Dr Amanda Kvalsvig, Dr Anna Brooks, Prof Nick Wilson, Dr Julie Bennett, Dr Jennifer Summers, Carmen Timu-Parata, Dr Cervantée Wild, Belinda Tuari-Toma, Constanza Jackson, Prof Michael Baker*
Longer-term (or ‘post-acute effects’) of Covid-19 in children (including multisystem inflammatory syndrome in children [MIS-C] and long Covid) are well-described. But there is a lack of robust evidence about the prevalence of these conditions. In this blog we summarise findings from a rapid review of the evidence. These findings indicate to us the need for a precautionary approach in Aotearoa New Zealand (NZ) with greater efforts to prevent children from being infected during the current Omicron outbreak. Protections for children could include improvements to ventilation, mask use, and vaccine equity, and a lower threshold for closing schools and early childhood facilities with greater support for temporary home learning when community transmission is high.
Post-acute effects of infection are a well-known phenomenon
The effects of infection are said to be ‘post-acute’ when they are not part of the original infective illness. Post-acute effects have been described in all infectious diseases of childhood of public health significance. For example, rheumatic fever is a post-acute complication of streptococcal infection of the throat or skin, and multiple sclerosis can occur years after Epstein-Barr infection (glandular fever).1
In the 21st century there have been three multi-region coronavirus epidemics/pandemics. In the first two, SARS-CoV from 2002 and MERS-CoV from 2012, post-acute effects have been noted up to 15 years after initial infection.2 In the third, the current SARS-CoV-2 pandemic causing Covid-19 infection, the full extent of post-acute effects is not yet known.
Overview of post-acute effects of Covid-19 infection in children
In childhood Covid-19 infection, it is useful to consider post-acute effects in three main groups:
- Multisystem inflammatory syndrome in children (MIS-C), a severe syndrome that occurs from about 2 weeks after the initial illness.
- Longer-term effects grouped under an umbrella term, long Covid; the most common features are fatigue, breathlessness, cognitive dysfunction, and loss of taste or smell, with evidence of multiple organ system involvement.
- Chronic conditions that were known prior to the pandemic and are now being seen with new onset triggered by Covid-19 infection, eg, damage to heart, lungs, and brain.
The above picture which is oriented around symptoms is likely to evolve with further research. Already symptomology shows significant overlap with other post-viral conditions;3 4 the associated immune dysfunction is not completely understood but is likely due to both direct viral infection of cells and indirect immune mediated mechanisms.
All of the above post-acute complications of Covid-19 illness appear to share a common underlying mechanism of dysfunction in the immune system (eg, development of autoimmunity, and unresolved inflammation) and/or widespread vascular/endothelial dysfunction resulting in disrupted blood clotting pathways.5 6 Viral persistence or debris may also be involved in ongoing inflammation in some cases. While most of this work has been conducted in adults, studies have demonstrated that the same pathways are also activated in children.7-9
Multisystem Inflammatory Syndrome in Children (MIS-C)
MIS-C (also known as Paediatric Inflammatory Multisystem Syndrome [PIMS] in some jurisdictions) is a severe inflammatory syndrome unique to Covid-19. Peaks in MIS-C incidence typically occur 2-5 weeks after peaks in acute infections.11
The CDC case definition includes a threshold level of clinical severity (hospitalisation, raised inflammatory markers); Covid-19 infection; and involvement of two or more organ systems (cardiac, renal, respiratory, haematologic, gastrointestinal, dermatologic or neurological). When children meet the case definition the majority require ICU care.11 12
MIS-C mainly affects primary school aged children with half of cases in the US aged 5-13 years (median age is 9 years). To date, there have been 7,459 cases and 63 deaths from MIS-C in the US (with more cases expected following the recent Omicron peak). Estimates of the population incidence of MIS-C cases during active outbreaks vary widely, from 11 cases per 100 000 population <20 years in New York City over four months in 2020,13 to a range of 138-627 cases per 1 000 000 SARS-CoV-2 infections in different US states.14 In NZ, it is currently still too early in the Omicron wave for cases to have been detected.
Inequities in risk are commonly seen: 58% of the total cases in the US have been children identifying as “Hispanic/Latino” or “Black, Non-Hispanic” ethnicity; these are minority populations in the US. An earlier US series also reported increased risk in children with ‘Asian or Pacific Islander’ ethnicity.14 The risk of clotting/thrombosis, a serious complication, is strongly associated with ethnicity.8 The CDC reports that vaccination appears protective against MIS-C in 12-18 year-olds, although with the caveat that this analysis was of a Delta outbreak.15
Long Covid is a condition that can occur following severe, mild, or even asymptomatic SARS-CoV-2 infection. It is also known as post-acute sequelae of SARS-CoV-2 infection (PASC). Long Covid is characterised by symptoms and pathology that persist beyond the acute episode. Almost any organ system can be involved, but common features in children are fatigue, sleep disturbances, headache, poor concentration, and loss of smell or taste.10 The proportion of child Covid-19 cases that progress to long Covid is difficult to ascertain because of a range of methodological challenges, in particular, accurately identifying children with no previous Covid-19 infection as controls, and the fact that Covid-19 pathology (eg, hypoperfusion) needs specialist investigations not usually performed by paediatric services.16 17 Our review has not identified any studies that have been able to overcome these difficulties and provide a valid and precise estimate of the proportion of child Covid-19 cases experiencing ongoing symptoms. More information is needed before we can quantify the likely impact in Aotearoa NZ.
However, as an indication of the potential scale of children experiencing prolonged symptoms, the most recent ONS study analysis in England shows that in the period March 2020 to November/December 2021 (ie, just before the Omicron peak), 1% of all primary school aged children and 2.7% of all secondary school aged children (ie, the full child population, not just Covid cases) met the study Delphi criteria for long Covid. This definition is a positive test for Covid-19 infection, the presence of symptoms continuously over a 12-week period or longer; and everyday life affected by these symptoms.18
Case data show that long Covid may make children feel unwell for months and some have not recovered two years after infection, with impacts on their physical and social development, education attainment, and mental health. As each individual experiences different patterns and varied severity of symptoms, accessing appropriate support from health providers can be difficult. In the UK some patients report receiving misguided assessment and treatment or dismissive behaviour from some health professionals.19 20 There is some evidence of a reduction in long Covid symptoms after vaccination in adults, but all previous studies were based on protection from the Delta variant, and as yet there are no study results for children.
Some examples of organ-specific damage in children that may lead to long-term impairment include:
- Brain and nervous system: A wide spectrum of neurological impacts of Covid-19 infection has been described in children,21 22 raising concerns about the impact of Covid-19 on the developing brain.
- Respiratory: Ongoing symptoms (eg, feeling short of breath) can occur in children following a mild initial infection23 and lung pathology may not be detectable using common investigations.16
- Gastrointestinal: Markers of viral persistence and inflammation in the gut in MIS-C24 and disruption of the gut microbiome25 indicate potential for future gastrointestinal disease.
- Cardiovascular system: Post-acute cardiovascular risks in adults are well-studied and are highly concerning.26 In children, myocarditis can occur as a component of MIS-C or in isolation. On average children experience milder cardiac symptoms than adults in the acute phase, but abnormal heart rhythms (measured by ECG) and raised inflammatory and cardiac markers can be detected in children in the post-acute phase,27 28 29 30 raising questions about ongoing subclinical levels of risk.
- Diabetes: The case is building for a causal impact of Covid-19 infection on onset of Type 1 diabetes. Type 1 diabetes has a genetic and immune origin. It is a lifelong condition, and onset is often associated with a previous infectious disease episode.31 Clinical reports32 33 are supported by research showing direct damage to β-cells (insulin-producing cells in the pancreas) by the SARS-CoV-2 virus.34 35
Chronic conditions may have serious and lifelong effects and the extent of these effects is still unknown. While most children are showing resolution of post-acute symptoms with time, there are children still experiencing significant symptoms two years after the initial infection in early 2020. Tissue-level effects such as endothelial damage may not develop into clinical disease until much later in life.36
Findings in adults suggest that vaccination is likely to provide some protection against long Covid risk, with the caveat that studies were based on the Delta variant where vaccination provided excellent protection against symptomatic infection. Given symptomatic infection from Omicron is common even when vaccinated, extrapolating these results may not predict protection accurately. A layered ‘vaccine plus’ approach to protection will be needed.
What are the potential long-term impacts of the pandemic for Aotearoa NZ?
Although Covid-19 is spread by the respiratory route, it is best considered as a multisystem disease. Research to date shows that serious effects are less common in children than in adults, but they can be life-changing or life-limiting. As more children become infected with Omicron, post-acute effects have the potential to generate population-level impacts. These impacts may be experienced throughout the life-course in underserved communities living with intergenerational history of chronic illnesses due to inadequate living standards and poor access to quality health care.
These new health problems could place additional demands on health and education services in NZ,37 and on workplaces through caregiver absenteeism. There is a high probability that post-acute impacts of Covid-19 will be focused in communities that were already at crisis point in health, education, justice, and overall wellness. Māori and Pacific children are likely to be at a significantly higher risk because vaccine coverage is lower and Covid-19 rates are higher (compared to Asian and European children in NZ), incidence of MIS-C is likely to be higher,11 13 and they will likely experience greater barriers to supportive health care.
Potential next steps for Aotearoa NZ
The current policy of the NZ Government that “closing schools is the last resort” is potentially problematic in that it allows for exposing a large number of children, families, and teachers to infection during the Omicron outbreak. Because post-acute effects have a time lag following acute infection, it will be many months before the impact of post-acute effects from the Omicron outbreak can be estimated in NZ. We propose the following measures to minimise the risk of post-acute effects of Covid-19 in NZ children:
- Until more is known, a precautionary approach should be taken, ie, we should try to minimise widespread Covid-19 infection in children. This position is supported by a child rights-focused and whānau-centred approach for children in the pandemic with particular protections for whānau at higher risk of infection and post-acute effects.
- Specific measures are needed to protect children’s health and wellbeing during the Omicron outbreak including reducing transmission in schools and early childhood education settings (eg, improving ventilation and appropriate mask use), and supporting online learning.
- Vaccination may reduce risk and should be actively promoted for children, and Government needs to better support and work alongside Māori leadership to achieve high equity in vaccine coverage.
- It is vital that parents and clinicians are provided with information about these conditions and that clinicians listen to family concerns.38 39 Because Omicron has often been mis-portrayed as a “mild” variant, families and clinicians may be unaware of the symptoms of post-acute effects.37 MIS-C is less common but straightforward to diagnose. Long Covid is more common, but can be difficult to identify.37 40 Research on treatment of post-acute effects of Covid is promising but it will likely require early diagnosis for optimum treatment efficacy; in the meantime families should be advised that children should not ‘push through’ fatigue and to seek professional care.
- NZ should use modelling with careful sensitivity analyses to estimate the range of possible impacts of post-acute effects of Covid-19 on NZ children, particularly those with existing acute and chronic conditions including disabilities. This modelling could inform further risk assessment and infection control policies relevant to children, eg, vaccine strategy and mask wearing. There are varying estimates of the prevalence of post-acute effects but there is reasonable understanding of the mechanisms by which different study designs under- or -overestimate prevalence,17 40 41 and there is enough evidence to indicate that this issue requires serious attention to both prevention and ongoing management.
- NZ needs a national survey (similar to the UK ONS survey) and utilisation of existing population surveys in NZ to monitor wellbeing including post-acute symptoms, with data linkage to follow this cohort of children over the coming decades using NZ’s Integrated Data Infrastructure (IDI). It is important to collect high-quality data on differential impacts by ethnicity in view of likely inequities in incidence and access to care.
* Author details: Brooks is an immunologist, School of Biological Sciences, University of Auckland; Wild is an Honorary Academic, Department of Paediatrics: Child and Youth Health, FMHS, University of Auckland and Girdlers’ Research Fellow, Department of Primary Care Health Sciences, University of Oxford; Tuari-Toma is a Policy Analyst Māori, Hauora. All other authors are with the Department of Public Health, University of Otago Wellington. The lead author (AK) is an epidemiologist and former paediatrician (Email: Amanda.Kvalsvig@otago.ac.nz).
- Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Sci 2022;375(6578):296-301. doi: doi:10.1126/science.abj8222
- O’Sullivan O. Long-term sequelae following previous coronavirus epidemics. Clin Med (Lond) 2020 doi: 10.7861/clinmed.2020-0204
- Campen CMCv, Rowe PC, Visser FC. Orthostatic Symptoms and Reductions in Cerebral Blood Flow in Long-Haul COVID-19 Patients: Similarities with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Medicina 2022;58(1):28.
- Petracek LS, Suskauer SJ, Vickers RF, et al. Adolescent and Young Adult ME/CFS After Confirmed or Probable COVID-19. Front Med (Lausanne) 2021;8 doi: 10.3389/fmed.2021.668944
- Mehandru S, Merad M. Pathological sequelae of long-haul COVID. Nat Immunol 2022;23(2):194-202. doi: 10.1038/s41590-021-01104-y
- Fogarty H, Townsend L, Morrin H, et al. Persistent endotheliopathy in the pathogenesis of long COVID syndrome. J Thromb Haemost 2021;19(10):2546-53. doi: https://doi.org/10.1111/jth.15490
- Diorio C, McNerney KO, Lambert M, et al. Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations. Blood Adv 2020;4(23):6051-63. doi: 10.1182/bloodadvances.2020003471
- Whitworth H, Sartain SE, Kumar R, et al. Rate of thrombosis in children and adolescents hospitalized with COVID-19 or MIS-C. Blood 2021;138(2):190-98. doi: 10.1182/blood.2020010218
- Gavriilaki E, Eftychidis I, Papassotiriou I. Update on endothelial dysfunction in COVID-19: severe disease, long COVID-19 and pediatric characteristics. J Lab Med 2021;45(6):293-302. doi: doi:10.1515/labmed-2021-0134
- Jiang DH, Roy DJ, Gu BJ, et al. Postacute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A State-of-the-Art Review. JACC Basic Transl Sci 2021;6(9):796-811. doi: https://doi.org/10.1016/j.jacbts.2021.07.002
- Belay ED, Abrams J, Oster ME, et al. Trends in Geographic and Temporal Distribution of US Children With Multisystem Inflammatory Syndrome During the COVID-19 Pandemic. JAMA Pediatrics 2021;175(8):837-45. doi: 10.1001/jamapediatrics.2021.0630
- Dufort EM, Koumans EH, Chow EJ, et al. Multisystem Inflammatory Syndrome in Children in New York State. N Engl J Med 2020;383(4):347-58. doi: 10.1056/NEJMoa2021756 [published Online First: 2020/06/29]
- Lee EH, Kepler KL, Geevarughese A, et al. Race/Ethnicity Among Children With COVID-19–Associated Multisystem Inflammatory Syndrome. JAMA Netw Open 2020;3(11):e2030280-e80. doi: 10.1001/jamanetworkopen.2020.30280
- Payne AB, Gilani Z, Godfred-Cato S, et al. Incidence of Multisystem Inflammatory Syndrome in Children Among US Persons Infected With SARS-CoV-2. JAMA Netw Open 2021;4(6):e2116420-e20. doi: 10.1001/jamanetworkopen.2021.16420
- Zambrano LD, Newhams MM, Olson SM, et al. Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA Vaccination Against Multisystem Inflammatory Syndrome in Children Among Persons Aged 12-18 Years – United States, July-December 2021. MMWR Morb Mortal Wkly Rep 2022;71(2):52-58. doi: 10.15585/mmwr.mm7102e1
- Buonsenso D, Di Giuda D, Sigfrid L, et al. Evidence of lung perfusion defects and ongoing inflammation in an adolescent with post-acute sequelae of SARS-CoV-2 infection. Lancet Child Adolesc Health 2021;5(9):677-80. doi: 10.1016/S2352-4642(21)00196-6
- Gurdasani D, Akrami A, Bradley VC, et al. Long COVID in children. Lancet Child Adolesc Health 2022;6(1):e2. doi: 10.1016/S2352-4642(21)00342-4
- Stephenson T, Pinto Pereira SM, Shafran R, et al. Physical and mental health 3 months after SARS-CoV-2 infection (long COVID) among adolescents in England (CLoCk): a national matched cohort study. Lancet Child Adolesc Health doi: 10.1016/S2352-4642(22)00022-0
- Gorna R, MacDermott N, Rayner C, et al. Long COVID guidelines need to reflect lived experience. Lancet 2021;397(10273):455-57. doi: 10.1016/s0140-6736(20)32705-7 [published Online First: 2020/12/29]
- Alwan NA. Lessons from Long COVID: working with patients to design better research. Nat Rev Immunol 2022 doi: 10.1038/s41577-022-00692-6
- Schober ME, Pavia AT, Bohnsack JF. Neurologic Manifestations of COVID-19 in Children: Emerging Pathophysiologic Insights. Pediatr Crit Care Med 2021 doi: 10.1097/PCC.0000000000002774
- Mun-Ching Wong A, Toh CH. Spectrum of neuroimaging mimics in children with COVID-19 infection. Biomed J 2021 doi: https://doi.org/10.1016/j.bj.2021.11.005
- Leftin Dobkin SC, Collaco JM, McGrath-Morrow SA. Protracted respiratory findings in children post-SARS-CoV-2 infection. Pediatr Pulmonol 2021;56(12):3682-87. doi: https://doi.org/10.1002/ppul.25671
- Yonker LM, Gilboa T, Ogata AF, et al. Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier. J Clin Invest 2021;131(14) doi: 10.1172/JCI149633
- Xu R, Liu P, Zhang T, et al. Progressive deterioration of the upper respiratory tract and the gut microbiomes in children during the early infection stages of COVID-19. Journal of Genetics and Genomics 2021;48(9):803-14. doi: https://doi.org/10.1016/j.jgg.2021.05.004
- Xie Y, Xu E, Bowe B, et al. Long-term cardiovascular outcomes of COVID-19. Nat Med 2022 doi: 10.1038/s41591-022-01689-3
- Güllü UU, Güngör Ş, İpek S, et al. Predictive value of cardiac markers in the prognosis of COVID-19 in children. Am J Emerg Med 2021;48:307-11. doi: https://doi.org/10.1016/j.ajem.2021.06.075
- Saed Aldien A, Ganesan GS, Wahbeh F, et al. Systemic Inflammation May Induce Cardiac Injury in COVID-19 Patients Including Children and Adolescents Without Underlying Cardiovascular Diseases: A Systematic Review. Cardiovasc Revasc Med 2022;35:169-78. doi: https://doi.org/10.1016/j.carrev.2021.04.007
- Ece İ, Koçoğlu M, Kavurt AV, et al. Assessment of Cardiac Arrhythmic Risk in Children With Covid-19 Infection. Pediatric Cardiology 2021;42(2):264-68. doi: 10.1007/s00246-020-02474-0
- Boehmer TK, Kompaniyets L, Lavery AM, et al. Association between COVID-19 and myocarditis using hospital-based administrative data—United States, March 2020–January 2021. Morb Mortal Wkly Rep 2021;70(35):1228.
- Katsarou A, Gudbjörnsdottir S, Rawshani A, et al. Type 1 diabetes mellitus. Nature Reviews Disease Primers 2017;3(1):17016. doi: 10.1038/nrdp.2017.16
- Gottesman BL, Yu J, Tanaka C, et al. Incidence of New-Onset Type 1 Diabetes Among US Children During the COVID-19 Global Pandemic. JAMA Pediatrics 2022 doi: 10.1001/jamapediatrics.2021.5801
- Alfishawy M, Nassar M, Mohamed M, et al. New-onset type 1 diabetes mellitus with diabetic ketoacidosis and pancreatitis in a patient with COVID-19. Sci African 2021;13:e00915.
- Mine K, Nagafuchi S, Mori H, et al. SARS-CoV-2 Infection and Pancreatic β Cell Failure. Biology (Basel) 2021;11(1) doi: 10.3390/biology11010022 [published Online First: 2022/01/22]
- Wu CT, Lidsky PV, Xiao Y, et al. SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment. Cell Metab 2021;33(8):1565-76.e5. doi: 10.1016/j.cmet.2021.05.013 [published Online First: 2021/06/04]
- Davignon J, Ganz P. Role of Endothelial Dysfunction in Atherosclerosis. Circulation 2004;109(23_suppl_1):III-27-III-32. doi: doi:10.1161/01.CIR.0000131515.03336.f8
- Magnusson K, Skyrud KD, Suren P, et al. Healthcare use in 700 000 children and adolescents for six months after covid-19: before and after register based cohort study. BMJ 2022;376:e066809. doi: 10.1136/bmj-2021-066809
- Munblit D, Simpson F, Mabbitt J, et al. Legacy of COVID-19 infection in children: long-COVID will have a lifelong health/economic impact. Arch Dis Child 2022;107(3):e2-e2. doi: 10.1136/archdischild-2021-321882
- Walker AJ, MacKenna B, Inglesby P, et al. Clinical coding of long COVID in English primary care: a federated analysis of 58 million patient records <em>in situ</em> using OpenSAFELY. British Journal of General Practice 2021;71(712):e806-e14. doi: 10.3399/bjgp.2021.0301
- Munblit D, Sigfrid L, Warner JO. Setting Priorities to Address Research Gaps in Long-term COVID-19 Outcomes in Children. JAMA Pediatrics 2021;175(11):1095-96. doi: 10.1001/jamapediatrics.2021.2281
- Roessler M, Tesch F, Batram M, et al. Post COVID-19 in children, adolescents, and adults: results of a matched cohort study including more than 150,000 individuals with COVID-19. MedRxiv 2021