TS had cardiac involvement and this degree of involvement is significantly more than other published series and emphasizes the need for specialist cardiac review. We believe that our multi-disciplinary team approach was crucial for the good short-term outcomes.
Published: 2020

5. The immune landscape of SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Children (MIS-C) from acute disease to recovery

Author: Pamela Kearns, Sascha Ott, Prasad Nagakumar, Wioleta M. Zelek, Scott Hackett, Hari Krishnan Kanthimathinathan, Pavle Vrljicak, Deepthi Jyothish, Eslam Al-Abadi, Pamela Dawson, Naeem Khan, Steven B. Welch, Eanna Fennell, Ashish Chikermane, Alex G. Richter, Sian E Faustini, Eleni Syrimi, Richard Stark, Barnaby R. Scholefield, Kate Davies, Sean Monaghan, Graham S. Taylor, and Paul Murray
Subjects: Multidisciplinary, business.industry, Monocyte, Science, Immunology, Disease, Genomics, medicine.disease, Article, Complement system, Arginase, medicine.anatomical_structure, Immune system, Immune system disorder, Medicine, Kawasaki disease, Immune response, business, CD163, CD8
Abstract: Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening disease occurring several weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Deep immune profiling showed acute MIS-C patients had highly activated neutrophils, classical monocytes and memory CD8+ T-cells, with increased frequencies of B-cell plasmablasts and double-negative B-cells. Post treatment samples from the same patients, taken during symptom resolution, identified recovery-associated immune features including increased monocyte CD163 levels, emergence of a new population of immature neutrophils and, in some patients, transiently increased plasma arginase. Plasma profiling identified multiple features shared by MIS-C, Kawasaki Disease and COVID-19 and that therapeutic inhibition of IL-6 may be preferable to IL-1 or TNF-α. We identified several potential mechanisms of action for IVIG, the most commonly used drug to treat MIS-C. Finally, we showed systemic complement activation with high plasma C5b-9 levels is common in MIS-C suggesting complement inhibitors could be used to treat the disease., Graphical abstract, Genomics; Immune response; Immune system disorder; Immunology
Published: 2021

6. Imaging of bronchial pathology in antibody deficiency

Author: Cinzia Milito, Maria Pia Bondioni, Scott Hackett, Esther de Vries, Alessandro Plebani, Vassilios Lougaris, Nicholas Screaton, Isabelle Meyts, Goffredo Serra, Nermeen Galal, Jamanda Haddock, M Lucas, Arpan K. Banerjee, Michael R. Loebinger, Vojtech Thon, Katharina Schütz, Peter M. van Hagen, Alison M. Condliffe, Robert G Stirling, Bodo Grimbacher, Annarosa Soresina, Luis Ignacio Gonzalez-Granado, John R. Hurst, Gertjan J. Driessen, Klaus Warnatz, Vera Postranecka, Peter Kelleher, Jiri Litzman, Dinakantha S. Kumararatne, Andrew Exley, Isabella Quinti, Judith Babar, Cesare Sirignano, Smita Y. Patel, Ieneke Hartmann, Ulrich Baumann, Giuseppe Spadaro, Francesco Fraioli, Sabine Dettmer, Alison Jones, Annemarie Bruining, Helen Chapel, Milica Mitrevski, Claire-Michèle Farber, Benjamin Gathmann, Diana Alecsandru, Schütz, Katharina, Alecsandru, Diana, Grimbacher, Bodo, Haddock, Jamanda, Bruining, Annemarie, Driessen, Gertjan, de Vries, Esther, van Hagen, Peter M., Hartmann, Ieneke, Fraioli, Francesco, Milito, Cinzia, Mitrevski, Milica, Quinti, Isabella, Serra, Goffredo, Kelleher, Peter, Loebinger, Michael, Litzman, Jiri, Postranecka, Vera, Thon, Vojtech, Babar, Judith, Condliffe, Alison M., Exley, Andrew, Kumararatne, Dinakantha, Screaton, Nick, Jones, Alison, Bondioni, Maria P., Lougaris, Vassilio, Plebani, Alessandro, Soresina, Annarosa, Sirignano, Cesare, Spadaro, Giuseppe, Galal, Nermeen, Gonzalez-Granado, Luis I., Dettmer, Sabine, Stirling, Robert, Chapel, Helen, Lucas, Mary, Patel, Smita, Farber, Claire-Michele, Meyts, Isabelle, Banerjee, Arpan K., Hackett, Scott, Hurst, John R., Warnatz, Klau, Gathmann, Benjamin, Baumann, Ulrich, Pediatrics, Public Health, Immunology, Internal Medicine, Radiology & Nuclear Medicine, Tranzo, Scientific center for care and wellbeing, and Geestelijke Gezondheidszorg
Subjects: Male, 0301 basic medicine, Pathology, bronchiectasis, X-linked agammaglobulinemia, LARGE COHORT, Disease, Pulmonary function testing, bronchiectasi, 0302 clinical medicine, Medical microbiology, Immunology and Allergy, Child, Immunodeficiency, medicine.diagnostic_test, CVID, X-LINKED AGAMMAGLOBULINEMIA, 3. Good health, LUNG-FUNCTION, 1107 Immunology, Child, Preschool, DISEASES, Female, Life Sciences & Biomedicine, Adult, Spirometry, medicine.medical_specialty, Adolescent, Immunology, CYSTIC FIBROSIS BRONCHIECTASIS, Bronchi, COMMON VARIABLE IMMUNODEFICIENCY, Chest CT in Antibody Deficiency Group, Young Adult, 03 medical and health sciences, Chest CT, bronchial pathology, primary antibody deficiency, medicine, MANAGEMENT, Humans, COMPUTED-TOMOGRAPHY, Thoracic Wall, Aged, Science & Technology, Bronchiectasis, business.industry, Common variable immunodeficiency, Immunologic Deficiency Syndromes, Infant, PULMONARY-FUNCTION, medicine.disease, 030104 developmental biology, Tomography, X-Ray Computed, business, SCAN, 030215 immunology
Abstract: Studies of chest computed tomography (CT) in patients with primary antibody deficiency syndromes (ADS) suggest a broad range of bronchial pathology. However, there are as yet no multicentre studies to assess the variety of bronchial pathology in this patient group. One of the underlying reasons is the lack of a consensus methodology, a prerequisite to jointly document chest CT findings. We aimed to establish an international platform for the evaluation of bronchial pathology as assessed by chest CT and to describe the range of bronchial pathologies in patients with antibody deficiency. Ffteen immunodeficiency centres from 9 countries evaluated chest CT scans of patients with ADS using a predefined list of potential findings including an extent score for bronchiectasis. Data of 282 patients with ADS were collected. Patients with common variable immunodeficiency disorders (CVID) comprised the largest subgroup (232 patients, 82.3%). Eighty percent of CVID patients had radiological evidence of bronchial pathology including bronchiectasis in 61%, bronchial wall thickening in 44% and mucus plugging in 29%. Bronchiectasis was detected in 44% of CVID patients aged less than 20 years. Cough was a better predictor for bronchiectasis than spirometry values. Delay of diagnosis as well as duration of disease correlated positively with presence of bronchiectasis. The use of consensus diagnostic criteria and a pre-defined list of bronchial pathologies allows for comparison of chest CT data in multicentre studies. Our data suggest a high prevalence of bronchial pathology in CVID due to late diagnosis or duration of disease.
Published: 2019

7. Author response for 'SARS‐CoV‐2‐specific IgG1/IgG3 but not IgM in children with Pediatric Inflammatory Multi‐System Syndrome'

Author: Eslam Al-Abadi, Deepthi Jyothish, Sian E Faustini, Eleni Syrimi, Joel D. Allen, Mahboob Salim, Marisol Perez-Toledo, Alex G. Richter, Steven B. Welch, Scott Hackett, Benjamin E. Willcox, Ashish Chikermane, Hari Krishnan Kanthimathinathan, Mark T. Drayson, Kavitha Masilamani, Tonny Veenith, Barnaby R. Scholefield, Max Crispinl, Margaret Goodall, Edith Marcial-Juarez, Carrie R. Willcox, Yasunori Watanabe, Adrian M Shields, David C. Wraith, Sian E Jossi, and Adam F. Cunningham
Subjects: business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunology, Medicine, business
Published: 2021

8. A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi process

Author: Rachel Harwood, Benjamin Allin, Christine E Jones, Elizabeth Whittaker, Padmanabhan Ramnarayan, Athimalaipet V Ramanan, Musa Kaleem, Robert Tulloh, Mark J Peters, Sarah Almond, Peter J Davis, Michael Levin, Andrew Tometzki, Saul N Faust, Marian Knight, Simon Kenny, Rachel Agbeko, Octavio Aragon, Jim Baird, Alasdair Bamford, Michael Bereford, Tara Bharucha, Paul Brogan, Karina Butler, Enitan Carroll, Katrina Cathie, Ashish Chikermane, Sharon Christie, Matthew Clark, Antigoni Deri, Conor Doherty, Simon Drysdale, Phouc Duong, Saravanan Durairaj, Marieke Emonts, Jennifer Evans, James Fraser, Scott Hackett, Rosie Hague, Paul Heath, Jethro Herberg, Marina Ilina, Nicola Jay, Dominic Kelly, Caroline Kerrison, Jeannette Kraft, Alice Leahy, Mike Linney, Hermione Lyall, Liza McCann, Paddy McMaster, Owen Miller, Sean O'Riordan, Stephen Owens, Clare Pain, Sanjay Patel, Nazima Pathan, James Pauling, David Porter, Andrew Prendergast, Kumar Ravi, Andrew Riorden, Marion Roderick, Barnaby R Scholefield, Malcolm G Semple, Ethan Sen, Fiona Shackley, Ian Sinha, Shane Tibby, Stefania Verganano, Steven B Welch, Nicholas Wilkinson, Mark Wood, and Iain Yardley
Subjects: medicine.medical_specialty, Delphi method, MEDLINE, Review, Disease, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Tocilizumab, Randomized controlled trial, law, 030225 pediatrics, Interim, hemic and lymphatic diseases, Developmental and Educational Psychology, Medicine, Pediatrics, Perinatology, and Child Health, 030212 general & internal medicine, Disease management (health), Intensive care medicine, business.industry, medicine.disease, Systemic inflammatory response syndrome, chemistry, Pediatrics, Perinatology and Child Health, business
Abstract: Paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS) is a novel condition that was first reported in April, 2020. We aimed to develop a national consensus management pathway for the UK to provide guidance for clinicians caring for children with PIMS-TS. A three-phase online Delphi process and virtual consensus meeting sought consensus over the investigation, management, and research priorities from multidisciplinary clinicians caring for children with PIMS-TS. We used 140 consensus statements to derive a consensus management pathway that describes the initial investigation of children with suspected PIMS-TS, including blood markers to help determine the severity of disease, an echocardiogram, and a viral and septic screen to exclude other infectious causes of illness. The importance of a multidisciplinary team in decision making for children with PIMS-TS is highlighted throughout the guidance, along with the recommended treatment options, including supportive care, intravenous immunoglobulin, methylprednisolone, and biological therapies. These include IL-1 antagonists (eg, anakinra), IL-6 receptor blockers (eg, tocilizumab), and anti-TNF agents (eg, infliximab) for children with Kawasaki disease-like phenotype and non-specific presentations. Use of a rapid online Delphi process has made it possible to generate a national consensus pathway in a timely and cost-efficient manner in the middle of a global pandemic. The consensus statements represent the views of UK clinicians and are applicable to children in the UK suspected of having PIMS-TS. Future evidence will inform updates to this guidance, which in the interim provides a solid framework to support clinicians caring for children with PIMS-TS. This process has directly informed new PIMS-TS specific treatment groups as part of the adaptive UK RECOVERY trial protocol, which is the first formal randomised controlled trial of therapies for PIMS-TS globally.
Published: 2021

9. Short Term Respiratory Outcomes in Children with Antibody Positive PIMS -TS

Author: Deevena Chinthala, Ashish Chickermane, Ciaran McCardle, Hari Krishnan Kanthimathinathan, Chris Hine, Barnaby R. Scholefield, Scott Hackett, Eslam Al Abadi, Prasad Nagakumar, Pamela Dawson, Steven B. Welch, and Deepthi Jyothish
Subjects: Spirometry, Pediatrics, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), biology, medicine.diagnostic_test, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Intensive care unit, law.invention, Term (time), law, hemic and lymphatic diseases, Respiratory morbidity, biology.protein, medicine, Antibody, Respiratory system, business
Abstract: Paediatric multisystem inflammatory syndrome: temporally associated with SARS-COV-2 (PIMS-TS) is a well described rare but severe COVID-19 related syndrome. PIMS-TS have been reported in children from geographical areas of high COVID-19 infection. Most children with PIMS-TS require management in an intensive care unit with variable respiratory involvement. Adults recovering from COVID-19 infection have been reported to suffer from respiratory morbidity but such outcomes are unknown in children. We present the first report of normal short term respiratory outcomes as measured by spirometry in children with SARS-COV-2 antibody positive, PIMS-TS syndrome managed at a specialist children’s hospital in the UK.
Published: 2021

10. The Innate and Adaptive Immune Landscape of SARS-CoV-2-Associated Multisystem Inflammatory Syndrome in Children (MIS-C) From Acute Disease to Recovery

Author: Eanna Fennell, Sean Monaghan, Prasad Nagakumar, Paul Murray, Barnaby R. Scholefield, Steven B. Welch, Richard Stark, Naeem Khan, Deepthi Jyothish, Pamela Kearns, Alex G. Richter, Hari Krishnan Kanthimathinathan, Sascha Ott, Wioleta M. Zelek, Ashish Chikermane, Kate Davies, Eleni Syrimi, Pamela Dawson, Graham S. Taylor, Eslam Al-Abadi, Sian E Faustini, Scott Hackett, and Pavle Vrljicak
Subjects: Drug, business.industry, media_common.quotation_subject, Disease, medicine.disease, Complement system, Arginase, Immune system, Immunology, medicine, Kawasaki disease, business, CD163, CD8, media_common
Abstract: Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening disease occurring several weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Deep immune profiling showed acute MIS-C patients had highly activated neutrophils, classical monocytes and memory CD8+ T-cells; increased frequencies of B-cell plasmablasts and double-negative B-cells. Post treatment samples from the same patients, taken when symptoms were resolving, identified recovery-associated immune features including CD163+ monocytes, emergence of a new population of immature neutrophils and, in some patients, a transient increase in arginase. Plasma profiling identified multiple features shared by MIS-C, Kawasaki Disease and COVID-19 and that therapeutic inhibition of IL6 may be preferable to IL1 or TNF-a. We identified potential new mechanisms of action for IVIG, the most commonly used drug to treat MIS-C. Finally, we showed systemic complement activation with high plasma C5b-9 levels is common in MIS-C, suggesting complement inhibitors could be used to treat the disease. Funding Information: Birmingham Women’s and Children’s Hospital Charity funded the single cell RNA sequencing analysis. No other external funding was received. Declaration of Interests: None declared. Ethics Approval Statement: Reviewed and approved by South of Birmingham Research Ethics Committee (REC: 17/WM/0453, IRAS: 233593).
Published: 2021

11. The Innate and Adaptive Immune Landscape of SARS-CoV-2-Associated Multisystem Inflammatory Syndrome in Children (MIS-C) from Acute Disease to Recovery

Author: Eanna Fennell, Deepthi Jyothish, Sian E Faustini, Ashish Chikermane, Eleni Syrimi, Sean Monaghan, Richard Stark, Pamela Kearns, Pamela Dawson, Steven B. Welch, Sascha Ott, Paul Murray, Barnaby R. Scholefield, Naeem Khan, Richter Ag, Prasad Nagakumar, Scott Hackett, Pavle Vrljicak, Hari Krishnan Kanthimathinathan, Eslam Al-Abadi, and Graham S. Taylor
Subjects: education.field_of_study, biology, business.industry, Population, Inflammation, Disease, medicine.disease, Immune system, Immunopathology, Immunology, biology.protein, Medicine, Kawasaki disease, Antibody, medicine.symptom, education, business, CD163
Abstract: Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening disease occurring several weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. MIS-C has overlapping clinical features with Kawasaki Disease (KD), a rare childhood vasculitis. MIS-C therapy is largely based on KD treatment protocols but whether these diseases share underpinning immunological perturbations is unknown. We performed deep immune profiling on blood samples from healthy children and patients with MIS-C or KD. Acute MIS-C patients had highly activated neutrophils, classical monocytes and memory CD8+ T-cells; increased frequencies of B-cell plasmablasts and CD27-IgD-double-negative B-cells; and increased levels of pro-inflammatory (IL6, IL18, IP10, MCP1) but also anti-inflammatory (IL-10, IL1-RA, sTNFR1, sTNFR2) cytokines. Increased neutrophil count correlated with inflammation,cardiac dysfunction and disease severity. Two days after intravenous immunoglobulin (IVIG) treatment, MIS-C patients had increased CD163 expression on monocytes, expansion of a novel population of immature neutrophils, and decreased levels of pro- and anti-inflammatory cytokines in the blood accompanied by a transient increase in arginase in some patients. Our data show MIS-C and KD share substantial immunopathology and identify potential new mechanisms of action for IVIG, a widely used anti-inflammatory drug used to treat MIS-C, KD and other inflammatory diseases.
Published: 2021

12. Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension

Author: Emilia M. Swietlik, Daniel Greene, Na Zhu, Karyn Megy, Marcella Cogliano, Smitha Rajaram, Divya Pandya, Tobias Tilly, Katie A. Lutz, Carrie C.L. Welch, Michael W. Pauciulo, Laura Southgate, Jennifer M. Martin, Carmen M. Treacy, Christopher J. Penkett, Jonathan C. Stephens, Harm J. Bogaard, Colin Church, Gerry Coghlan, Anna W. Coleman, Robin Condliffe, Christina A. Eichstaedt, Mélanie Eyries, Henning Gall, Stefano Ghio, Barbara Girerd, Ekkehard Grünig, Simon Holden, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Jim Lordan, Rajiv D. Machado, Robert V. MacKenzie Ross, Colm McCabe, Shahin Moledina, David Montani, Horst Olschewski, Joanna Pepke-Zaba, Laura Price, Christopher J. Rhodes, Werner Seeger, Florent Soubrier, Jay Suntharalingam, Mark R. Toshner, Anton Vonk Noordegraaf, John Wharton, James M. Wild, Stephen John Wort, Allan Lawrie, Martin R. Wilkins, Richard C. Trembath, Yufeng Shen, Wendy K. Chung, Andrew J. Swift, William C. Nichols, Nicholas W. Morrell, Stefan Gräf, Stephen Abbs, Lara Abulhoul, Julian Adlard, Munaza Ahmed, Timothy J. Aitman, Hana Alachkar, David J. Allsup, Philip Ancliff, Richard Antrobus, Ruth Armstrong, Gavin Arno, Sofie Ashford, William J. Astle, Anthony Attwood, Paul Aurora, Christian Babbs, Chiara Bacchelli, Tamam Bakchoul, Siddharth Banka, Tadbir Bariana, Julian Barwell, Joana Batista, Helen E. Baxendale, Phil L. Beales, David L. Bennett, Agnieszka Bierzynska, Tina Biss, Maria A.K. Bitner-Glindzicz, Graeme C. Black, Marta Bleda, Iulia Blesneac, Detlef Bockenhauer, Sara Boyce, John R. Bradley, Gerome Breen, Paul Brennan, Carole Brewer, Matthew Brown, Andrew C. Browning, Michael J. Browning, Rachel J. Buchan, Matthew S. Buckland, Teofila Bueser, Carmen Bugarin Diz, John Burn, Siobhan O. Burns, Oliver S. Burren, Nigel Burrows, Carolyn Campbell, Gerald Carr-White, Keren Carss, Ruth Casey, Mark J. Caulfield, Jenny Chambers, John Chambers, Melanie M.Y. Chan, Floria Cheng, Patrick F. Chinnery, Manali Chitre, Martin T. Christian, Jill Clayton-Smith, Maureen Cleary, Naomi Clements Brod, Elizabeth Colby, Trevor R.P. Cole, Janine Collins, Peter W. Collins, Cecilia J. Compton, H. Terence Cook, Stuart Cook, Nichola Cooper, Paul A. Corris, Nicola S. Curry, Matthew J. Daniels, Mehul Dattani, Louise C. Daugherty, John Davis, Anthony De Soyza, Sri V.V. Deevi, Timothy Dent, Charu Deshpande, Eleanor F. Dewhurst, Peter H. Dixon, Sofia Douzgou, Kate Downes, Anna M. Drazyk, Elizabeth Drewe, Daniel Duarte, Tina Dutt, J. David M. Edgar, Karen Edwards, William Egner, Melanie N. Ekani, Perry Elliott, Wendy N. Erber, Marie Erwood, Maria C. Estiu, Dafydd Gareth Evans, Gillian Evans, Tamara Everington, Hiva Fassihi, Remi Favier, Debra Fletcher, Frances A. Flinter, R. Andres Floto, Tom Fowler, James Fox, Amy J. Frary, Courtney E. French, Kathleen Freson, Mattia Frontini, Abigail Furnell, Daniel P. Gale, Vijeya Ganesan, Michael Gattens, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Kate Gibson, Kimberly C. Gilmour, Nicholas S. Gleadall, Sarah Goddard, Keith Gomez, Pavels Gordins, David Gosal, Jodie Graham, Luigi Grassi, Lynn Greenhalgh, Andreas Greinacher, Paolo Gresele, Philip Griffiths, Sofia Grigoriadou, Detelina Grozeva, Mark Gurnell, Scott Hackett, Charaka Hadinnapola, Rosie Hague, William M. Hague, Matthias Haimel, Matthew Hall, Helen L. Hanson, Eshika Haque, Kirsty Harkness, Andrew R. Harper, Claire L. Harris, Daniel Hart, Ahamad Hassan, Grant Hayman, Alex Henderson, Archana Herwadkar, Jonathan Hoffman, Rita Horvath, Henry Houlden, Arjan C. Houweling, Fengyuan Hu, Gavin Hudson, Aarnoud P. Huissoon, Matthew Hurles, Melita Irving, Louise Izatt, Roger James, Sally A. Johnson, Stephen Jolles, Jennifer Jolley, Dragana Josifova, Neringa Jurkute, Mary A. Kasanicki, Hanadi Kazkaz, Rashid Kazmi, Peter Kelleher, Anne M Kelly, Wilf Kelsall, Carly Kempster, Nathalie Kingston, Nils Koelling, Myrto Kostadima, Ania Koziell, Roman Kreuzhuber, Taco W. Kuijpers, Ajith Kumar, Dinakantha Kumararatne, Manju A. Kurian, Michael A. Laffan, Fiona Lalloo, Michele Lambert, Hana Lango Allen, D. Mark Layton, Claire Lentaigne, Tracy Lester, Adam P. Levine, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Eleni Louka, Paul A. Lyons, Bella Madan, Eamonn R. Maher, Jesmeen Maimaris, Samantha Malka, Sarah Mangles, Rutendo Mapeta, Kevin J. Marchbank, Stephen Marks, Hugh S. Markus, Hanns-Ulrich Marschall, Andrew Marshall, Mary Mathias, Emma Matthews, Heather Maxwell, Paul McAlinden, Mark I. McCarthy, Harriet McKinney, Stuart Meacham, Adam J. Mead, Sarju G. Mehta, Michel Michaelides, Carolyn Millar, Shehla N. Mohammed, Anthony T. Moore, Monika Mozere, Keith W. Muir, Andrew D. Mumford, Andrea H. Nemeth, William G. Newman, Michael Newnham, Sadia Noorani, Paquita Nurden, Jennifer O’Sullivan, Samya Obaji, Chris Odhams, Steven Okoli, Andrea Olschewski, Kai Ren Ong, S. Helen Oram, Elizabeth Ormondroyd, Willem H. Ouwehand, Claire Palles, Sofia Papadia, Soo-Mi Park, David Parry, Smita Patel, Joan Paterson, Andrew Peacock, Simon H. Pearce, Kathelijne Peerlinck, Romina Petersen, Clarissa Pilkington, Kenneth E.S. Poole, Bethan Psaila, Angela Pyle, Richard Quinton, Shamima Rahman, Anupama Rao, F. Lucy Raymond, Paula J. Rayner-Matthews, Augusto Rendon, Tara Renton, Andrew S.C. Rice, Alex Richter, Leema Robert, Irene Roberts, Sarah J. Rose, Robert Ross-Russell, Catherine Roughley, Noemi B.A. Roy, Deborah M. Ruddy, Omid Sadeghi-Alavijeh, Moin A. Saleem, Nilesh Samani, Crina Samarghitean, Alba Sanchis-Juan, Ravishankar B. Sargur, Robert N. Sarkany, Simon Satchell, Sinisa Savic, Genevieve Sayer, John A. Sayer, Laura Scelsi, Andrew M. Schaefer, Sol Schulman, Richard Scott, Marie Scully, Claire Searle, Arjune Sen, W.A. Carrock Sewell, Denis Seyres, Neil Shah, Olga Shamardina, Susan E. Shapiro, Adam C. Shaw, Keith Sibson, Lucy Side, Ilenia Simeoni, Michael A. Simpson, Matthew C. Sims, Suthesh Sivapalaratnam, Damian Smedley, Katherine R. Smith, Kenneth G.C. Smith, Katie Snape, Nicole Soranzo, Olivera Spasic-Boskovic, Simon Staines, Emily Staples, Hannah Stark, Kathleen E. Stirrups, Alex Stuckey, Petros Syrris, R. Campbell Tait, Kate Talks, Rhea Y.Y. Tan, Jenny C. Taylor, John M. Taylor, James E. Thaventhiran, Andreas C. Themistocleous, David Thomas, Ellen Thomas, Moira J. Thomas, Patrick Thomas, Kate Thomson, Adrian J. Thrasher, Chantal Thys, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Ian P. Tomlinson, Matthew Traylor, Paul Treadaway, Salih Tuna, Ernest Turro, Philip Twiss, Tom Vale, Chris Van Geet, Natalie van Zuydam, Anthony M Vandersteen, Marta Vazquez-Lopez, Julie von Ziegenweidt, Annette Wagner, Quinten Waisfisz, Neil Walker, Suellen M. Walker, James S. Ware, Hugh Watkins, Christopher Watt, Andrew R. Webster, Lucy Wedderburn, Wei Wei, Steven B. Welch, Julie Wessels, Sarah K. Westbury, John-Paul Westwood, Deborah Whitehorn, James Whitworth, Andrew O.M. Wilkie, Catherine Williamson, Brian T. Wilson, Edwin K.S. Wong, Nicholas Wood, Yvette Wood, Christopher Geoffrey Woods, Emma R. Woodward, Austen Worth, Michael Wright, Katherine Yates, Patrick F.K. Yong, Timothy Young, Ping Yu, Patrick Yu-Wai-Man, Eliska Zlamalova, Russel Hirsch, R. James White, Marc Simon, David Badesch, Erika Rosenzweig, Charles Burger, Murali Chakinala, Thenappan Thenappan, Greg Elliott, Robert Simms, Harrison Farber, Robert Frantz, Jean Elwing, Nicholas Hill, Dunbar Ivy, James Klinger, Steven Nathan, Ronald Oudiz, Ivan Robbins, Robert Schilz, Terry Fortin, Jeffrey Wilt, Delphine Yung, Eric Austin, Ferhaan Ahmad, Nitin Bhatt, Tim Lahm, Adaani Frost, Zeenat Safdar, Zia Rehman, Robert Walter, Fernando Torres, Sahil Bakshi, Stephen Archer, Rahul Argula, Christopher Barnett, Raymond Benza, Ankit Desai, Veeranna Maddipati, University of Cambridge [UK] (CAM), Columbia University [New York], University of Sheffield [Sheffield], University of Cincinnati (UC), St George's, University of London, Vrije Universiteit Amsterdam [Amsterdam] (VU), Golden Jubilee National Hospital, Glasgow, Royal Free Hospital [London, UK], Heidelberg University Hospital [Heidelberg], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Technische Hochschule Mittelhessen - University of Applied Sciences [Giessen] (THM), Fondazione IRCCS Policlinico San Matteo, Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Universität Heidelberg [Heidelberg], Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Imperial College London, Royal Hallamshire Hospital, University of Graz, Freeman Hospital, Royal United Hospitals Bath (RUH), Great Ormond Street Hospital for Children [London] (GOSH), Royal Papworth Hospital, Cambridge Biomedical Campus, Cambridge, United Kingdom., King‘s College London, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität [Graz, Autriche], Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Swietlik, Emilia [0000-0002-4095-8489], Megy, Karyn [0000-0002-2826-3879], Tilly, Tobias [0000-0002-6762-5342], Stephens, Jonathan [0000-0003-2020-9330], Toshner, Mark [0000-0002-3969-6143], Morrell, Nicholas [0000-0001-5700-9792], Graf, Stefan [0000-0002-1315-8873], Apollo - University of Cambridge Repository, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität Graz, HAL-SU, Gestionnaire, British Heart Foundation, and The Academy of Medical Sciences
Subjects: 0301 basic medicine, Candidate gene, Cardiac & Cardiovascular Systems, genetic association studies, 030204 cardiovascular system & hematology, Biology, Bayesian inference, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, pulmonary hypertension, medicine, Family history, Gene, Genetics & Heredity, Genetics, family history, Science & Technology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Kinase insert domain receptor, computed tomography, General Medicine, Original Articles, medicine.disease, Pulmonary hypertension, Phenotype, 3. Good health, 030104 developmental biology, Cardiovascular System & Cardiology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Life Sciences & Biomedicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, vascular endothelial growth factor receptor
Abstract: Supplemental Digital Content is available in the text., Background: Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods: We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed. Results: Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions: The Bayesian inference approach allowed us to independently validate KDR, which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.
Published: 2020

13. Critical Care Course of Pediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 and Response to Immunomodulation

Author: Steven B. Welch, Alex G. Richter, Scott Hackett, Sanket Sontakke, Nicholas Richens, Heather P Duncan, Eslam Al-Abadi, Deepthi Jyothish, Hari Krishnan Kanthimathinathan, Ashish Chikermane, and Barnaby R. Scholefield
Subjects: Inotrope, medicine.medical_specialty, biology, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), medicine.medical_treatment, 030208 emergency & critical care medicine, Critical Care and Intensive Care Medicine, Myocardial function, Child health, Ferritin, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Internal medicine, Pediatrics, Perinatology and Child Health, biology.protein, Extracorporeal membrane oxygenation, Medicine, Pediatrics, Perinatology, and Child Health, Antibody, business
Abstract: We describe the critical care course of children with a novel hyperinflammatory syndrome associated with coronavirus disease 2019 (COVID-19) pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with focus on trajectory before and after immunomodulation. Overall, 10 patients who met the U.K. Royal College of Pediatrics and Child Health case definition during a 2-month study period were analyzed. All tested positive for SARS-CoV-2 IgG antibody. Although only 20% were ventilated, 100% required inotropic or vasopressor support. All children had significantly raised inflammatory markers with a median C-reactive protein of 248 (175–263) mg/L, ferritin of 1,561 (726–2,255) µg/L, and troponin-I of 723 (351–2,235) ng/L. Six patients had moderately impaired myocardial function and two had severe impairment. None needed extracorporeal membrane oxygenation. Despite severe illness only a brief period of critical care support of 3 to 5 days was required. Eight received at least one dose of intravenous immunoglobulin. Six received high-dose steroids. Clinical improvement including cardiovascular stability and reduction in inflammatory markers may have occurred with and without immunomodulation.
Published: 2020

14. Serology confirms SARS-CoV-2 infection in PCR-negative children presenting with Paediatric Inflammatory Multi-System Syndrome

Author: Steven B. Welch, Marisol Perez-Toledo, Barnaby R. Scholefield, Margaret Goodall, Adam F. Cunningham, Masilamani K, Adrian M Shields, David C. Wraith, Mark T. Drayson, Eslam Al-Abadi, Scott Hackett, Ashish Chikermane, Sian E Faustini, Hari Krishnan Kanthimathinathan, Alex G. Richter, Sian E Jossi, Yasunori Watanabe, Deepthi Jyothish, Joel D. Allen, Tonny Veenith, and Max Crispin
Subjects: biology, business.industry, SARS-CoV-2, Outbreak, Toxic shock syndrome, COVID-19, Disease, medicine.disease, Antibodies, Viral, Article, Systemic Inflammatory Response Syndrome, Serology, Immunoglobulin M, Intensive care, Immunoglobulin G, Immunology, biology.protein, medicine, Humans, Kawasaki disease, Antibody, business, Child, Viral load
Abstract: BackgroundDuring the COVID-19 outbreak, reports have surfaced of children who present with features of a multisystem inflammatory syndrome with overlapping features of Kawasaki disease and toxic shock syndrome – Paediatric Inflammatory Multisystem Syndrome-temporally associated with SARS-CoV-2 pandemic (PIMS-TS). Initial reports find that many of the children are PCR-negative for SARS-CoV-2, so it is difficult to confirm whether this syndrome is a late complication of viral infection in an age group largely spared the worst consequences of this infection, or if this syndrome reflects enhanced surveillance.MethodsChildren hospitalised for symptoms consistent with PIMS-TS between 28 April and 8 May 2020, and who were PCR-negative for SARS-CoV-2, were tested for antibodies to viral spike glycoprotein using an ELISA test.ResultsEight patients (age range 7–14 years, 63% male) fulfilled case-definition for PIMS-TS during the study period. Six of the eight patients required admission to intensive care. All patients exhibited significant IgG and IgA responses to viral spike glycoprotein. Further assessment showed that the IgG isotypes detected in children with PIMS-TS were of the IgGl and lgG3 subclasses, a distribution similar to that observed in samples from hospitalised adult COVID-19 patients. In contrast, lgG2 and lgG4 were not detected in children or adults. IgM was not detected in children, which contrasts with adult hospitalised adult COVID-19 patients of whom all had positive IgM responses.ConclusionsStrong IgG antibody responses can be detected in PCR-negative children with PIMS-TS. The low detection rate of IgM in these patients is consistent with infection having occurred weeks previously and that the syndrome onset occurs well after the control of SARS-CoV-2 viral load. This implies that the disease is largely immune-mediated. Lastly, this indicates that serology can be an appropriate diagnostic tool in select patient groups.
Published: 2020

15. Are infection control measures helpful in reducing paediatric ward infections?

Author: Yvonne Beuvink and Scott Hackett
Subjects: medicine.medical_specialty, Isolation (health care), integumentary system, business.industry, education, antibiotic stewardship, handwashing, 030501 epidemiology, infection control and prevention, Article, Cost improvement, Seasonal influenza, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Pediatrics, Perinatology and Child Health, medicine, Infection control, Antibiotic Stewardship, 0305 other medical science, Intensive care medicine, business
Abstract: As the majority of children on paediatric wards, especially in winter, have infections all paediatricians will be involved in infection control and prevention (ICP) without realising it. ICP measures include decisions on isolation of patients, which can be difficult with small numbers of cubicles. Children, who are highly infectious, have potential severe infections and those who are more at risk of developing severe infections (e.g. immunocompromised) should be isolated. Handwashing/decontamination is the central and most essential part of ICP measures. It should be actively encouraged and regularly monitored to ensure adherence. The ward layout will influence how we manage ICP. This includes placement and number of alcohol dispensers, sinks, bathrooms, equipment storage and the number of cubicles. It is also worth reviewing ward cleaning policies to assess whether these can be streamlined, potentially freeing up beds/cubicles earlier and leading to cost improvement without putting patients and staff at risk. We encourage all our staff to be fully vaccinated (including seasonal influenza vaccines and MMR). Paediatricians need to be closely involved in antibiotic stewardship and act as role models for all aspects of infection control, particularly proper handwashing.
Published: 2020

16. Characterization of the Clinical and Immunologic Phenotype and Management of 157 Individuals with 56 Distinct Heterozygous NFKB1 Mutations

Author: Tiziana Lorenzini, Manfred Fliegauf, Nils Klammer, Natalie Frede, Michele Proietti, Alla Bulashevska, Nadezhda Camacho-Ordonez, Markku Varjosalo, Matias Kinnunen, Esther de Vries, Jos W.M. van der Meer, Rohan Ameratunga, Chaim M. Roifman, Yael D. Schejter, Robin Kobbe, Timo Hautala, Faranaz Atschekzei, Reinhold E. Schmidt, Claudia Schröder, Polina Stepensky, Bella Shadur, Luis A. Pedroza, Michiel van der Flier, Mónica Martínez-Gallo, Luis Ignacio Gonzalez-Granado, Luis M. Allende, Anna Shcherbina, Natalia Kuzmenko, Victoria Zakharova, João Farela Neves, Peter Svec, Ute Fischer, Winnie Ip, Oliver Bartsch, Safa Barış, Christoph Klein, Raif Geha, Janet Chou, Mohammed Alosaimi, Lauren Weintraub, Kaan Boztug, Tatjana Hirschmugl, Maria Marluce Dos Santos Vilela, Dirk Holzinger, Maximilian Seidl, Vassilios Lougaris, Alessandro Plebani, Laia Alsina, Monica Piquer-Gibert, Angela Deyà-Martínez, Charlotte A. Slade, Asghar Aghamohammadi, Hassan Abolhassani, Lennart Hammarström, Outi Kuismin, Merja Helminen, Hana Lango Allen, James E. Thaventhiran, Alexandra F. Freeman, Matthew Cook, Shahrzad Bakhtiar, Mette Christiansen, Charlotte Cunningham-Rundles, Niraj C. Patel, William Rae, Tim Niehues, Nina Brauer, Jaana Syrjänen, Mikko R.J. Seppänen, Siobhan O. Burns, Paul Tuijnenburg, Taco W. Kuijpers, Klaus Warnatz, Bodo Grimbacher, Zoe Adhya, Hana Alachkar, Ariharan Anantharachagan, Richard Antrobus, Gururaj Arumugakani, Sofie Ashford, William J. Astle, Anthony Attwood, Chiara Bacchelli, Joana Batista, Helen E. Baxendale, Claire Bethune, Shahnaz Bibi, Marta Bleda, Barbara Boardman, Claire Booth, John R. Bradley, Gerome Breen, Matthew Brown, Michael J. Browning, Mary Brownlie, Matthew S. Buckland, Oliver S. Burren, Keren Carss, John Chambers, Anita Chandra, Naomi Clements Brod, Hayley Clifford, Nichola Cooper, Louise C. Daugherty, E.G. Davies, Sophie Davies, John Davis, Sarah Deacock, Sri V.V. Deevi, John Dempster, Lisa A. Devlin, Eleanor F. Dewhurst, Kate Downes, Elizabeth Drewe, Daniel Duarte, J. David M. Edgar, Karen Edwards, William Egner, Tariq El-Shanawany, Marie Erwood, Debra Fletcher, James Fox, Amy J. Frary, Mattia Frontini, Abigail Furnell, H. Bobby Gaspar, Rohit Ghurye, Kimberly C. Gilmour, Nicholas S. Gleadall, Sarah Goddard, Pavels Gordins, Stefan Gräf, Luigi Grassi, Daniel Greene, Sofia Grigoriadou, Scott Hackett, Rosie Hague, Matthias Haimel, Lorraine Harper, Grant Hayman, Archana Herwadkar, Fengyuan Hu, Stephen Hughes, Aarnoud P. Huissoon, Roger James, Stephen Jolles, Jennifer Jolley, Julie Jones, Yousuf Karim, Mary A. Kasanicki, Peter Kelleher, Carly Kempster, Sorena Kiani, Nathalie Kingston, Nigel Klein, Myrto Kostadima, Roman Kreuzhuber, Dinakantha Kumararatne, James Laffan, Sara E. Lear, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Paul A. Lyons, Jesmeen Maimaris, Ania Manson, Rutendo Mapeta, Jennifer Martin, Mark I. McCarthy, Elizabeth M. McDermott, Harriet McKinney, Stuart Meacham, Karyn Megy, Hazel Millar, Anoop Mistry, Valerie Morrisson, Sai H.K. Murng, Iman Nasir, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Christopher J. Penkett, Romina Petersen, Mark J. Ponsford, Waseem Qasim, Ellen Quinn, Isabella Quinti, F. Lucy Raymond, Paula J. Rayner-Matthews, Alex Richter, Nilesh Samani, Crina Samarghitean, Alba Sanchis-Juan, Ravishankar B. Sargur, Sinisa Savic, Suranjith L. Seneviratne, W.A. Carrock Sewell, Denis Seyres, Fiona Shackley, Olga Shamardina, Ilenia Simeoni, Michael A. Simpson, Kenneth G.C. Smith, Simon Staines, Emily Staples, Hannah Stark, Hans Stauss, Cathal L. Steele, Jonathan Stephens, Kathleen E. Stirrups, David Thomas, Moira J. Thomas, Patrick Thomas, Adrian J. Thrasher, Tobias Tilly, Catherine Titterton, Paul Treadaway, Salih Tuna, Ernest Turro, Rafal Urniaz, Julie von Ziegenweidt, Neil Walker, Christopher Watt, Steven B. Welch, Deborah Whitehorn, Lisa Willcocks, Nicholas Wood, Yvette Wood, Sarita Workman, Austen Worth, Katherine Yates, Nigel Yeatman, Patrick F.K. Yong, Timothy Young, Ping Yu, Eliska Zlamalova, Tranzo, Scientific center for care and wellbeing, Huisarts & Ziekenhuis, Lorenzini, Tiziana, Fliegauf, Manfred, Klammer, Nils, Frede, Natalie, Proietti, Michele, Bulashevska, Alla, Camacho-Ordonez, Nadezhda, Varjosalo, Markku, Kinnunen, Matias, de Vries, Esther, van der Meer, Jos W. M., Ameratunga, Rohan, Roifman, Chaim M., Schejter, Yael D., Kobbe, Robin, Hautala, Timo, Atschekzei, Faranaz, Schmidt, Reinhold E., Schroeder, Claudia, Stepensky, Polina, Shadur, Bella, Pedroza, Luis A., van der Flier, Michiel, Martinez-Gallo, Monica, Ignacio Gonzalez-Granado, Luis, Allende, Luis M., Shcherbina, Anna, Kuzmenko, Natalia, Zakharova, Victoria, Neves, Joao Farela, Svec, Peter, Fischer, Ute, Ip, Winnie, Bartsch, Oliver, Baris, Safa, Klein, Christoph, Geha, Raif, Chou, Janet, Alosaimi, Mohammed, Weintraub, Lauren, Boztug, Kaan, Hirschmugl, Tatjana, Dos Santos Vilela, Maria Marluce, Holzinger, Dirk, Seidl, Maximilian, Lougaris, Vassilios, Plebani, Alessandro, Alsina, Laia, Piquer-Gibert, Monica, Deya-Martinez, Angela, Slade, Charlotte A., Aghamohammadi, Asghar, Abolhassani, Hassan, Hammarstrom, Lennart, Kuismin, Outi, Helminen, Merja, Allen, Hana Lango, Thaventhiran, James E., Freeman, Alexandra F., Cook, Matthew, Bakhtiar, Shahrzad, Christiansen, Mette, Cunningham-Rundles, Charlotte, Patel, Niraj C., Rae, William, Niehues, Tim, Brauer, Nina, Syrjanen, Jaana, Seppanen, Mikko R. J., Burns, Siobhan O., Tuijnenburg, Paul, Kuijpers, Taco W., Warnatz, Klaus, Grimbacher, Bodo, Experimental Immunology, Graduate School, AII - Inflammatory diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Molecular Systems Biology, Institute of Biotechnology, University of Helsinki, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Children's Hospital, HUS Children and Adolescents, Clinicum, Department of Medicine, and Pediatric surgery
Subjects: 0301 basic medicine, Male, NF-KAPPA-B, Medizin, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Fluorescent Antibody Technique, Autoimmunity, Disease, NUCLEAR-FACTOR, Kaplan-Meier Estimate, medicine.disease_cause, Hypogammaglobulinemia, 0302 clinical medicine, NFKB1 variants and mutations, autosomal dominant inheritance, common variable immunodeficiency, reduced penetrance, variable expressivity, HDE PED, Immunology and Allergy, variants and mutations, NF-κB1-related phenotype, Immunodeficiency, IMMUNODEFICIENCY, NF-?B1-related phenotype, 1184 Genetics, developmental biology, physiology, Disease Management, Middle Aged, NF-kappa B1-related phenotype, Prognosis, Penetrance, Immunohistochemistry, Magnetic Resonance Imaging, 3. Good health, Phenotype, NFKB1 variant, Female, Haploinsufficiency, NFKB1 mutation, Adult, Heterozygote, Immunology, HAPLOINSUFFICIENCY, Article, 03 medical and health sciences, autosomal dominant, medicine, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Aged, business.industry, Common variable immunodeficiency, NF-kappa B p50 Subunit, NF-KAPPA-B1, Immune dysregulation, medicine.disease, 030104 developmental biology, Biological Variation, Population, CELLS, Mutation, Primary immunodeficiency, 3111 Biomedicine, business, Tomography, X-Ray Computed, Biomarkers, 030215 immunology
Abstract: Contains fulltext : 229571.pdf (Publisher’s version ) (Closed access) BACKGROUND: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. OBJECTIVE: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. METHODS: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. RESULTS: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. CONCLUSIONS: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.
Published: 2020

17. Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration

Author: Gavin Arno, Keren J. Carss, Sarah Hull, Ceniz Zihni, Anthony G. Robson, Alessia Fiorentino, Alison J. Hardcastle, Graham E. Holder, Michael E. Cheetham, Vincent Plagnol, Anthony T. Moore, F. Lucy Raymond, Karl Matter, Maria S. Balda, Andrew R. Webster, Graeme Black, Georgina Hall, Stuart Ingram, Rachel Gillespie, Forbes Manson, Panagiotis Sergouniotis, Chris Inglehearn, Carmel Toomes, Manir Ali, Martin McKibbin, James Poulter, Kamron Khan, Emma Lord, Andrea Nemeth, Susan Downes, Stephanie Halford, Jing Yu, Stefano Lise, Nikos Ponitkos, Michel Michaelides, Veronica van Heyningen, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Ruth Armstrong, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Maria Bitner-Glindzicz, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Natalie Canham, Jenny Carmichael, Keren Carss, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Virginia Clowes, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Charu Deshpande, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, Frances Flinter, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Neeti Ghali, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Detelina Grozeva, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Simon Holden, Muriel Holder, Susan Holder, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Jane Hurst, Roger James, Stephen Jolles, Dragana Josifova, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Melissa Lees, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Sarju Mehta, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Soo-Mi Park, Alasdair Parker, John Pasi, Chris Patch, Joan Paterson, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Julia Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Elisabeth Rosser, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Alba Sanchis-Juan, Richard Sandford, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Richard Scott, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie Vogt, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Emma Wakeling, Ivy Wanjiku, Timothy Q. Warner, Evangeline Wassmer, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Pediatric surgery, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), and Med Microbiol, Infect Dis & Infect Prev
Subjects: Male, 0301 basic medicine, Retinal degeneration, Biallelic Mutation, RHOA, PROTEIN, Eye, Medical and Health Sciences, ACTIVATION, chemistry.chemical_compound, 0302 clinical medicine, 2.1 Biological and endogenous factors, Missense mutation, Exome, Aetiology, Genetics (clinical), Genetics & Heredity, Genetics, biology, Retinal Degeneration, Cell Polarity, MOSAIC EYES, Biological Sciences, Middle Aged, Phenotype, inherited retinal dystrophy, Pedigree, UK Inherited Retinal Disease Consortium, Female, apicobasal polarity, Retinal Dystrophies, Adult, NIHR Bioresource - Rare Diseases Consortium, ARHGEF18, Genotype, Mutation, Missense, Nerve Tissue Proteins, Retina, 03 medical and health sciences, Rare Diseases, retinitis pigmentosa, Report, CRB1, Retinitis pigmentosa, medicine, Humans, Amino Acid Sequence, Eye Proteins, Eye Disease and Disorders of Vision, Alleles, Human Genome, Neurosciences, Genetic Variation, Membrane Proteins, Epithelial Cells, Retinal, CELL FEATURES, medicine.disease, NUCLEOTIDE EXCHANGE FACTOR, p114RhoGEF, 030104 developmental biology, INTEGRATIVE GENOMICS VIEWER, OKO-MEDUZY, chemistry, Mutation, MORPHOGENESIS, 030221 ophthalmology & optometry, biology.protein, Missense, rhoA GTP-Binding Protein, Rho Guanine Nucleotide Exchange Factors, Genome-Wide Association Study
Abstract: Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts of affected individuals revealed biallelic mutations in ARHGEF18 in three such individuals. ARHGEF18 encodes ARHGEF18, a guanine nucleotide exchange factor that activates RHOA, a small GTPase protein that is a key component of tight junctions and adherens junctions. This biological pathway is known to be important for retinal development and function, as mutation of CRB1, encoding another component, causes retinal dystrophy. The retinal structure in individuals with ARHGEF18 mutations resembled that seen in subjects with CRB1 mutations. Five mutations were found on six alleles in the three individuals: c.808A>G (p.Thr270Ala), c.1617+5G>A (p.Asp540Glyfs ∗ 63), c.1996C>T (p.Arg666 ∗ ), c.2632G>T (p.Glu878 ∗ ), and c.2738_2761del (p.Arg913_Glu920del). Functional tests suggest that each disease genotype might retain some ARHGEF18 activity, such that the phenotype described here is not the consequence of nullizygosity. In particular, the p.Thr270Ala missense variant affects a highly conserved residue in the DBL homology domain, which is required for the interaction and activation of RHOA. Previously, knock-out of Arhgef18 in the medaka fish has been shown to cause larval lethality which is preceded by retinal defects that resemble those seen in zebrafish Crumbs complex knock-outs. The findings described here emphasize the peculiar sensitivity of the retina to perturbations of this pathway, which is highlighted as a target for potential therapeutic strategies.
Published: 2017

18. Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Author: Keren J. Carss, Gavin Arno, Marie Erwood, Jonathan Stephens, Alba Sanchis-Juan, Sarah Hull, Karyn Megy, Detelina Grozeva, Eleanor Dewhurst, Samantha Malka, Vincent Plagnol, Christopher Penkett, Kathleen Stirrups, Roberta Rizzo, Genevieve Wright, Dragana Josifova, Maria Bitner-Glindzicz, Richard H. Scott, Emma Clement, Louise Allen, Ruth Armstrong, Angela F. Brady, Jenny Carmichael, Manali Chitre, Robert H.H. Henderson, Jane Hurst, Robert E. MacLaren, Elaine Murphy, Joan Paterson, Elisabeth Rosser, Dorothy A. Thompson, Emma Wakeling, Willem H. Ouwehand, Michel Michaelides, Anthony T. Moore, Andrew R. Webster, F. Lucy Raymond, Timothy Aitman, Hana Alachkar, Sonia Ali, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Natalie Canham, Keren Carss, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Colin Church, Naomi Clements-Brod, Virginia Clowes, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Charu Deshpande, Lisa Devlin, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, Frances Flinter, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Neeti Ghali, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Simon Holden, Muriel Holder, Susan Holder, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Melissa Lees, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Sarju Mehta, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Sofia Papadia, Soo-Mi Park, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Julia Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Richard Sandford, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Richard Scott, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie Vogt, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Evangeline Wassmer, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Pediatric surgery, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), Rue-Albrecht, K, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis, Biochemie, Raymond, Lucy [0000-0003-2652-3355], Apollo - University of Cambridge Repository, Vascular Medicine, and Paediatric Infectious Diseases / Rheumatology / Immunology
Subjects: 0301 basic medicine, Male, DNA Mutational Analysis, EXOME, PROTEIN, Eye, whole-genome sequence, NIHR-BioResource Rare Diseases Consortium, Medical and Health Sciences, Choroideremia, ACTIVATION, 0302 clinical medicine, Ethnicity, 2.1 Biological and endogenous factors, Exome, rare sequence variant, Copy-number variation, Aetiology, MUTATION, Genetics (clinical), Exome sequencing, Genetics & Heredity, Genetics, Genome, Adaptor Proteins, Biological Sciences, DYSTROPHY, copy-number variants, Female, Human, Common disease-common variant, LEBER CONGENITAL AMAUROSIS, Ethnic Groups, Genes, Recessive, Biology, DIAGNOSIS, Article, 03 medical and health sciences, Rare Diseases, Retinal Diseases, STARGARDT DISEASE, Clinical Research, REVEALS, Journal Article, medicine, Recessive, Humans, retinal dystrophy, Eye Disease and Disorders of Vision, Alleles, Adaptor Proteins, Signal Transducing, Whole genome sequencing, Base Sequence, Genome, Human, Human Genome, Signal Transducing, Neurosciences, Genetic Variation, medicine.disease, GENE, Introns, Stargardt disease, Good Health and Well Being, 030104 developmental biology, Genes, Mutation, 030221 ophthalmology & optometry, Human genome
Abstract: Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.
Published: 2017

19. Correction to: Imaging of Bronchial Pathology in Antibody Deficiency: Data from the European Chest CT Group

Author: Ieneke Hartmann, Goffredo Serra, Jamanda Haddock, Isabella Quinti, Scott Hackett, Diana Alecsandru, Annemarie Bruining, Katharina Schütz, Judith Babar, Alison Jones, Daniel Berthold, M Lucas, Giuseppe Spadaro, Ulrich Baumann, Vassilios Lougaris, Smita Y. Patel, Robert G Stirling, Annarosa Soresina, Nicholas Screaton, Helen Chapel, Claire Michele Farber, Nermeen Galal, Benjamin Gathmann, Arpan K. Banerjee, Dinakantha S. Kumararatne, Klaus Warnatz, Isabelle Meyts, Alison M. Condliffe, Milica Mitrevski, Peter Kelleher, Bodo Grimbacher, Cinzia Milito, Jiri Litzman, Esther de Vries, Vera Postranecka, Alessandro Plebani, Peter M. van Hagen, Vojtech Thon, John R. Hurst, Gertjan J. Driessen, Andrew Exley, Francesco Fraioli, Cesare Sirignano, Sabine Dettmer, Maria Pia Bondioni, Michael R. Loebinger, Jürgen Weidemann, Luis Ignacio Gonzalez-Granado, Schütz, Katharina, Alecsandru, Diana, Grimbacher, Bodo, Haddock, Jamanda, Bruining, Annemarie, Driessen, Gertjan, de Vries, Esther, M van Hagen, Peter, Hartmann, Ieneke, Fraioli, Francesco, Milito, Cinzia, Mitrevski, Milica, Quinti, Isabella, Serra, Goffredo, Kelleher, Peter, Loebinger, Michael, Litzman, Jiri, Postranecka, Vera, Thon, Vojtech, Babar, Judith, M Condliffe, Alison, Exley, Andrew, Kumararatne, Dinakantha, Screaton, Nick, Jones, Alison, P Bondioni, Maria, Lougaris, Vassilio, Plebani, Alessandro, Soresina, Annarosa, Sirignano, Cesare, Spadaro, Giuseppe, Galal, Nermeen, I Gonzalez-Granado, Lui, Dettmer, Sabine, Stirling, Robert, Chapel, Helen, Lucas, Mary, Patel, Smita, Farber, Claire-Michele, Meyts, Isabelle, K Banerjee, Arpan, Hackett, Scott, R Hurst, John, Warnatz, Klau, Gathmann, Benjamin, Weidemann, Jürgen, Berthold, Daniel, and Baumann, Ulrich
Subjects: Antibody deficiency, medicine.medical_specialty, business.industry, Immunology, medicine, MEDLINE, Chest ct, Immunology and Allergy, Radiology, business
Abstract: In the original version of this article unfortunately two authors were missing: Dr. Jurgen Weidemann and Dr. Daniel Berthold. The correct list of authors is presented above.
Published: 2019

20. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author: Kathleen M. Gorman, Esther Meyer, Detelina Grozeva, Egidio Spinelli, Amy McTague, Alba Sanchis-Juan, Keren J. Carss, Emily Bryant, Adi Reich, Amy L. Schneider, Ronit M. Pressler, Michael A. Simpson, Geoff D. Debelle, Evangeline Wassmer, Jenny Morton, Diana Sieciechowicz, Eric Jan-Kamsteeg, Alex R. Paciorkowski, Mary D. King, J. Helen Cross, Annapurna Poduri, Heather C. Mefford, Ingrid E. Scheffer, Tobias B. Haack, Gary McCullagh, John J. Millichap, Gemma L. Carvill, Jill Clayton-Smith, Eamonn R. Maher, F. Lucy Raymond, Manju A. Kurian, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Siddharth Banka, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Saeed Al Turki, Carl Anderson, Richard Anney, Dinu Antony, Maria Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Lu Chen, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Aaron Day-Williams, Ian N.M. Day, Thomas Down, Yuanping Du, Ian Dunham, Sarah Edkins, Peter Ellis, David Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David R. Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Matthias Geihs, Daniel Geschwind, Heather Griffin, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Bryan Howie, Liren Huang, Tim Hubbard, Steve E. Humphries, Pirro Hysi, David K. Jackson, Yalda Jamshidi, Tian Jing, Chris Joyce, Jane Kaye, Thomas Keane, Julia Keogh, John Kemp, Karen Kennedy, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Yingrui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Iotchkova, Daniel MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Peter McGuffin, Andrew McIntosh, Andrew G. McKechanie, Andrew McQuillin, Sarah Metrustry, Hannah Mitchison, Alireza Moayyeri, James Morris, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O'Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Olli Pietilainen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Karola Rehnström, Susan Ring, Graham R.S. Ritchie, Nicola Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, So-Youn Shin, David Skuse, Kerrin Small, Lorraine Southam, Olivera Spasic-Boskovic, David St Clair, Jim Stalker, Elizabeth Stevens, Beate St Pourcian, Jianping Sun, Jaana Suvisaari, Ionna Tachmazidou, Martin D. Tobin, Ana Valdes, Margriet Van Kogelenberg, Peter M. Visscher, Louise V. Wain, James T.R. Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Elanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Kim Wong, ChangJiang Xu, Jian Yang, Fend Zhang, Pingbo Zhang, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gavin Arno, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Jenny Carmichael, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Pediatric surgery, APH - Aging & Later Life, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and APH - Quality of Care
Subjects: 0301 basic medicine, Male, Adolescent, Loss of Heterozygosity, Context (language use), Postnatal microcephaly, Neurotransmission, medicine.disease_cause, Bioinformatics, Synaptic Transmission, Loss of heterozygosity, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Calcium Channels, N-Type, Report, Genetics, medicine, Humans, Child, Genetics (clinical), Mutation, Dyskinesias, business.industry, Infant, medicine.disease, Hypotonia, Pedigree, 030104 developmental biology, Dyskinesia, Child, Preschool, Calcium, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: © 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.
Published: 2018

21. Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis and intestinal inflammation

Author: Scott Hackett, Daniela Siegmund, Sergey Nejentsev, Delphine Cuchet-Lourenço, Changxin Wu, Emma Goss, Harald Wajant, Chris M. Bacon, Miguel B. Gaspar, Mofareh AlZahrani, Peter D. Arkwright, Ali Alisaac, Rainer Doffinger, Olivier Papapietro, Lourdes Ceron-Gutierrez, Davide Eletto, Dinakantha S. Kumararatne, Vincent Plagnol, Eman AlIdrissi, Badr AlSaleem, Mario Abinun, Mailis Maes, James Curtis, Cuchet-Lourenço, Delphine [0000-0002-9501-6122], Eletto, Davide [0000-0002-2650-1968], Plagnol, Vincent [0000-0002-5597-9215], Papapietro, Olivier [0000-0001-5072-5235], Bacon, Chris M [0000-0002-8268-2812], Alsaleem, Badr [0000-0003-3348-4550], Maes, Mailis [0000-0002-0266-6557], Alisaac, Ali [0000-0003-1463-4488], Goss, Emma [0000-0002-5277-4249], AlIdrissi, Eman [0000-0003-2462-3571], Wajant, Harald [0000-0002-2005-3949], Kumararatne, Dinakantha [0000-0001-8438-4686], Arkwright, Peter D [0000-0002-7411-5375], Abinun, Mario [0000-0002-7050-3565], Doffinger, Rainer [0000-0002-9841-3617], Nejentsev, Sergey [0000-0002-7528-4461], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Male, Severe Combined Immunodeficiency/genetics, Necroptosis, medicine.medical_treatment, Arthritis, Inflammation, 03 medical and health sciences, RIPK1, Immune system, Lymphopenia, Lymphopenia/genetics, medicine, Humans, Immunodeficiency, Alleles, Fibroblasts/metabolism, Inflammatory Bowel Diseases/genetics, Multidisciplinary, business.industry, Cytokines/metabolism, Fibroblasts, Receptor-Interacting Protein Serine-Threonine Kinases/genetics, Inflammatory Bowel Diseases, medicine.disease, 3. Good health, Pedigree, 030104 developmental biology, Cytokine, Receptor-Interacting Protein Serine-Threonine Kinases, Immunology, Cytokines, Severe Combined Immunodeficiency, Cytokine secretion, Female, Arthritis/genetics, Mitogen-Activated Protein Kinases, medicine.symptom, business, Mitogen-Activated Protein Kinases/metabolism
Abstract: Humans as models of human disease Mice are a convenient model for exploring the functions of cellular signaling pathways. Occasionally, however, an “experiment of nature” highlights the perils of overreliance on mice. RIPK1 is a well studied protein kinase that regulates cell death. Mice deficient in RIPK1 die soon after birth because of the protein's widespread role in multiple tissues and organs. Cuchet-Lourenço et al. studied patients with inherited immunodeficiency of unknown cause (see the Perspective by Pasparakis and Kelliher). They identified inactivating mutations in the RIPK1 gene in four individuals. Unlike what has been seen in mice, the deleterious effects of RIPK1 loss in humans were confined to the immune system, a finding with potential therapeutic implications. Science , this issue p. 810 ; see also p. 756
Published: 2018

22. De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures

Author: Yoko Ito, Keren J. Carss, Sofia T. Duarte, Taila Hartley, Boris Keren, Manju A. Kurian, Isabelle Marey, Perinne Charles, Carla Mendonça, Caroline Nava, Rolph Pfundt, Alba Sanchis-Juan, Hans van Bokhoven, Anthony van Essen, Conny van Ravenswaaij-Arts, Kym M. Boycott, Kristin D. Kernohan, Sarah Dyack, F. Lucy Raymond, Timothy Aitman, David Bennett, Mark Caulfield, Patrick Chinnery, Daniel Gale, Ania Koziell, Taco W. Kuijpers, Michael A. Laffan, Eamonn Maher, Hugh S. Markus, Nicholas W. Morrell, Willem H. Ouwehand, David J. Perry, Irene Roberts, Kenneth G.C. Smith, Adrian Thrasher, Hugh Watkins, Catherine Williamson, Geoffrey Woods, Sofie Ashford, John R. Bradley, Debra Fletcher, Tracey Hammerton, Roger James, Nathalie Kingston, Christopher J. Penkett, Kathleen Stirrups, Marijke Veltman, Tim Young, Matthew Brown, Naomi Clements-Brod, John Davis, Eleanor Dewhurst, Helen Dolling, Marie Erwood, Amy Frary, Rachel Linger, Jennifer M. Martin, Sofia Papadia, Karola Rehnstrom, Hannah Stark, David Allsup, Steve Austin, Tamam Bakchoul, Tadbir K. Bariana, Paula Bolton-Maggs, Elizabeth Chalmers, Janine Collins, Peter Collins, Wendy N. Erber, Tamara Everington, Remi Favier, Kathleen Freson, Bruce Furie, Michael Gattens, Johanna Gebhart, Keith Gomez, Daniel Greene, Andreas Greinacher, Paolo Gresele, Daniel Hart, Johan W.M. Heemskerk, Yvonne Henskens, Rashid Kazmi, David Keeling, Anne M. Kelly, Michele P. Lambert, Claire Lentaigne, Ri Liesner, Mike Makris, Sarah Mangles, Mary Mathias, Carolyn M. Millar, Andrew Mumford, Paquita Nurden, Jeanette Payne, John Pasi, Kathelijne Peerlinck, Shoshana Revel-Vilk, Michael Richards, Matthew Rondina, Catherine Roughley, Sol Schulman, Harald Schulze, Marie Scully, Suthesh Sivapalaratnam, Matthew Stubbs, R. Campbell Tait, Kate Talks, Jecko Thachil, Cheng-Hock Toh, Ernest Turro, Chris Van Geet, Minka De Vries, Timothy Q. Warner, Henry Watson, Sarah Westbury, Abigail Furnell, Rutendo Mapeta, Paula Rayner-Matthews, Ilenia Simeoni, Simon Staines, Jonathan Stephens, Christopher Watt, Deborah Whitehorn, Antony Attwood, Louise Daugherty, Sri V.V. Deevi, Csaba Halmagyi, Fengyuan Hu, Vera Matser, Stuart Meacham, Karyn Megy, Olga Shamardina, Catherine Titterton, Salih Tuna, Ping Yu, Julie von Ziegenweldt, William Astle, Marta Bleda, Stefan Gräf, Matthias Haimel, Hana Lango-Allen, Sylvia Richardson, Paul Calleja, Stuart Rankin, Wojciech Turek, Julie Anderson, Christine Bryson, Jenny Carmichael, Coleen McJannet, Sophie Stock, Louise Allen, Gautum Ambegaonkar, Ruth Armstrong, Gavin Arno, Maria Bitner-Glindzicz, Angie Brady, Natalie Canham, Manali Chitre, Emma Clement, Virginia Clowes, Patrick Deegan, Charu Deshpande, Rainer Doffinger, Helen Firth, Frances Flinter, Courtney French, Alice Gardham, Neeti Ghali, Paul Gissen, Detelina Grozeva, Robert Henderson, Anke Hensiek, Simon Holden, Muriel Holder, Susan Holder, Jane Hurst, Dragana Josifova, Deepa Krishnakumar, Melissa Lees, Robert MacLaren, Anna Maw, Sarju Mehta, Michel Michaelides, Anthony Moore, Elaine Murphy, Soo-Mi Park, Alasdair Parker, Chris Patch, Joan Paterson, Julia Rankin, Evan Reid, Elisabeth Rosser, Richard Sandford, Saikat Santra, Richard Scott, Aman Sohal, Penelope Stein, Ellen Thomas, Dorothy Thompson, Marc Tischkowitz, Julie Vogt, Emma Wakeling, Evangeline Wassmer, Andrew Webster, Sonia Ali, Souad Ali, Harm J. Boggard, Colin Church, Gerry Coghlan, Victoria Cookson, Paul A. Corris, Amanda Creaser-Myers, Rosa DaCosta, Natalie Dormand, Mélanie Eyries, Henning Gall, Pavandeep K. Ghataorhe, Stefano Ghio, Ardi Ghofrani, J. Simon R. Gibbs, Barbara Girerd, Alan Greenhalgh, Charaka Hadinnapola, Arjan C. Houweling, Marc Humbert, Anna Huis in’t Veld, Fiona Kennedy, David G. Kiely, Gabor Kovacs, Allan Lawrie, Rob V. Mackenzie Ross, Rajiv Machado, Larahmie Masati, Sharon Meehan, Shahin Moledina, David Montani, Shokri Othman, Andrew J. Peacock, Joanna Pepke-Zaba, Val Pollock, Gary Polwarth, Lavanya Ranganathan, Christopher J. Rhodes, Kevin Rue-Albrecht, Gwen Schotte, Debbie Shipley, Florent Soubrier, Laura Southgate, Laura Scelsi, Jay Suntharalingam, Yvonne Tan, Mark Toshner, Carmen M. Treacy, Richard Trembath, Anton Vonk Noordegraaf, Sara Walker, Ivy Wanjiku, John Wharton, Martin Wilkins, Stephen J. Wort, Katherine Yates, Hana Alachkar, Richard Antrobus, Gururaj Arumugakani, Chiara Bacchelli, Helen Baxendale, Claire Bethune, Shahnaz Bibi, Claire Booth, Michael Browning, Siobhan Burns, Anita Chandra, Nichola Cooper, Sophie Davies, Lisa Devlin, Elizabeth Drewe, David Edgar, William Egner, Rohit Ghurye, Kimberley Gilmour, Sarah Goddard, Pavel Gordins, Sofia Grigoriadou, Scott Hackett, Rosie Hague, Lorraine Harper, Grant Hayman, Archana Herwadkar, Aarnoud Huissoon, Stephen Jolles, Peter Kelleher, Dinakantha Kumararatne, Sara Lear, Hilary Longhurst, Lorena Lorenzo, Jesmeen Maimaris, Ania Manson, Elizabeth McDermott, Sai Murng, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Mark Ponsford, Waseem Qasim, Isabella Quinti, Alex Richter, Crina Samarghitean, Ravishankar Sargur, Sinisa Savic, Suranjith Seneviratne, Carrock Sewell, Emily Staples, Hans Stauss, James Thaventhiran, Moira Thomas, Steve Welch, Lisa Willcocks, Nigel Yeatman, Patrick Yong, Phil Ancliff, Christian Babbs, Mark Layton, Eleni Louka, Simon McGowan, Adam Mead, Noémi Roy, Jenny Chambers, Peter Dixon, Cecelia Estiu, Bill Hague, Hanns-Ulrich Marschall, Michael Simpson, Sam Chong, Ingrid Emmerson, Lionel Ginsberg, David Gosal, Rob Hadden, Rita Horvath, Mohamed Mahdi-Rogers, Adnan Manzur, Andrew Marshall, Emma Matthews, Mark McCarthy, Mary Reilly, Tara Renton, Andrew Rice, Andreas Themistocleous, Tom Vale, Natalie Van Zuydam, Suellen Walker, Liz Ormondroyd, Gavin Hudson, Wei Wei, Patrick Yu Wai Man, James Whitworth, Maryam Afzal, Elizabeth Colby, Moin Saleem, Omid S. Alavijeh, H. Terry Cook, Sally Johnson, Adam P. Levine, Edwin K.S. Wong, Rhea Tan, Alex MacKenzie, Jacek Majewski, Michael Brudno, Dennis Bulman, David Dyment, Freson, Kathleen, Peerlinck, Kathelijne, Van Geet, Christel, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, Medical Research Council (MRC), Clinical Cognitive Neuropsychiatry Research Program (CCNP), APH - Aging & Later Life, Pediatric surgery, Human genetics, ACS - Atherosclerosis & ischemic syndromes, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, and Molecular cell biology and Immunology
Subjects: 0301 basic medicine, Male, Care4Rare Canada Consortium, WAVE FAMILY PROTEINS, actin cytoskeleton, PROTEIN, HDE NEU PED, medicine.disease_cause, Whole Exome Sequencing, 0302 clinical medicine, Neurodevelopmental disorder, SYNAPTIC PLASTICITY, Intellectual disability, WAVE1 complex, PLASTICITY, EXCHANGE, 11 Medical and Health Sciences, Exome sequencing, Genetics (clinical), seizures, Genetics & Heredity, Genetics, Mutation, WASF1, DENDRITIC SPINES, developmental delay, Female, DISEASE GENE-DISCOVERY, Adult, Heterozygote, GENES, DISORDERS, autism, Biology, ACTIN, 03 medical and health sciences, Young Adult, Seizures, Report, Intellectual Disability, Exome Sequencing, medicine, Humans, PROTRUSIONS, recurrent de novo truncating mutations, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], COMPLEX, lamellipodia, neurodevelopmental disorder, Actin remodeling, Heterozygote advantage, NIHR BioResource, 06 Biological Sciences, medicine.disease, Actin cytoskeleton, Wiskott-Aldrich Syndrome Protein Family, 030104 developmental biology, WAVE, RETARDATION, 030217 neurology & neurosurgery
Abstract: Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:103 issue:1 pages:144-153 ispartof: location:United States status: published
Published: 2018

23. Spectrum and Management of Complement Immunodeficiencies (Excluding Hereditary Angioedema) Across Europe

Author: C. Bangs, Helen Baxendale, Andrew J. Turley, Jiří Litzman, Suranjith L. Seneviratne, Scott Hackett, Pavlína Králíčková, Markus G. Seidel, G Dueckers, Hana Alachkar, Benjamin Gathmann, Sophie Hambleton, Peter D. Arkwright, Necil Kutukculer, Joachim Roesler, László Maródi, Aarnoud Huissoon, Henrike Ritterbusch, M. Bradbury, and Luis Ignacio Gonzalez-Granado
Subjects: Adult, Male, Adolescent, Databases, Factual, Genotype, Immunology, Consanguinity, Young Adult, Atypical hemolytic uremic syndrome, medicine, Humans, Immunology and Allergy, Child, Complement Activation, Immunodeficiency, Aged, Mannan-binding lectin, business.industry, Immunologic Deficiency Syndromes, Disease Management, Infant, Complement System Proteins, Middle Aged, medicine.disease, Complement system, Complement (complexity), Europe, Child, Preschool, Hereditary angioedema, Female, business
Abstract: Complement immunodeficiencies (excluding hereditary angioedema and mannose binding lectin deficiency) are rare. Published literature consists largely of case reports and small series. We collated data from 18 cities across Europe to provide an overview of primarily homozygous, rather than partial genotypes and their impact and management.Patients were recruited through the ESID registry. Clinical and laboratory information was collected onto standardized forms and analyzed using SPSS software.Seventy-seven patients aged 1 to 68 years were identified. 44 % presented in their first decade of life. 29 % had C2 deficiency, defects in 11 other complement factors were found. 50 (65 %) had serious invasive infections. 61 % of Neisseria meningitidis infections occurred in patients with terminal pathway defects, while 74 % of Streptococcus pneumoniae infections occurred in patients with classical pathway defects (p 0.001). Physicians in the UK were more likely to prescribe antibiotic prophylaxis than colleagues on the Continent for patients with classical pathway defects. After diagnosis, 16 % of patients suffered serious bacterial infections. Age of the patient and use of prophylactic antibiotics were not associated with subsequent infection risk. Inflammatory/autoimmune diseases were not seen in patients with terminal pathway, but in one third of patients classical and alternative pathway defects.The clinical phenotypes of specific complement immunodeficiencies vary considerably both in terms of the predominant bacterial pathogen, and the risk and type of auto-inflammatory disease. Appreciation of these phenotypic differences should help both immunologists and other specialists in their diagnosis and management of these rare and complex patients.
Published: 2015

24. Duration of intravenous antibiotic therapy for children with acute osteomyelitis or septic arthritis:a feasibility study

Author: Priya Sukhtankar, Hans de Graaf, Carrol Gamble, Delane Shingadia, Philip Henman, Catherine Spowart, Kate Armon, Nusreen Ahmad, Paula R Williamson, A. Pallett, Barbara Arch, Saul N. Faust, Marieke Emonts, Scott Hackett, Helen Hickey, Annmarie Jeanes, Adam Finn, Stuart C. Clarke, Amanda Lees, Peter Marsh, Mike Sharland, Claire Ballinger, Andrew J. Pollard, Andrew Riordan, Abigail Bennett, Colin Powell, Jethro Herberg, and Nicholas Clarke
Subjects: Parents, Pediatrics, medicine.medical_treatment, law.invention, 0807 Library And Information Studies, 0302 clinical medicine, Randomized controlled trial, law, Epidemiology, 030212 general & internal medicine, Prospective Studies, REAL-TIME PCR, Prospective cohort study, Child, KINGELLA-KINGAE, Health Policy, RESISTANT STAPHYLOCOCCUS-AUREUS, Osteomyelitis, C-REACTIVE PROTEIN, 3. Good health, Anti-Bacterial Agents, 1117 Public Health And Health Services, lcsh:R855-855.5, Child, Preschool, Acute Disease, Health Policy & Services, Administration, Intravenous, Life Sciences & Biomedicine, Cohort study, Research Article, medicine.medical_specialty, lcsh:Medical technology, Adolescent, SKELETAL INFECTIONS, ERYTHROCYTE SEDIMENTATION-RATE, ACUTE HEMATOGENOUS OSTEOMYELITIS, 03 medical and health sciences, 030225 pediatrics, medicine, Humans, Arthritis, Infectious, Science & Technology, business.industry, Infant, medicine.disease, R1, United Kingdom, Clinical trial, Health Care Sciences & Services, PEDIATRIC PATHOGEN, Intravenous therapy, 0806 Information Systems, Feasibility Studies, Septic arthritis, KINGAE OSTEOARTICULAR INFECTIONS, JOINT INFECTIONS, business
Abstract: BackgroundThere is little current consensus regarding the route or duration of antibiotic treatment for acute osteomyelitis (OM) and septic arthritis (SA) in children.ObjectiveTo assess the overall feasibility and inform the design of a future randomised controlled trial (RCT) to reduce the duration of intravenous (i.v.) antibiotic use in paediatric OM and SA.Design(1) A prospective service evaluation (cohort study) to determine the current disease spectrum and UK clinical practice in paediatric OM/SA; (2) a prospective cohort substudy to assess the use of targeted polymerase chain reaction (PCR) in diagnosing paediatric OM/SA; (3) a qualitative study to explore families’ views and experiences of OM/SA; and (4) the development of a core outcome set via a systematic review of literature, Delphi clinician survey and stakeholder consensus meeting.SettingForty-four UK secondary and tertiary UK centres (service evaluation).ParticipantsChildren with OM/SA.InterventionsPCR diagnostics were compared with culture as standard of care. Semistructured interviews were used in the qualitative study.ResultsData were obtained on 313 cases of OM/SA, of which 218 (61.2%) were defined as simple disease and 95 (26.7%) were defined as complex disease. The epidemiology of paediatric OM/SA in this study was consistent with existing European data. Children who met oral switch criteria less than 7 days from starting i.v. antibiotics were less likely to experience treatment failure (9.6%) than children who met oral switch criteria after 7 days of i.v. therapy (16.1% when switch was between 1 and 2 weeks; 18.2% when switch was > 2 weeks). In 24 out of 32 simple cases (75%) and 8 out of 12 complex cases (67%) in which the targeted PCR was used, a pathogen was detected. The qualitative study demonstrated the importance to parents and children of consideration of short- and long-term outcomes meaningful to families themselves. The consensus meeting agreed on the following outcomes: rehospitalisation or recurrence of symptoms while on oral antibiotics, recurrence of infection, disability at follow-up, symptom free at 1 year, limb shortening or deformity, chronic OM or arthritis, amputation or fasciotomy, death, need for paediatric intensive care, and line infection. Oral switch criteria were identified, including resolution of fever for ≥ 48 hours, tolerating oral food and medicines, and pain improvement.LimitationsData were collected in a 6-month period, which might not have been representative, and follow-up data for long-term complications are limited.ConclusionsA future RCT would need to recruit from all tertiary and most secondary UK hospitals. Clinicians have implemented early oral switch for selected patients with simple disease without formal clinical trial evidence of safety. However, the current criteria by which decisions to make the oral switch are made are not clearly established or evidence based.Future workA RCT in simple OM and SA comparing shorter- or longer-course i.v. therapy is feasible in children randomised after oral switch criteria are met after 7 days of i.v. therapy, excluding children meeting oral switch criteria in the first week of i.v. therapy. This study design meets clinician preferences and addresses parental concerns not to randomise prior to oral switch criteria being met.FundingThe National Institute for Health Research Health Technology Assessment programme.
Published: 2017

25. Systemic reactions and anaphylaxis with an acute serum tryptase ≥14 μg/L: retrospective characterisation of aetiology, severity and adherence to National Institute of Health and Care Excellence (NICE) guidelines for serial tryptase measurements and specialist referral

Author: Aarnoud Huissoon, Matthew Cooke, Scott Hackett, Susan Dorrian, Sapna Srivastava, Victoria Barrett, and Mamidipudi Thirumala Krishna
Subjects: Adult, Male, Clinical audit, Pediatrics, medicine.medical_specialty, Allergy, Time Factors, Tryptase, Severity of Illness Index, Pathology and Forensic Medicine, Predictive Value of Tests, Risk Factors, medicine, Humans, Anaphylaxis, Referral and Consultation, Aged, Retrospective Studies, Medical Audit, biology, business.industry, General Medicine, Guideline, Emergency department, Clinical Enzyme Tests, Middle Aged, medicine.disease, United Kingdom, Up-Regulation, Practice Guidelines as Topic, Cohort, biology.protein, Etiology, Female, Tryptases, Guideline Adherence, business, Biomarkers
Abstract: AIMS To characterise patients with systemic reactions and anaphylaxis with an acute serum tryptase of ≥14 μg/L against recently published World Allergy Organisation (WAO) diagnostic criteria. To also perform a clinical audit to assess adherence to National Institute of Health and Care Excellence (NICE) guideline recommendations regarding serial tryptase measurements and specialist referral. METHODS A systematic retrospective survey (2006-2010) was carried out (n=171; males=86; mean age±SD 48±20 years) and data were extracted from emergency department and specialist allergy clinic records. RESULTS 34 patients (20%) had a grade 1 reaction, 61 (36%) grade 2, 46 (27%) grade 3 and 6 patients (4%) grade 4 (24 patients (13%) could not be graded due to lack of adequate clinical details) and 6% developed a biphasic response. Serial tryptase measurements were not available in 117 (69%) of the cohort. 97 (57%) patients were referred for specialist assessment, and 72 (74%) attended. 50% of cases were diagnosed with idiopathic systemic reactions/anaphylaxis and 28%, 14% and 8% triggered by drugs, foods and other allergies including disorders of mast cell overload, respectively. A weak positive correlation was detected between acute serum tryptase and severity. CONCLUSIONS The correlation between acute serum tryptase and severity of anaphylaxis/systemic reactions is weak. A significant proportion of patients with raised acute serum tryptase had mild reactions which did not meet WAO criteria for anaphylaxis and this may reduce the specificity of the test. The commonest aetiology in this cohort was idiopathic followed by drug and food allergies. NICE guidelines relating to serial tryptase measurements and specialist referral were not followed, and there is an urgent need to raise the awareness among clinicians involved in the management of anaphylaxis.
Published: 2014

26. Republished: Immune deficiencies in children: an overview

Author: S Jyothi, S Welch, S Lissauer, and Scott Hackett
Subjects: medicine.medical_specialty, Pediatrics, Immune system, business.industry, Infectious disease (medical specialty), Epidemiology, medicine, Signs and symptoms, General Medicine, Malignancy, medicine.disease, business, Stepwise approach
Abstract: Primary immune deficiencies (PIDs) are disorders of the immune system that result in increased susceptibility to infectious disease, autoimmunity and malignancy. They are challenging to paediatricians as they can present anytime from birth to adolescence with a wide variety of signs and symptoms. It is important to diagnose PIDs promptly, especially more severe forms to prevent significant morbidity and mortality. However, significant challenges exist in deciding which children to investigate and when. We aim to give a basic understanding of the human immune system, the different presentations in a child that should alert a paediatrician about the possibility of PID and the possible underlying diagnosis. Additionally, we have developed a framework for a stepwise approach to investigating these children.
Published: 2013

27. UK vaccination schedule: persistence of immunity to hepatitis B in children vaccinated after perinatal exposure

Author: Tom A Yates, Ly-Mee Yu, Karthikeyan Paranthaman, Sarah Lang, Andrew J. Pollard, Scott Hackett, Elizabeth Davis, Steven B. Welch, and Matthew D. Snape
Subjects: Pediatrics, medicine.medical_specialty, Vaccination schedule, Immunology, Immunization, Secondary, Booster dose, Pregnancy, medicine, Humans, Hepatitis B Vaccines, Hepatitis B Antibodies, Toddler, Child, Immunization Schedule, Vaccines, Synthetic, Booster (rocketry), Perinatal Exposure, business.industry, Vaccination, Immunity, Hepatitis B, medicine.disease, United Kingdom, Immunisation, Immunization, Child, Preschool, Prenatal Exposure Delayed Effects, Pediatrics, Perinatology and Child Health, Female, Original Article, business, Immunologic Memory
Abstract: Objective To assess persistence of immunity to hepatitis B (HBV) in primary school children vaccinated following perinatal exposure. Design Serological survey. Setting Five UK sites (Berkshire East, Birmingham, Buckinghamshire, Milton Keynes and Oxfordshire). Participants Children from 3 years 4 months to 10 years of age (mean age 6.2 years), vaccinated against HBV from birth following perinatal exposure. Interventions A single booster dose of the paediatric formulation of a recombinant HBV vaccine. Main outcome measures Titres of antibody against hepatitis B Surface Antigen (anti-HBs) measured immediately before and 21–35 days after the HBV vaccine booster. Results Prebooster anti-HBs titres were >10 mIU/ml in 84.6% of children (n=26; 95% CI 65.1 to 95.6%). All children (n=25, 95% CI 86.3 to 100%) had titres >100 mIU/ml after the booster. Conclusions This study of antibody persistence among UK children born to hepatitis B infected women, immunised with a 3-dose infant schedule with a toddler booster suggests sustained immunity through early childhood. These data should prompt further studies to address the need for a preschool booster. Trial registration Eudract Number 2008-004785-98.
Published: 2013

28. Degos disease: a new simulator of non-accidental injury

Author: Clive A J Ryder, Geoff Debelle, Celia Moss, Hossain Shahidullah, Spyros Sgouros, Scott Hackett, Evangeline Wassmer, Roger Malcomson, and Helen Goodyear
Subjects: Male, business.industry, Infant, Poison control, Degos disease, Subdural Fluid, medicine.disease, Revised diagnosis, Diagnosis, Differential, Malignant Atrophic Papulosis, Fatal Outcome, Developmental Neuroscience, Accidental, Pediatrics, Perinatology and Child Health, Injury prevention, medicine, Humans, Wounds and Injuries, Neurology (clinical), Presentation (obstetrics), Skin lesion, business, Simulation
Abstract: Recent high-profile cases have made paediatricians very aware of the serious implications of either missing or wrongly diagnosing non-accidental injury. Subdural fluid collections in non-mobile infants usually represent haemorrhage caused by non-accidental injury. We report a 6-month-old male who presented to the Accident and Emergency Department of Birmingham Heartlands Hospital with bilateral subdural fluid collections and skin ulcers resembling cigarette burns. Non-accidental injury was considered to be the most likely diagnosis. However, while under observation in hospital, the child's neurological condition deteriorated with progressive cerebral infarctions, and serial photographs of the skin lesions showed failure to heal. The revised diagnosis, confirmed histologically, was Degos disease, an extremely rare and often fatal occlusive vasculopathy. The child was treated palliatively and died 8 weeks after presentation. This report informs doctors of a new simulator of non-accidental injury to be considered in infants with otherwise unexplained subdural fluid collections.
Published: 2009

29. Anaphylaxis and ethnicity: higher incidence in British South Asians

Author: Aarnoud Huissoon, Mamidipudi Thirumala Krishna, Richard Crossman, Richard Buka, Matthew Cooke, Cathryn Melchior, Scott Hackett, and Susan Dorrian
Subjects: Adult, Male, medicine.medical_specialty, Allergy, Multivariate analysis, Adolescent, Immunology, Population, Ethnic group, Logistic regression, White People, Young Adult, Age Distribution, Asian People, Epidemiology, medicine, Immunology and Allergy, Humans, Sex Distribution, education, Child, Socioeconomic status, Anaphylaxis, Aged, Retrospective Studies, Aged, 80 and over, education.field_of_study, business.industry, Incidence (epidemiology), Incidence, Infant, Newborn, Infant, Middle Aged, medicine.disease, United Kingdom, Child, Preschool, Female, business, Demography
Abstract: BACKGROUND The incidence of anaphylaxis in South Asians (Indian, Pakistani and Bangladeshi ethnicity) is unknown. Birmingham is a British city with a disproportionately large population of South Asians (22.5%) compared with the rest of the UK (4.9%). The main aims of this study were to determine the incidence and severity of anaphylaxis in this population and to investigate the differences between the South Asian and White populations. METHODS A retrospective electronic search of emergency department attendances at three hospitals in Birmingham during 2012 was carried out. Wide search terms were used, medical notes were scrutinized, and the World Allergy Organization diagnostic criteria for anaphylaxis were applied. Patients' age, sex, ethnicity and home postal code were collected, reactions were graded by severity, and other relevant details including specialist assessment were extracted. Multivariate analysis was undertaken using 2011 UK census data. RESULTS Age-, sex- and ethnicity-standardized incidence rate of anaphylaxis was 34.5 per 100 000 person-years. Multivariate logistic regression which controlled for the confounders of age, sex and level of socioeconomic deprivation showed that incidence was higher in the South Asian population (OR 1.48, P = 0.005). Incidence rate in the South Asian population was 58.3 cases per 100 000 person-years compared to 31.5 in the White population. South Asian children were more likely to present with severe anaphylaxis (OR 5.31, P = 0.002). CONCLUSIONS Incidence of anaphylaxis is significantly higher in British South Asians compared to the white population. British South Asian children are at a greater risk of severe anaphylaxis than White children.
Published: 2015

30. Anaphylaxis and Clinical Utility of Real-World Measurement of Acute Serum Tryptase in UK Emergency Departments

Author: Mamidipudi Thirumala Krishna, Cathryn Melchior, Rebecca Knibb, Susan Dorrian, Richard Crossman, Richard Buka, Scott Hackett, Aarnoud Huissoon, and Matthew Cooke
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Allergy, Adolescent, Tryptase, Sensitivity and Specificity, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Positive predicative value, Internal medicine, Acute care, Humans, Immunology and Allergy, Medicine, Child, Anaphylaxis, Retrospective Studies, biology, business.industry, Emergency department, Odds ratio, Middle Aged, Prognosis, medicine.disease, United Kingdom, Surgery, 030104 developmental biology, 030228 respiratory system, Child, Preschool, Predictive value of tests, Practice Guidelines as Topic, biology.protein, Female, Tryptases, Emergency Service, Hospital, business
Abstract: Background: British guidelines recommend that serial acute serum tryptase measurements be checked in all adults and a subset of children presenting with anaphylaxis. This is the first study reporting the clinical utility of acute serum tryptase in a “real-world” emergency department (ED) setting following the publication of the World Allergy Organization (WAO) criteria for anaphylaxis. Objectives: To (1) assess sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of acute serum tryptase in anaphylaxis; (b) determine factors associated with higher acute serum tryptase levels; and (c) audit compliance of acute serum tryptase measurement in the ED. Methods: The methods used were retrospective electronic search for ED admissions to 3 acute care hospitals in Birmingham, UK, with anaphylaxis in 2012 using wide search terms followed by scrutiny of electronic clinical records and application of the WAO diagnostic criteria for anaphylaxis. Patients with an acute serum tryptase measurement were included in the analysis. Results: Acute serum tryptase level was measured in 141 of 426 (33.1%) cases. Mean time from the onset of symptoms to the measurement of acute serum tryptase level was 4 hours 42 minutes (SD ± 05:03 hours) and no patients had serial measurements conforming to British guidelines. Acute serum tryptase level of more than 12.4 ng/mL (75th centile) was associated with a sensitivity, specificity, PPV, and NPV of 28%, 88%, 0.93, and 0.17, respectively. Multiple regression analysis showed that male sex (odds ratio, 2.66; P = .003) and hypotension (odds ratio, 7.08; P = .001) predicted higher acute serum tryptase level. Conclusions: An acute serum tryptase level of more than 12.4 ng/mL in an ED setting carries high PPV and specificity, but poor sensitivity and NPV.
Published: 2017

31. Inflammatory and autoimmune manifestations in X-linked carriers of chronic granulomatous disease in the United Kingdom

Author: Andrew R. Gennery, Scott Hackett, A Battersby, David Goldblatt, Dawn Barge, Stephen M. Hughes, Mark S. Pearce, Catherine M. Cale, Siobhan O. Burns, and Helen Braggins
Subjects: 0301 basic medicine, Heterozygote, Immunology, Autoimmunity, Symptom assessment, Granulomatous Disease, Chronic, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Chronic granulomatous disease, Genes, X-Linked, medicine, Humans, Immunology and Allergy, business.industry, Heterozygote advantage, medicine.disease, Phenotype, United Kingdom, 030104 developmental biology, Granulomatous disease, Symptom Assessment, business, Biomarkers, 030215 immunology
Published: 2017

32. Toxic shock syndrome surveillance in UK children

Author: Julia E Clark, T Dawson, Scott Hackett, and Shazia Adalat
Subjects: Male, Pediatrics, medicine.medical_specialty, genetic structures, Adolescent, medicine.disease_cause, Streptococcal Infections, medicine, Humans, Child, business.industry, Incidence (epidemiology), Paediatric intensive care, Incidence, Toxic shock syndrome, Clindamycin, Infant, Guideline, Staphylococcal Infections, bacterial infections and mycoses, medicine.disease, Shock, Septic, United Kingdom, Child, Preschool, Pediatrics, Perinatology and Child Health, Streptococcus pyogenes, Epidemiological Monitoring, Female, Fresh frozen plasma, Outcomes research, business, Ireland, medicine.drug
Abstract: BACKGROUND Toxic shock syndrome (TSS) is an acute toxin-mediated illness caused by toxin-producing strains of Staphylococcus aureus and Streptococcus pyogenes. There is no recent data regarding incidence, management and mortality of TSS in UK children. METHODS Consultants from paediatric and burns units in the UK and Ireland, reported cases of TSS seen between November 2008 and December 2009, via the British Paediatric Surveillance Unit. Respondents were sent questionnaires requesting detailed information about TSS cases. Established criteria were used to divide cases into staphylococcal or streptococcal TSS. RESULTS Forty-nine cases were identified overall; 29 cases of streptococcal TSS (18 confirmed and 11 probable) and 20 cases of staphylococcal TSS (15 confirmed and 5 probable). The incidence of TSS children in the UK & the Republic of Ireland was calculated to be 0.38 per 100 000 children. Children with staphylococcal TSS were older than those with streptococcal TSS (9.5 vs 3.8 years; p
Published: 2014

33. Management of a Transcranial Abscess Secondary to Interleukin-1 Receptor Associated Kinase 4 Deficiency

Author: Hiroshi Nishikawa, Fateh Ahmad, Thomas E. Pidgeon, Desiderio Rodrigues, and Scott Hackett
Subjects: Primary Immunodeficiency Diseases, Brain Abscess, Bioinformatics, medicine, Humans, Pseudomonas Infections, Abscess, Receptor, Brain abscess, Soft tissue abscess, Interleukin-1 receptor–associated kinase 4 deficiency, biology, business.industry, Immunologic Deficiency Syndromes, Infant, General Medicine, medicine.disease, Interleukin-1 Receptor-Associated Kinases, Treatment Outcome, Otorhinolaryngology, Child, Preschool, Pseudomonas aeruginosa, Immunology, biology.protein, Primary immunodeficiency, Female, Surgery, Disease Susceptibility, Dura Mater, Presentation (obstetrics), business
Abstract: Interleukin-1 receptor associated kinase 4 (IRAK-4) deficiency is a primary immunodeficiency that predisposes to opportunistic pyogenic infections in affected patients. The presentation can be variable, and the microbiological and immunologic management of this condition has been documented; however, the atypical nature of its presentation calls for a different approach in its surgical management. This is the first reported case of transcranial progression of a soft tissue abscess in a patient with IRAK-4 deficiency, with an emphasis on a multidisciplinary approach to treat infection at an extremely vulnerable anatomic site.
Published: 2015

34. Immune deficiencies in children: an overview

Author: S Welch, S Jyothi, Scott Hackett, and S Lissauer
Subjects: Male, Pediatrics, medicine.medical_specialty, Adolescent, business.industry, Immunologic Deficiency Syndromes, Infant, Signs and symptoms, Malignancy, medicine.disease, Autoimmune Diseases, Immune system, Infectious disease (medical specialty), Child, Preschool, Pediatrics, Perinatology and Child Health, Practice Guidelines as Topic, medicine, Humans, Female, Severe Combined Immunodeficiency, business, Stepwise approach
Abstract: Primary immune deficiencies (PIDs) are disorders of the immune system that result in increased susceptibility to infectious disease, autoimmunity and malignancy. They are challenging to paediatricians as they can present anytime from birth to adolescence with a wide variety of signs and symptoms. It is important to diagnose PIDs promptly, especially more severe forms to prevent significant morbidity and mortality. However, significant challenges exist in deciding which children to investigate and when. We aim to give a basic understanding of the human immune system, the different presentations in a child that should alert a paediatrician about the possibility of PID and the possible underlying diagnosis. Additionally, we have developed a framework for a stepwise approach to investigating these children.
Published: 2013

35. The United Kingdom Primary Immune Deficiency (UKPID) Registry: report of the first 4 years' activity 2008-2012

Author: Aarnoud Huissoon, EG Davies, Grant Hayman, Alison M. Condliffe, P. Wood, E. McDermott, Ravishankar Sargur, Rashmi Jain, Z. Panahloo, Tariq El-Shanawany, Katherine Henderson, David Guzman, Hilary Longhurst, Veronika Reiser, Gavin P. Spickett, JD Edgar, M. Abuzakouk, Viviane Knerr, Sarita Workman, Anna Shrimpton, Lisa Devlin, S. E. Marshall, Dinakantha S. Kumararatne, Claire Bethune, Niall Conlon, Richard Herriot, Sofia Grigoriadou, A Herwadkar, Marc Turner, Bodo Grimbacher, Stéphane Paulus, Sadia Noorani, C. J. Darroch, Peter D. Arkwright, Christine Symons, M T Krishna, Mary Slatter, Andrew R. Gennery, C. Bangs, Z. Allwood, Smita Y. Patel, K. Ford, Matthew Helbert, Helen Baxendale, Scott Hackett, H. Alachkar, Sujoy Khan, Paul T. Heath, Stephen Jolles, and Matthew Buckland
Subjects: Male, Internet, business.industry, Immunology, Prevalence, Immunologic Deficiency Syndromes, Original Articles, medicine.disease, United Kingdom, Kingdom, Treatment modality, Clinical diagnosis, Registry report, Primary immunodeficiency, medicine, Immunology and Allergy, Humans, Female, National registry, Registries, Database research, business
Abstract: Summary This report summarizes the establishment of the first national online registry of primary immune deficency in the United Kingdom, the United Kingdom Primary Immunodeficiency (UKPID Registry). This UKPID Registry is based on the European Society for Immune Deficiency (ESID) registry platform, hosted on servers at the Royal Free site of University College, London. It is accessible to users through the website of the United Kingdom Primary Immunodeficiency Network (http://www.ukpin.org.uk). Twenty-seven centres in the United Kingdom are actively contributing data, with an additional nine centres completing their ethical and governance approvals to participate. This indicates that 36 of 38 (95%) of recognized centres in the United Kingdom have engaged with this project. To date, 2229 patients have been enrolled, with a notable increasing rate of recruitment in the past 12 months. Data are presented on the range of diagnoses recorded, estimated minimum disease prevalence, geographical distribution of patients across the United Kingdom, age at presentation, diagnostic delay, treatment modalities used and evidence of their monitoring and effectiveness.
Published: 2013

36. A UK national audit of hereditary and acquired angioedema

Author: Aarnoud Huissoon, Ceri Phillips, C. Bangs, J. Lortan, Sujoy Khan, C. Pastacaldi, C. Simon, Sofia Grigoriadou, Matthew Helbert, S. Deacock, Mario Abinun, Hilary Longhurst, A Herwadkar, Emily Carne, Moira Thomas, Gabriel K Wong, M. D. Tarzi, H. Mian, Tariq El-Shanawany, J. Darroch, V. Pavaladurai, Scott Hackett, H. Alachkar, V. Platts, Stephen Jolles, Hayley Bennett, P. Williams, John Dempster, and Peter D. Arkwright
Subjects: Larynx, Adult, Male, Abdominal pain, Time Factors, Immunology, Disease, C1-inhibitor, Quality of life, Cost of Illness, medicine, Immunology and Allergy, Humans, Medical Audit, biology, business.industry, Angioedemas, Hereditary, Original Articles, Middle Aged, medicine.disease, United Kingdom, medicine.anatomical_structure, Hereditary angioedema, biology.protein, Vomiting, Quality of Life, Abdomen, Female, medicine.symptom, business
Abstract: Summary Hereditary angioedema (HAE) and acquired angioedema (AAE) are rare life-threatening conditions caused by deficiency of C1 inhibitor (C1INH). Both are characterized by recurrent unpredictable episodes of mucosal swelling involving three main areas: the skin, gastrointestinal tract and larynx. Swelling in the gastrointestinal tract results in abdominal pain and vomiting, while swelling in the larynx may be fatal. There are limited UK data on these patients to help improve practice and understand more clearly the burden of disease. An audit tool was designed, informed by the published UK consensus document and clinical practice, and sent to clinicians involved in the care of HAE patients through a number of national organizations. Data sets on 376 patients were received from 14 centres in England, Scotland and Wales. There were 55 deaths from HAE in 33 families, emphasizing the potentially lethal nature of this disease. These data also show that there is a significant diagnostic delay of on average 10 years for type I HAE, 18 years for type II HAE and 5 years for AAE. For HAE the average annual frequency of swellings per patient affecting the periphery was eight, abdomen 5 and airway 0·5, with wide individual variation. The impact on quality of life was rated as moderate or severe by 37% of adult patients. The audit has helped to define the burden of disease in the UK and has aided planning new treatments for UK patients.
Published: 2013

37. STAT2 deficiency and susceptibility to viral illness in humans

Author: Stephen Goodbourn, Scott Hackett, Andrew J. Cant, Richard E. Randall, Naomi McGovern, Dan F. Young, M Valappil, Sophie Hambleton, Paul Dickinson, Neil V. Morgan, Siti Mardhiana Mohamad, and Peter Ghazal
Subjects: Proband, Biology, Immunity, medicine, Humans, Genetic Predisposition to Disease, RNA, Messenger, Gene, Cells, Cultured, DNA Primers, Oligonucleotide Array Sequence Analysis, Multidisciplinary, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, STAT2 Transcription Factor, Biological Sciences, Acquired immune system, medicine.disease, Virology, Pedigree, Viral replication, Infectious disease (medical specialty), Virus Diseases, Child, Preschool, Immunology, Interferon Type I, Primary immunodeficiency, Female, Interferon type I, medicine.drug
Abstract: Severe infectious disease in children may be a manifestation of primary immunodeficiency. These genetic disorders represent important experiments of nature with the capacity to elucidate nonredundant mechanisms of human immunity. We hypothesized that a primary defect of innate antiviral immunity was responsible for unusually severe viral illness in two siblings; the proband developed disseminated vaccine strain measles following routine immunization, whereas an infant brother died after a 2-d febrile illness from an unknown viral infection. Patient fibroblasts were indeed abnormally permissive for viral replication in vitro, associated with profound failure of type I IFN signaling and absence of STAT2 protein. Sequencing of genomic DNA and RNA revealed a homozygous mutation in intron 4 of STAT2 that prevented correct splicing in patient cells. Subsequently, other family members were identified with the same genetic lesion. Despite documented infection by known viral pathogens, some of which have been more severe than normal, surviving STAT2-deficient individuals have remained generally healthy, with no obvious defects in their adaptive immunity or developmental abnormalities. These findings imply that type I IFN signaling [through interferon-stimulated gene factor 3 (ISGF3)] is surprisingly not essential for host defense against the majority of common childhood viral infections.
Published: 2013

38. An audit of lymphopenia in infants under 3 months of age

Author: Aarnoud Huissoon, Mamidipudi Thirumala Krishna, Emily Cheadle, Scott Hackett, Julie Tarrant, and Sadia Noorani
Subjects: Severe combined immunodeficiency, Pediatrics, medicine.medical_specialty, Medical Audit, business.industry, Incidence (epidemiology), Infant, Newborn, Absolute lymphocyte count, Infant, Audit, medicine.disease, United Kingdom, Lymphopenia, Pediatrics, Perinatology and Child Health, Practice Guidelines as Topic, T cell immunity, Primary immunodeficiency, Medicine, Humans, Severe Combined Immunodeficiency, business, Paediatric emergency, Retrospective Studies
Abstract: Severe combined immunodeficiency (SCID) describes a group of rare genetic disorders characterised by deficient or absent T cell immunity, with an estimated incidence of 1 in 50 000 to 1 in 500 000.1 SCID is considered a paediatric emergency, but early clues, such as lymphopenia, are often not noted.2 As a result, the UK Primary Immunodeficiency Network (UK PIN) recommends that children under 2 years of age with an absolute lymphocyte count (ALC) below 3000/μl must be screened for SCID.3 A …
Published: 2007

39. Characterisation Of Anaphylaxis In a Large UK City With An Ethnically Diverse Population

Author: Mamidipudi Thirumala Krishna, Aarnoud Huissoon, Matthew Cooke, Richard Buka, Cathryn Derbridge, Richard Crossman, Scott Hackett, and Susan Dorrian
Subjects: education.field_of_study, Pediatrics, medicine.medical_specialty, Allergy, business.industry, Incidence (epidemiology), Immunology, Population, Ethnic group, Emergency department, medicine.disease, Atopy, Etiology, Immunology and Allergy, Medicine, education, business, Anaphylaxis
Abstract: RATIONALE: Little is known about anaphylaxis in the non-white population (NWP). Birmingham is the second largest city in UK with an ethnically diverse population; 42% are ‘non-white’ as opposed to an overall proportion of 15% in England. East Birmingham is a relatively deprived area with a high density of NWP (50%). METHODS: We retrospectively applied the World Allergy Organisation (WAO) diagnostic criteria to patients admitted to our emergency department in 2012. RESULTS: Annual incidence of anaphylaxis in this population is approximately 8.8 per 10000. 220 attendances fulfilled the WAO criteria, mean age 32.5 (6 22.4 SD). 53 (24%) were
Published: 2014

40. Challenges of 'peanut challenge'

Author: Srinivas Bandi and Scott Hackett
Subjects: Pulmonary and Respiratory Medicine, business.industry, Immunology, Immunology and Allergy, Medicine, Engineering ethics, business
Published: 2007

41. Severe/combined immunodeficiency in children – a cohort of 19 patients

Author: S Welch, S Jyothi, S Pollock, Scott Hackett, Aarnoud Huissoon, and M Guckian
Subjects: Pediatrics, medicine.medical_specialty, Severe combined immunodeficiency, Heel, business.industry, Skin infection, medicine.disease, medicine.anatomical_structure, Pediatrics, Perinatology and Child Health, Failure to thrive, Cohort, medicine, medicine.symptom, Family history, Presentation (obstetrics), business, Immunodeficiency
Abstract: Background Severe Combined Immunodeficiency (SCID/CID) is a primary immune deficiency and usually has severe defect in both T- & B-lymphocyte systems. This usually results in onset of one or more serious infections within first few months of life. Aim Review all cases presented or referred to our immunology department in the past 8 years with suspected immune deficiency. Methods Case notes, correspondence and results were reviewed for all children diagnosed with SCID/CID at Birmingham Heartlands Hospital in last 7 years. Results A total of 19 patients were reviewed: 10 males and 9 females were identified. All were born at term and had no antenatal diagnosis of SCID. 9 were born to consanguineous parents and 9 had family history of immunodeficiency. The initial age at presentation varied from 1 day to 24 months. The age at final diagnosis was 2 days to 5 years. Symptoms at presentation included chest infections, diarrhoea, failure to thrive, skin infections and complicated medical problems. 11 were referred to our department for paediatric immunological opinion from other hospitals. 18 of these children were referred for bone marrow transplant to Great Ormond Street Hospital, London or Newcastle-Upon-Tyne Hospitals and 10 have been transplanted to date. 3 are awaiting a donor. One is currently receiving gene therapy and 1 awaiting thymus transplant. 6 of these children did not survive (3 died post transplant and 3 while awaiting transplant) and rest are still under follow up. Conclusions SCID / CID is a relatively common condition in West Midlands. Presentation of infants with SCID is variable and needs to be considered. Universal screening of Guthrie card heel pricks for T-cell receptor excision circles (TRECs) would allow patients to be identified sooner and hopefully improve survival rates.
Published: 2012

42. Panhypopituitarism after tuberculous meningitis with suprasellar abscess

Author: S Welch, S Karandikar, D Iyer, S Denniston, R Walsh, G Jones, N Shaw, S Lissauer, and Scott Hackett
Subjects: medicine.medical_specialty, medicine.diagnostic_test, business.industry, Mantoux test, medicine.disease, Tuberculous meningitis, Surgery, Polyuria, Intensive care, Pediatrics, Perinatology and Child Health, Diabetes insipidus, medicine, Tuberculoma, medicine.symptom, business, Abscess, Polydipsia
Abstract: Background Central nervous system tuberculosis in children accounts for 2.2% of tuberculosis in England and Wales at presentation. Suprasellar tubercular abscess is extremely rare, especially in children, with only a few cases reported worldwide. Case report A 15 year old, previously well, Somalian boy presented with 4 week history of intermittent nocturnal fever and sore throat. He had moved from Somalia to the UK 4 months prior to presentation. His clinical examination, chest x-ray and initial blood tests were unremarkable. The following day, he was noted to be confused and had multiple, brief generalised tonic clonic seizures. He was intubated for airway protection and urgent CT scan of head showed multiple, multilocular ring enhancing lesions extending from suprasellar cistern into the hypothalamus. Cerebrospinal fluid examination revealed 102 white cells (97 lymphocytes), 2.79 g/l protein, but no organisms on gram and acid fast staining. Clinical diagnosis of tuberculous abscess was made. Quadruple anti-tuberculous medications and prednisolone were commenced. Subsequently, his mantoux test was strongly positive. Smears from gastric washings and endotracheal aspirates were negative for acid fast bacilli and culture results are awaited. He was monitored on intensive care where he was noted to have polyuria. For further management he was transferred to regional neurosurgical unit where he was managed conservatively, although, persisted to have polyuria and polydipsia. Investigations revealed hypernatraemia (151 mmol/l) with low urine osmolality (307 mOsm/l) suggesting diabetes insipidus. Further endocrine investigations confirmed panhypopituitarism. He was started on oral thyroxine, DDAVP, hydrocortisone and monthly intramuscular injections of testosterone. He is making good clinical progress. His MRI scan 6 weeks after initial diagnosis revealed no change in the tuberculoma with no new tuberculomas or hydrocephalus. Conclusion Suprasellar tubercular abscess is extremely rare form of tuberculosis in children. It can be associated with significant endocrine abnormalities, which require high index of clinical suspicion and prompt investigations.
Published: 2011

43. Surveillance of toxic shock syndrome in the paediatric population in the UK

Author: Scott Hackett, T Dawson, Julia E Clark, and Shazia Adalat
Subjects: Pediatrics, medicine.medical_specialty, genetic structures, business.industry, medicine.drug_class, Incidence (epidemiology), Antibiotics, Clindamycin, Toxic shock syndrome, Disease, bacterial infections and mycoses, medicine.disease, chemistry.chemical_compound, chemistry, Intensive care, Pediatrics, Perinatology and Child Health, Linezolid, medicine, Fresh frozen plasma, business, medicine.drug
Abstract: Background and aims A UK-wide study of Toxic Shock Syndrome (TSS) cases in UK children under 16 years of age was undertaken beginning November 2008 until the end of November 2009. Little data regarding incidence, management and outcomes has been published about children with TSS. Previous literature suggested staphylococcal TSS to have a significantly greater incidence than streptococcal TSS. Methods Consultants from paediatric and burns units notified the British Paediatric Surveillance Unit of cases. Questionnaires requesting detailed information on case presentation and progression were sent to notifying consultants. TSS cases were identified as staphylococcal or streptococcal if they met the established criteria used by the US Centre for Disease Control and American Academy of Paediatrics respectively. Results 50 confirmed and probable cases were identified. 15 were confirmed and 5 probable staphylococcal cases; 18 were confirmed and 12 probable streptococcal cases. There were nine deaths, all from the confirmed or probable streptococcal groups. Mortality was 18% overall but 30% of the streptococcal cases. Four were reported to have residual morbidity. 78% (n=39) received treatment in paediatric intensive care facilities. 70% (n=35) required invasive ventilatory support, 68% (n=34) inotropic support and12% (n=6) haemofiltration. All patients received antibiotics, with two thirds (n=33) receiving clindamycin and only two receiving linezolid. 20% (n=10) received immunoglobulin and 40% (n=20) fresh frozen plasma. Conclusions This study demonstrates streptococcal TSS to have a higher incidence than staphylococcal TSS, in contrast to previous literature. This finding is in keeping with the increasing incidence of other types of invasive streptococcal disease. A significantly higher mortality was seen with streptococcal TSS indicating it may be a more virulent disease than staphylococcal TSS. Intensive care support facilities were required in three-fourth of patients. It was noted that proven antitoxin therapies which have been shown to reduce toxin production, such as clindamycin and linezolid, appeared to be underused. This study highlights the need for education on patho-aetiology and management of TSS.
Published: 2011

44. Dual Proteolytic Pathways Govern Glycolysis and Immune Competence

Author: Sharon Sanderson, Jeremy H. Lakey, Qian Zhang, Anna Katharina Simon, Helen Griffin, Louise N. Reynard, Scott Hackett, Mauro Santibanez Koref, Andrew J. Cant, Wei Lu, Nic Robertson, Michael J. Lenardo, Stuart E. Turvey, Tim Prestidge, Viktor I. Korolchuk, Yu Zhang, David McDonald, Helen C. Su, Neil V. Morgan, Huie Jing, Julie M. Hall, Lixin Zheng, Helen F. Matthews, Sophie Hambleton, Bernadette Carroll, and Heardley M. Murdock
Subjects: Male, Models, Molecular, Molecular Sequence Data, Adaptive Immunity, Protein degradation, Biology, Aminopeptidases, Article, General Biochemistry, Genetics and Molecular Biology, Lysosome, medicine, Animals, Humans, Amino Acid Sequence, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Genetics, Innate immune system, Effector, Biochemistry, Genetics and Molecular Biology(all), Serine Endopeptidases, Autophagy, Immunologic Deficiency Syndromes, Tripeptidyl peptidase II, Acquired immune system, Immunity, Innate, Pedigree, Cell biology, medicine.anatomical_structure, Proteasome, Proteolysis, Female, Lysosomes, Glycolysis, Sequence Alignment
Abstract: SummaryProteasomes and lysosomes constitute the major cellular systems that catabolize proteins to recycle free amino acids for energy and new protein synthesis. Tripeptidyl peptidase II (TPPII) is a large cytosolic proteolytic complex that functions in tandem with the proteasome-ubiquitin protein degradation pathway. We found that autosomal recessive TPP2 mutations cause recurrent infections, autoimmunity, and neurodevelopmental delay in humans. We show that a major function of TPPII in mammalian cells is to maintain amino acid levels and that TPPII-deficient cells compensate by increasing lysosome number and proteolytic activity. However, the overabundant lysosomes derange cellular metabolism by consuming the key glycolytic enzyme hexokinase-2 through chaperone-mediated autophagy. This reduces glycolysis and impairs the production of effector cytokines, including IFN-γ and IL-1β. Thus, TPPII controls the balance between intracellular amino acid availability, lysosome number, and glycolysis, which is vital for adaptive and innate immunity and neurodevelopmental health.
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