Poor Association Between Clinical Characteristics and Seropositivity in Children With Suspected [LC]—A Single-Centre Study, 2025, Olsson-Åkefeld et al

Poor Association Between Clinical Characteristics and Seropositivity in Children With Suspected Long COVID—A Single-Centre Study

S. Olsson-Åkefeldt, J. Luthander, L. Anmyr, L. Villard, S. Arnason, M. K. Kemani, E. Wållgren, S. Röstlund, M. Tingborn, M. Pettersson, E. George, M. Ryd-Rinder, O. Hertting

Aim
We aimed to compare characteristics and clinical presentation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody positive or negative children attending a specialist outpatient clinic for suspected paediatric long COVID.

Methods
A cross-sectional study was conducted of 113 children and adolescents enrolled between 1 December 2020 to 14 September 2021 in a multidisciplinary programme. Clinical and epidemiological data were collected with standardised interviews and laboratory tests including SARS-CoV-2 spike antibody measurement.

Results
A serological link to SARS-CoV-2 infection was found in 52%. Most patients (94.7%) reported several symptoms. Fatigue, post-exertional malaise, dizziness, nausea, headache, and concentration difficulties were the most common. Seronegative children had a higher number of individual symptoms. School absence and drop-out from leisure activities was substantial in both groups with higher numbers for the seronegative group. Self-reported health was low in both groups.

Conclusion
Children attending a specialist paediatric long COVID clinic experienced multiple symptoms and poor self-reported health. The symptomatology was similar regardless of serological status, implying multifactorial causes. A multidisciplinary assessment of this cohort was essential considering the broad spectrum of symptoms displayed and their substantial impact on everyday functioning.

Link | PDF (Acta Paediatrica) [Open Access]

 

Additionally, it is well known that viruses other than SARS-CoV-2, like Epstein–Barr virus, can cause long-standing fatigue in children and adolescents [13]. We aimed to study if children with COVID-19 antibodies, differed from seronegative children in symptom characteristics, school attendance and self-reported health.

(…)

This study cohort comprised patients 0–18 years referred to a specialist outpatient clinic at Astrid Lindgren Children's Hospital in Stockholm, Sweden 1 December 2020 to 14 September 2021. All had long-term symptoms after suspected, probable or confirmed COVID-19 as classified by the World Health Organisation (WHO) case definition [15].

(…)

Our study had several limitations. Certain data on symptom characteristics were missing for some participants, making the data sets incomplete. This may have influenced the findings. Most evident is however that, since PCR was not readily used in the early phase of the pandemic, PCR data are lacking. Instead, we used the WHO Case definition for COVID-19. These criteria are more subjective and may not accurately define COVID-19 disease. All patients were tested for SARS-CoV-2 antibodies, which is suggested by Stephenson as part of the definition of long COVID if PCR or antigen testing is not available [11].

(…)

From supplement file 1:
Laboratory tests:
Blood: ESR, CRP, full blood count, white blood cells, TSH, T4, sodium, potassium, calcium, magnesium, phosphate, chloride, creatinine, urea, cystatin-C, albumin, AST, ALT, ALP, GT, bilirubin, LD, ferritin, CK, CKMB, troponin T, NT-proBNP, INR, fibrinogen, d-dimer

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Maybe the seronegative patients had EBV or another infection they didn’t test for? It’s reasonable to assume that parents or doctors assume they had Covid in the middle of a pandemic, even though they might have had something else. This is a massive source of selection bias because all the participants were referrals to a specialist clinic.

Of course they conclude that multidiciplinary approaches might be warranted..

 

With the slightest possible nod to the reality that they actually had Covid (this was let-it rip Sweden after all) but didn't seroconvert. From Wikipedia —

But no: apparently lock-downs.

 

@Midnattsol mentioned elsewhere that serumnegative does not alway equal no covid-infection - if I got that right?

So some of the negative kids might have had LC.

 

Studies looking at seronegativity —

Divergent adaptive immune responses define two types of long COVID (2023, Frontiers in Immunology)

Distinct T cell functional profiles in SARS-CoV-2 seropositive and seronegative children associated with endemic human coronavirus cross-reactivity (2023, Preprint: MedRxiv)

Memory SARS-CoV-2 T-cell response in convalescent COVID-19 patients with undetectable specific IgG antibodies: a comparative study (2023, Frontiers in Immunology)

Evidence of previous SARS-CoV-2 infection in seronegative patients with long COVID (2022, Lancet: eBioMedicine)

Comparison of Seroconversion in Children and Adults With Mild COVID-19 (2022, JAMA Network Open)

Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2 (2021, Nature)

 

It can vary greatly between individuals and also based on when the infection occurred. Seronegatively should not lead to an automatic assumption that the person did not have COVID-19.

 

Given that essentially everyone has had Covid at least once, seronegativity may turn out to be a risk factor for LC —

Divergent adaptive immune responses define two types of long COVID (2023, Frontiers in Immunology) —

Clinical and serological predictors of post COVID-19 condition–findings from a Canadian prospective cohort study (2024, Frontiers in Public Health) —

 

good point.