Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study

Dear Editor,

It was a pleasure for us to read the article titled ‘Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study’ by Swann et al.[1], in your esteemed journal. It is a succinctly written article and we would like to commend the authors on their excellent effort. It is a topic of interest for us and we feel we could add a few important points here which would enrich the paper further.

It has been reported in literature that infants and children can have high viral loads of nCoV-19 in the nasopharynx and still be asymptomatic or have minimal symptoms [2]. This is important to note in the present context as these children may not always present to the hospital system with symptoms and may be a dormant reservoir of the virus in the community and play an important role in community transmission. Hence, it may be very difficult to establish the true incidence of COVID-19 in the pediatric population and as our knowledge of the true extent of the syndrome-complexes associated with COVID-19 is still limited, these apparently asymptomatic children may yet present with newer symptoms to the health system, and so a higher degree of suspicion among pediatricians and general practitioners is essential.

As mentioned in the present study, MIS-C is associated with cardiovascular abnormalities such as cardiomegaly, congestive heart failure and pulmonary edema, and a strong association of the same was found in a study by Blumfield et al.[3] They found that MIS-C was also associated with solid visceral organ, gallbladder and bowel abnormalities, as well as ascites, and they suggested that this constellation of imaging findings should alert pediatricians and radiologists to the diagnosis of MIS-C, prior to rapid deterioration of patients.

A final point we would like to make pertains to the issue of fecal viral shedding and fecal-oral transmission in children. Epidemiological investigations have found viral RNA in the stool of 8 of 10 children who tested positive for the virus via nasopharyngeal swab and moreover, the virus was detected in stool up to 27 days after admission, compared with up to 15 days via nasopharyngeal swab and at higher magnitudes of viral RNA detected in stool as compared to nasopharyngeal samples. However more studies are needed to determine if detection of viral RNA correlates to infectious virus in stool. [4] Certain recent reports identified viable virus in fecal samples from adult patients. [5] Given the large proportions of asymptomatic pediatric infections, lower severity of disease, and potential risk of fecal-oral transmission, it is highly likely that children have a distinct role in population transmission. We believe that the development of reliable and specific serological tests for SARS-CoV-2, such as those based on binding of serum antibodies to the viral spike protein, will play an important role in accurate detection of rates of infection in children.

1) Swann OV, Holden KA, Turtle L, Pollock L, Fairfield CJ, Drake TM, et al. Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study. BMJ. 2020;370:m3249.
http://dx.doi.org/10.1136/bmj.m3249

2) Kam K, Yung CF, Cui L, Lin RTP, Mak TM, Maiwald M, et al. A well infant with coronavirus disease 2019 with high viral load. Clin Infect Dis. 2020;71(15):847-9.

3) Blumfield E, Levin TL, Kurian J, Lee EY, Liszewski MC. Imaging findings in multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. -19. AJR. 2020. doi:10.2214/AJR.20.24032

4) Xu Y, Li X, Zhu B, et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med. March 2020:1-4. doi:10.1038/s41591-020-0817-4

5) Gu J, Han B, Wang J. COVID-19: Gastrointestinal manifestations and potential fecal-oral transmission. Gastroenterology. 2020;(April):118-119. doi:10.1053/j.gastro.2020.02.054

Competing interests: No competing interests

Dear Editor,

Swann et al clearly demonstrate that even in the rare case where a child is hospitalised with COVID-19, they are extremely unlikely to come to serious harm(1). This is some rare good news from this pandemic, along with the currently understanding that they are not primary drivers of disease spread(2). Children and young people do however continue to be hugely affected by lockdown and social-distancing policies (3).

We congratulate the government, schools, and teachers on achieving a return-to-school for the vast majority of pupils in the England, but are aghast to hear reports of mass exclusions and 14-day home imprisonment without exercise (“self isolation”) in the first few weeks of school-return, sometimes on the basis of single cases of children with positive PCR tests.

In several cases reported to us, one child with a positive PCR is leading to the two week exclusion of 100 other asymptomatic children in their year cohort or “bubble”, with no provision for home- or online-education. There is nothing to stop this recurring many times for the same child throughout this winter. On what basis? Public Health England guidance clearly states that exclusion should be made on the basis of “close contact”(4). When asked in parliament to clarify, the Secretary of State for Health Matt Hancock introduced the “bubble” concept in addition; as ever with covid-19 in England, confusion reigns supreme(5).

We urge the English Chief Medical Officer and Public Health colleagues to act urgently at a national and local level to prevent mass school-exclusion without good grounds. Until this is rectified, it is not accurate to say schools are open. The Royal College of Paediatrics & Child Health has spoken out consistently and clearly on the much greater risk to children of these exclusions over covid-19 itself (6), and is likely to be an important ally given their expertise in child health and wellbeing. We also urge BMJ readers who are school-governors, parents and members of local communities to challenge overzealous measures that are not in-line with Public Health guidance, in both the state and private sectors.

Today’s children are the future of our nation. Their education, socialisation and health are too important to be sacrificed without good reason. Without urgent action, the impact of overzealous measures will be felt for decades to come. Let us act now.

1. Swann OV, Holden KA, Turtle L, Pollock L, Fairfield CJ, Drake TM, et al. Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study. BMJ [Internet]. 2020 Aug 27;370. Available from: https://www.bmj.com/content/370/bmj.m3249
2. Boast A. An evidence summary of Paediatric COVID-19 literature. DFTB [Internet]. 2020 Apr 3; Available from: https://dontforgetthebubbles.com/evidence-summary-paediatric-covid-19-li...
3. Bhopal S, Devakumar D. Damage of the lockdown for children and young people – let’s choose a different path [Internet]. Reachwell. 2020. Available from: https://reachwell.org/2020/09/07/sunil-bhopal-and-delan-devakumar-damage...
4. Guidance for full opening: schools [Internet]. GOV.UK. [cited 2020 Sep 12]. Available from: https://www.gov.uk/government/publications/actions-for-schools-during-th...
5. Covid-19 Update - Hansard [Internet]. Available from: https://hansard.parliament.uk/Commons/2020-09-10/debates/9916644B-878C-4...
6. Royal College of Paediatrics & Child Health. Statement on schools re-opening [Internet]. [cited 2020 Sep 12]. Available from: https://www.rcpch.ac.uk/news-events/news/statement-schools-re-opening

Dear Editor

Swann et al.’s report of the ISARIC study identified a ‘systemic mucocutaneous-enteric’ cluster of paediatric COVID-19 symptoms: headache, myalgia, sore throat, vomiting, abdominal pain, diarrhoea, fatigue, rash, lymphadenopathy, and conjunctivitis (1). These symptoms mirror the Multisystem Inflammatory Syndrome in Children criteria and several were associated with disease severity in the study (1). Systematic reviews of COVID-19 in children have also posited that these systemic symptoms represent the more severe end of a spectrum of paediatric disease caused by SARS-CoV-2 (2). This is an important concept in terms of risk stratification and triage of COVID-19 patients, but could also be a unique feature of COVID-19 among other viral respiratory infections.

While reviews of paediatric viral respiratory infection have identified extrapulmonary manifestations of common viruses, these are quite rare (3). Dissemination of Respiratory Syncytial Virus is a known phenomenon and is thought to involve haematogenous spread to the cardiac and nervous system during very severe disease (4). This is quite different to SARS-CoV-2, which has been shown to regularly replicate in the intestinal mucosa, even if it has been cleared from the respiratory tract (5).

Evidence from systematic reviews has shown that influenza causes gastrointestinal manifestations in 2.8-30.9% of patients (6). These symptoms are not implicated in increased morbidity, though dissemination to multiple organs during end stage disease, similar to RSV, is reported (6). There is evidence that influenza can replicate within the GI tract, though it is poorly understood and studies explicitly linking stool PCR-positivity to faecal-oral transmission are lacking (6). Equally, studies analysing the clinical signs which predict severe outcomes in paediatric influenza infection usually report respiratory signs, such as chest indrawing/retractions, rather than systemic mucocutaneous-enteric symptoms (7, 8).

Reviews of the symptoms and outcomes of both parainfluenza virus and rhinovirus report predominantly respiratory symptoms with rare mention of enteric or mucocutaneous symptoms outside severe, disseminated disease (9, 10). Adenovirus causes a wide spectrum of disease, and the presentation of pharyngoconjunctival fever, which includes headache, lymphadenopathy, malaise and conjunctivitis, does bear some similarities with the mucocutaneous-enteric symptom cluster (11). Despite this, most paediatric deaths and admissions to intensive care from adenovirus are attributed to respiratory manifestations (11).

Rashes and conjunctivitis are also reported in paediatric viral respiratory infections, but they are typically not associated with severe outcomes (3). Indeed, mucocutaneous manifestations in childhood viral infection tend to be associated with different families of viruses such as herpesviruses (12).

In summary, while cutaneous and gastrointestinal symptoms are documented in common paediatric respiratory viruses they are typically not associated with disease severity and do not form their own clinical syndrome or cluster of symptoms, with the possible exception of adenovirus. This implies that COVID-19 in children is a more systemic infection than other paediatric viruses, with the ability to cause a variety of presentations.

This could be a useful factor to consider when trying to differentiate COVID-19 from other causes of paediatric viral illness, something that may become more important as we enter winter, the peak season for such viruses. Laboratory testing, of course, will remain the gold standard but these tests can take over 24 hours to be returned and, as recent events here in the North East have shown us, may not always be immediately available (13).

Finally, the regularity and severity of the extrapulmonary manifestations of paediatric COVID-19 support the argument of Gupta et al., that a more systemic treatment strategy, aiming to simultaneously manage both the respiratory and non-respiratory pathologies, may be required(14). This could include the usage of more systemically administered medications and wider panels of blood tests, as opposed to older treatment strategies for paediatric viral illnesses which tend to focus on respiratory support(3, 14).

1. Swann OV, Holden KA, Turtle L, Pollock L, Fairfield CJ, Drake TM, et al. Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study. BMJ. 2020;370:m3249.
2. Hoang A, Chorath K, Moreira A, Evans M, Burmeister-Morton F, Burmeister F, et al. COVID-19 in 7780 pediatric patients: A systematic review. EClinicalMedicine.
3. Tregoning JS, Schwarze J. Respiratory viral infections in infants: causes, clinical symptoms, virology, and immunology. Clin Microbiol Rev. 2010;23(1):74-98.
4. Eisenhut M. Extrapulmonary manifestations of severe respiratory syncytial virus infection--a systematic review. Crit Care. 2006;10(4):R107-R.
5. Yang L, Tu L. Implications of gastrointestinal manifestations of COVID-19. The Lancet Gastroenterology & Hepatology. 2020;5(7):629-30.
6. Minodier L, Charrel RN, Ceccaldi P-E, van der Werf S, Blanchon T, Hanslik T, et al. Prevalence of gastrointestinal symptoms in patients with influenza, clinical significance, and pathophysiology of human influenza viruses in faecal samples: what do we know? Virol J. 2015;12:215-.
7. Shi T, Nie Z, Huang L, Fan H, Lu G, Yang D, et al. Mortality risk factors in children with severe influenza virus infection admitted to the pediatric intensive care unit. Medicine (Baltimore). 2019;98(35):e16861-e.
8. Dalziel SR, Thompson JMD, Macias CG, Fernandes RM, Johnson DW, Waisman Y, et al. Predictors of severe H1N1 infection in children presenting within Pediatric Emergency Research Networks (PERN): retrospective case-control study. BMJ : British Medical Journal. 2013;347:f4836.
9. Jacobs SE, Lamson DM, St. George K, Walsh TJ. Human Rhinoviruses. Clinical Microbiology Reviews. 2013;26(1):135.
10. Branche AR, Falsey AR. Parainfluenza Virus Infection. Semin Respir Crit Care Med. 2016;37(4):538-54.
11. Khanal S, Ghimire P, Dhamoon AS. The Repertoire of Adenovirus in Human Disease: The Innocuous to the Deadly. Biomedicines. 2018;6(1):30.
12. Vander Straten M, Tyring SK. Mucocutaneous manifestations of viral diseases in children. Clinics in Dermatology. 2002;20(1):67-73.
13. J H, H P. Coronavirus tests run out in north-east England as cases surge. The Guardian. 2020.
14. Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nature Medicine. 2020;26(7):1017-32.

Dear Editor.

Lessons for the current and future pandemics.

In the week the children are returning to school in the UK, although it is acknowledged they are at low risk from COVID (Swann et al., 2020), it is surprising we are still having the debate about the use of face masks. From the beginning, we have been told the government is ‘following the science’, which in turn waited for published evidence to be generated on issues ranging from whether SARS-CoV-2 spreads by droplets or aerosols to how long it can survive on various surfaces. However, the benefits of wearing a face mask, avoiding crowded places and social distancing, for a respiratory condition spread by an airborne virus, are a matter of common sense. The benefits of these measures were recognised at the time of the Spanish flu in 1918 (Markel et al., 2007). Recently, there has been a dramatic decrease in the number of deaths from flu in the southern hemisphere, which also reflects the benefits of restrictions on international travel (Servick, 2020). It then follows that hand washing and social distancing alone might be giving people a false sense of security, and we don’t need to wait for a peer reviewed publication, to inform us of the importance of adequate ventilation in all enclosed spaces.

Many critical policy mistakes have been made in the UK since the start of the pandemic. We ignored early warnings dating back to 2015 (Gates, 2015; Menachery, 2015). We ignored the devastating impact of COVID-19 in mainland Europe, dithering between mitigation and suppression, playing a blame game, and delaying the lockdown. We relied too much on modelling to predict what the worst case scenario might be, and at what point will our hospitals be unable to cope, while ignoring the tasks at hand - the devastating effects on front line healthcare workers, lack of availability of PPE, disproportionate effect of COVID on minorities, track and tracing, to name a few. We acted too late. We have amongst the worst rates for COVID in the world. Unlike other countries with a far better record of containment, including China, South Korea and Taiwan, we have not been preparing for this pandemic. Interestingly, the vice president of Taiwan, Chen-Jen, a former epidemiologist trained at Johns Hopkins university, put plans in place that have been in the making for almost 20 years.

It is about time we recognize the best science in the world is not just being carried out in UK and major new insights into COVID-19 have come out of studies from China, USA, Germany and the rest of the world. Therefore, it would make sense to broaden the government scientific advisory base to include more basic scientists, especially virologists, and follow the lead of the MRC and the Wellcome Trust scientific advisory panels to include international experts.

Meanwhile COVID19 has highlighted some stark inequalities, with a disproportionate effect on some communities. Many of the underlying comorbidities are most prevalent in the most deprived and under-represented members of society, and in light of the ‘Black Lives Matter’ campaign, racism is now recognised as a public health issue. Coronavirus doesn’t see race but responds to racism. Furthermore, we cannot exclude the environmental effects of malnutrition, and adverse life circumstances or poverty, on our genes.

Many questions remain, including the origin of SARS-CoV-2. No intermediate hosts have been identified despite the fact its nearest match is the horseshoe bat coronavirus (RaTG13) which diverged approximately 40 years ago (Boni et al., 2020). The origin of SARS, which also originated from bats in China, also remains unknown almost 20 years since the outbreak (Cui, Li, and Shi, 2019). It was proposed the virus adapted in humans by natural selection (Andersen et al., 2020), but there is no evidence for this, and moreover this appears to be a slowly mutating virus (Kupferschmidt, 2020).

Bats are natural reservoirs for viruses that have some of the highest fatality rates of any viruses that people acquire from wild animals – including rabies, Ebola and the SARS coronavirus. Yet attempts to identify the source in bats have been stopped in their tracks by political meddling from the Trump administration which rescinded NIH funding to the EcoHealth Alliance (Wadman, 2020). On the other hand, the inadvertent escape of viruses from research labs (Nomile, 2004) is also a big concern and needs policing.

Amidst all this uncertainty and gloom, the only thing we can be certain of is the presence of hundreds of bat coronaviruses with zoonotic potential (Latinne et al., 2020). With increasing globalisation, destruction of ecosystems and trade in and consumption of endangered species, future pandemics can’t be ruled out, so let’s prepare for the worst. Even the 2011 blockbuster movie Contagion, saw this coming!

Jamal Nasir, Ph.D. Division of Life Sciences, University of Northampton.
Nirmal Vadgama, Ph.D. Department of Cardiovascular Surgery, Stanford University School of Medicine.

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