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      Gastrointestinal features in children with COVID-19: an observation of varied presentation in eight children

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          Abstract

          We report eight children with COVID-19 presenting at a single centre in the UK with symptoms of atypical appendicitis before rapid deterioration requiring hospitalisation and, in some cases, intensive care support. All children had imaging confirming terminal ileitis and no surgical intervention was required at the time of writing. We draw attention to an unusual presentation of COVID-19 in children and adolescents and we recommend abdominal imaging when investigating for possible appendicitis. There have been 4 730 968 confirmed cases and 315 488 deaths from COVID-19 worldwide since emergence of the infection in December, 2019, in Wuhan, China. 1 To date, most of the case load and mortality has been seen in the adult population. Currently in the UK, there is concern regarding an inflammatory syndrome related to COVID-19 in children with gastrointestinal symptoms in the presence of both positive and negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR tests.2, 3 Children have been observed to have milder clinical manifestations of the virus than do adults, sometimes acting as asymptomatic carriers of infection. 4 Although gastrointestinal symptoms have not been recognised in the early stages of the pandemic, and are infrequently reported in the literature on infection in adults, 5 it has been reported that a high mean viral load in the nasopharynx is associated with the occurrence of diarrhoea in patients with severe acute respiratory syndrome. 6 We draw attention to COVID-19 presenting in paediatric patients with primary symptoms of fever and abdominal pain, which might be mistaken for appendicitis. Eight patients in a tertiary paediatric institution were referred for a surgical review over an 8-day period (April 25–May 2, 2020). All patients presented with a combination of symptoms including fever, abdominal pain, diarrhoea, and vomiting. The working diagnosis was of systemic sepsis based on raised blood inflammatory markers thought to be secondary to suspected appendicitis. All patients apart from one presented with markedly elevated C-reactive protein. Further clinical details are provided in the appendix (pp 1–2). Patients received antibiotics and fluids, and were investigated with blood tests, urine and bloods cultures, and, in patient 4, a lumbar puncture. All patients, except for patient 6, initially had an abdominal ultrasound scan. Patients 4, 5, 6, and 7 had abdominal CT scans and patient 6 had an abdominal ultrasound following the CT. Findings on ultrasound were in line with lymphadenopathy and presence of inflammatory fat throughout the mesentery, with thickening of the terminal ileum (appendix pp 1–2). These findings were mirrored on CT (appendix pp 1–2), which represents a better modality to show a non-inflamed appendix than does ultrasonography. Patient 4 had a severe inflammatory response and myocarditis, and was transferred from another institution to be offered extracorporeal membrane oxygenation. Three patients (3, 5, and 6) developed a systemic inflammatory response and were transferred directly to paediatric intensive care due to haemodynamic instability. Patients 3 and 6 were initially planned for laparoscopy and appendicectomy in the local institution. Plans for operative intervention were subsequently abandoned due to haemodynamic instability, requirement for inotropes and intensive care support, and, in the case of patient 3, a positive SARS-CoV-2 PCR. Although SARS-CoV-2 PCR was negative, patients 2 and 7 were suspected to have COVID-19 because of the similarity of their clinical presentation and imaging (appendix pp 1–2). Patient 7 presented with a 5-day history of right iliac fossa pain and fever. The radiological findings common to patients in this series are shown in the figure . Figure Imaging for patient 7 (A) Initial ultrasound shows lymphadenopathy and inflammatory fat throughout the mesentery (arrowheads) and thickening of the terminal ileum (arrow). (B) CT confirms this finding (arrow) and shows a non-inflamed appendix and adjacent mesenteric fat. Patients 2, 3, 4, and 6 received immunoglobulin and steroid treatment for atypical Kawasaki disease. Patient 2 had peripheral oedema and patient 3 had periorbital oedema, but no specific features of Kawasaki disease. Patients 4 and 6 were treated because of the perceived benefit in managing the severe systemic inflammatory syndrome. All patients, except for patients 1 and 8 (who have been discharged), are receiving ongoing inpatient care and their outcomes are unknown. No patients have died. We note that six patients were from a black or Asian ethnic group (appendix pp 1–2). Disparity in outcome of frontline workers and the general population in black and minority ethnic groups has been widely reported across the UK, Europem, and North America, and is now addressed as a priority for public health research. 7 Ethnicity represents a complex entity and the ethnic make-up of this cohort, albeit a small patient group, supports the theory of a possible interaction of ethnicity-related factors on SARS-CoV-2 infection likelihood and severity. Our experience serves to increase the awareness of this clinical presentation, particularly for clinicians and surgeons who assess and manage children with abdominal pain and suspected appendicitis. Although clinical examination should guide decision making, and ultrasound is often the only diagnostic imaging modality to exclude appendicitis in the UK, cross-sectional imaging was necessary for differential diagnosis in half (four) of our patients. Given the convincing nature of clinical findings for appendicitis in children with COVID-19, we stress the importance of abdominal imaging and a swab for SARS-CoV-2 PCR in all children before surgical intervention. It is important to stress the need to visualise the appendix through ultrasound, CT, or both. Broad-spectrum antibiotics should be adopted in these patients and transfer to a tertiary paediatric centre should be considered early in the disease course because their condition can rapidly deteriorate. We encourage others to report their experience to better understand how COVID-19 presents in children.

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          Hyperinflammatory shock in children during COVID-19 pandemic

          South Thames Retrieval Service in London, UK, provides paediatric intensive care support and retrieval to 2 million children in South East England. During a period of 10 days in mid-April, 2020, we noted an unprecedented cluster of eight children with hyperinflammatory shock, showing features similar to atypical Kawasaki disease, Kawasaki disease shock syndrome, 1 or toxic shock syndrome (typical number is one or two children per week). This case cluster formed the basis of a national alert. All children were previously fit and well. Six of the children were of Afro-Caribbean descent, and five of the children were boys. All children except one were well above the 75th centile for weight. Four children had known family exposure to coronavirus disease 2019 (COVID-19). Demographics, clinical findings, imaging findings, treatment, and outcome for this cluster of eight children are shown in the table . Table Demographics, clinical findings, imaging findings, treatment, and outcome from PICU Age; weight; BMI; comorbidities Clinical presentation Organ support Pharmacological treatment Imaging results Laboratory results Microbiology results PICU length of stay; outcome Initial PICU referral Patient 1 (male, AfroCaribbean) 14 years; 95 kg; BMI 33 kg/m2; no comorbidities 4 days >40°C; 3 days non-bloody diarrhoea; abdominal pain; headache BP 80/40 mmHg; HR 120 beats/min; RR 40 breaths per min; work of breathing; SatO2 99% NCO2 MV, RRT, VA-ECMO Dopamine, noradrenaline, argipressin, adrenaline milrinone, hydroxicortisone, IVIG, ceftriaxone, clindamycin RV dysfunction/elevate RVSP; ileitis, GB oedema and dilated biliary tree, ascites, bilateral basal lung consolidations and diffuse nodules Ferritin 4220 μg/L; D-dimers 13·4 mg/L; troponin 675 ng/L; proBNP >35 000; CRP 556 mg/L; procalcitonin>100 μg/L; albumin 20 g/L; platelets 123 × 109 SARS-CoV-2 positive (post mortem) 6 days; demise (right MCA and ACA ischaemic infarction) Patient 2 (male, AfroCaribbean) 8 years; 30 kg; BMI 18 kg/m2; no comorbidities 5 days >39°C; non-bloody diarrhoea; abdominal pain; conjunctivitis; rash BP 81/37 mmHg; HR 165 beats/min; RR 40 breaths/min; SVIA MV Noradrenaline, adrenaline, IVIG, infliximab, methylprednisolone, ceftriaxone, clindamycin Mild biventricular dysfunction, severely dilated coronaries; ascites, pleural effusions Ferritin 277 μg/L; D-dimers 4·8 mg/L; troponin 25 ng/L; CRP 295 mg/L; procalcitonin 8·4 μg/L; albumin 18 g/L; platelets 61 × 109 SARS-CoV-2 negative; likely COVID-19 exposure from mother 4 days; alive Patient 3 (male, Middle-Eastern) 4 years; 18 kg; BMI 17 kg/m2; no comorbidities 4 days >39°C; diarrhoea and vomiting; abdominal pain; rash; conjunctivitis BP 90/30 mmHg; HR 170 beats/min; RR 35 breaths/min; SVIA MV Noradrenaline, adrenaline, IVIG ceftriaxone, clindamycin Ascites, pleural effusions Ferritin 574 μg/L; D-dimers 11·7 mg/L; tropinin 45 ng/L; CRP 322 mg/L; procalcitonin 10·3 μg/L; albumin 22 g/L; platelets 103 × 109 Adenovirus positive; HERV positive 4 days; alive Patient 4 (female, AfroCaribbean) 13 years; 64 kg; BMI 33 kg/m2; no comorbidities 5 days >39°C; non-bloody diarrhoea; abdominal pain; conjunctivitis BP 77/41 mmHg; HR 127 beats/min; RR 24 breaths/min; SVIA HFNC Noradrenaline, milrinone, IVIG, ceftriaxone, clindamycin Moderate-severe LV dysfunction; ascites Ferritin 631 μg/L; D-dimers 3·4 mg/L; troponin 250 ng/L; proBNP 13427 ng/L; CRP 307 mg/L; procalcitonin 12·1 μg/L; albumin 21 g/L; platelets 146 × 109 SARS-CoV-2 negative 5 days; alive Patient 5 (male, Asian) 6 years; 22 kg; BMI 14 kg/m2; autism, ADHD 4 days >39°C; odynophagia; rash; conjunctivitis BP 85/43 mmHg; HR 150 beats/min; RR 50 breaths/min; SVIA NIV Milrinone, IVIG, methylprednisolone, aspirin, ceftriaxone Dilated LV, AVVR, pericoronary hyperechogenicity Ferritin 550 μg/L; D-dimers 11·1 mg/L; troponin 47 ng/L; NT-proBNP 7004 ng/L; CRP 183 mg/L; albumin 24 g/L; platelets 165 × 109 SARS-CoV-2 positive; likely COVID-19 exposure from father 4 days; alive Patient 6 (female, AfroCaribbean) 6 years; 26 kg; BMI 15 kg/m2; no comorbidities 5 days >39°C; myalgia; 3 days diarrhoea and vomiting; conjunctivitis BP 77/46 mmHg; HR 120 beats/min; RR 40 breaths/min; SVIA NIV Dopamine, noradrenaline, milrinone, IVIG, methylprednisolone, aspirin, ceftriaxone, clindamycin Mild LV systolic impairment Ferritin 1023 μg/L; D-dimers 9·9 mg/L; troponin 45 ng/L; NT-proBNP 9376 ng/L; CRP mg/L 169; procalcitonin 11·6 μg/L; albumin 25 g/L; platelets 158 SARS-CoV-2 negative; confirmed COVID-19 exposure from grandfather 3 days; alive Patient 7 (male, AfroCaribbean 12 years; 50kg; BMI 20 kg/m2; alopecia areata, hayfever 4 days >39°C; 2 days diarrhoea and vomiting; abdominal pain; rash; odynophagia; headache BP 80/48 mmHg; HR 125 beats/min; RR 47 breaths/min; SatO2 98%; HFNC FiO2 0.35 MV Noradrenaline, adrenaline, milrinone, IVIG, methylprednisolone, heparin, ceftriaxone, clindamycin, metronidazole Severe biventricular impairment; ileitis, ascites, pleural effusions Ferritin 958 μg/L; D-dimer 24·5 mg/L; troponin 813 ng/L; NT-proBNP >35 000 ng/L; CRP 251 mg/L; procalcitonin 71·5 μg/L; albumin 24 g/L; platelets 273 × 109 SARS-CoV-2 negative 4 days; alive Patient 8 (female, AfroCaribbean) 8 years; 50 kg; BMI 25 kg/m2; no comorbidities 4 days >39°C; odynophagia; 2 days diarrhoea and vomiting; abdominal pain BP 82/41 mmHg; HR 130 beats/min; RR 35 breaths/min; SatO2 97% NCO2 MV Dopamine, noradrenaline, milrinone, IVIG, aspirin, ceftriaxone, clindamycin Moderate LV dysfunction Ferritin 460 μg/L; D-dimers 4·3 mg/L; troponin 120 ng/L; CRP 347 mg/L; procalcitonin 7·42 μg/L; albumin 22 g/L; platelets 296 × 109 SARS-CoV-2 negative; likely COVID-19 exposure from parent 7 days; alive ACA= anterior cerebral artery. ADHD=attention deficit hyperactivity disorder. AVR=atrioventricular valve regurgitation. BMI=body mass index. BP=blood pressure. COVID-19=coronavirus disease 2019. CRP=C-reactive protein. FiO2=fraction of inspired oxygen. HERV=human endogenous retrovirus. HFNC=high-flow nasal canula. HR=heart rate. IVIG=human intravenous immunoglobulin. LV=left ventricle. MCA=middle cerebral artery. MV=mechanical ventilation via endotracheal tube. NIV=non-invasive ventilation. PICU=paediatric intensive care unit. RA=room air. RR=respiratory rate. RRT=renal replacement therapy. RV=right ventricle. RVSP=right ventricular systolic pressure. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. SatO2=oxygen saturation. SVIA=self-ventilating in air. VA-ECMO=veno-arterial extracorporeal membrane oxygenation. Clinical presentations were similar, with unrelenting fever (38–40°C), variable rash, conjunctivitis, peripheral oedema, and generalised extremity pain with significant gastrointestinal symptoms. All progressed to warm, vasoplegic shock, refractory to volume resuscitation and eventually requiring noradrenaline and milrinone for haemodynamic support. Most of the children had no significant respiratory involvement, although seven of the children required mechanical ventilation for cardiovascular stabilisation. Other notable features (besides persistent fever and rash) included development of small pleural, pericardial, and ascitic effusions, suggestive of a diffuse inflammatory process. All children tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on broncho-alveolar lavage or nasopharyngeal aspirates. Despite being critically unwell, with laboratory evidence of infection or inflammation 3 including elevated concentrations of C-reactive protein, procalcitonin, ferritin, triglycerides, and D-dimers, no pathological organism was identified in seven of the children. Adenovirus and enterovirus were isolated in one child. Baseline electrocardiograms were non-specific; however, a common echocardiographic finding was echo-bright coronary vessels (appendix), which progressed to giant coronary aneurysm in one patient within a week of discharge from paediatric intensive care (appendix). One child developed arrhythmia with refractory shock, requiring extracorporeal life support, and died from a large cerebrovascular infarct. The myocardial involvement 2 in this syndrome is evidenced by very elevated cardiac enzymes during the course of illness. All children were given intravenous immunoglobulin (2 g/kg) in the first 24 h, and antibiotic cover including ceftriaxone and clindamycin. Subsequently, six children have been given 50 mg/kg aspirin. All of the children were discharged from PICU after 4–6 days. Since discharge, two of the children have tested positive for SARS-CoV-2 (including the child who died, in whom SARS-CoV-2 was detected post mortem). All children are receiving ongoing surveillance for coronary abnormalities. We suggest that this clinical picture represents a new phenomenon affecting previously asymptomatic children with SARS-CoV-2 infection manifesting as a hyperinflammatory syndrome with multiorgan involvement similar to Kawasaki disease shock syndrome. The multifaceted nature of the disease course underlines the need for multispecialty input (intensive care, cardiology, infectious diseases, immunology, and rheumatology). The intention of this Correspondence is to bring this subset of children to the attention of the wider paediatric community and to optimise early recognition and management. As this Correspondence goes to press, 1 week after the initial submission, the Evelina London Children's Hospital paediatric intensive care unit has managed more than 20 children with similar clinical presentation, the first ten of whom tested positive for antibody (including the original eight children in the cohort described above).
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            Diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts’ consensus statement

            Since the outbreak of 2019 novel coronavirus infection (2019-nCoV) in Wuhan City, China, by January 30, 2020, a total of 9692 confirmed cases and 15,238 suspected cases have been reported around 31 provinces or cities in China. Among the confirmed cases, 1527 were severe cases, 171 had recovered and been discharged at home, and 213 died. And among these cases, a total of 28 children aged from 1 month to 17 years have been reported in China. For standardizing prevention and management of 2019-nCoV infections in children, we called up an experts’ committee to formulate this experts’ consensus statement. This statement is based on the Novel Coronavirus Infection Pneumonia Diagnosis and Treatment Standards (the fourth edition) (National Health Committee) and other previous diagnosis and treatment strategies for pediatric virus infections. The present consensus statement summarizes current strategies on diagnosis, treatment, and prevention of 2019-nCoV infection in children.
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              Ethnicity and COVID-19: an urgent public health research priority

              As the coronavirus disease 2019 (COVID-19) pandemic continues advancing globally, reporting of clinical outcomes and risk factors for intensive care unit admission and mortality are emerging. Early Chinese and Italian reports associated increasing age, male sex, smoking, and cardiometabolic comorbidity with adverse outcomes. 1 Striking differences between Chinese and Italian mortality indicate ethnicity might affect disease outcome, but there is little to no data to support or refute this. Ethnicity is a complex entity composed of genetic make-up, social constructs, cultural identity, and behavioural patterns. 2 Ethnic classification systems have limitations but have been used to explore genetic and other population differences. Individuals from different ethnic backgrounds vary in behaviours, comorbidities, immune profiles, and risk of infection, as exemplified by the increased morbidity and mortality in black and minority ethnic (BME) communities in previous pandemics. 3 As COVID-19 spreads to areas with large cosmopolitan populations, understanding how ethnicity affects COVID-19 outcomes is essential. We therefore reviewed published papers and national surveillance reports on notifications and outcomes of COVID-19 to ascertain ethnicity data reporting patterns, associations, and outcomes. Only two (7%) of 29 publications reported ethnicity disaggregated data (both were case series without outcomes specific to ethnicity). We found that none of the ten highest COVID-19 case-notifying countries reported data related to ethnicity; UK mortality reporting, for example, does not require information on ethnicity. This omission seems stark given the disproportionate number of deaths among health-care workers from BME backgrounds.4, 5 Recent UK data from intensive care units indicate that over a third of patients are from BME backgrounds. 6 Given previous pandemic experience, it is imperative that policy makers urgently ensure ethnicity forms part of a minimum dataset. More importantly, ethnicity-disaggregated data must occur to permit identification of potential outcome risk factors through adjustment for recognised confounders. BME communities might be at increased risk of acquisition, disease severity, and poor outcomes in COVID-19 for several reasons (figure ). Specific ethnic groups, such as south Asians, have higher rates of some comorbidities, such as diabetes, hypertension, and cardiovascular diseases, which have been associated with severe disease and mortality in COVID-19. 7 Ethnicity could interplay with virus spread through cultural, behavioural, and societal differences including lower socioeconomic status, health-seeking behaviour, and intergenerational cohabitation. Disentangling the relative importance of these factors requires both prospective studies, focusing on quantifying absolute risks and outcomes, and qualitative studies of behaviours and responses to pandemic control messages. Figure The potential interaction of ethnicity related factors on SARS-CoV-2 infection likelihood and COVID-19 outcomes COVID-19=coronavirus disease 2019. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. If ethnicity is found to be associated with adverse COVID-19 outcomes, this must directly, and urgently, inform public health interventions globally.
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                Author and article information

                Contributors
                Journal
                Lancet Child Adolesc Health
                Lancet Child Adolesc Health
                The Lancet. Child & Adolescent Health
                Elsevier Ltd.
                2352-4642
                2352-4650
                20 May 2020
                20 May 2020
                Affiliations
                [a ]Department of Specialist Paediatric and Neonatal Surgery, Great Ormond Street Hospital for Children, London WC1N 3JH, UK
                [b ]Department of Radiology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK
                [c ]National Institute for Health Research Biomedical Research Centre, University College London Great Ormond Street Institute of Child Health, London, UK
                [d ]Population, Policy and Practice, University College London Great Ormond Street Institute of Child Health, London, UK
                [e ]Stem Cell and Cancer Biology Laboratory, the Francis Crick Institute, London, UK
                Article
                S2352-4642(20)30165-6
                10.1016/S2352-4642(20)30165-6
                7237361
                32442420
                b53cdcd8-64b8-4e1a-a4df-3f33195d4738
                © 2020 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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