Limitations of this review

This review has several limitations:

• First, due to our strict selection criteria and our distinction between prevalence of long COVID (or symptom) and symptom frequency, our conclusions may differ from other reviews that include studies from any setting, with a lower sample size, and which report risk factors identified in non-adjusted analyses as well, or studies not comparing long COVID to short COVID.

• Second, the interpretation of results is limited by our inclusion criteria, since we include only studies from Europe and US. Risk factors and comorbidities can considerably vary also within the countries that we selected.

• Third, the paediatric population is underrepresented in our review.

Studies including children are sparse and have frequently limited size (case reports, case series). Reported prevalences are heterogeneous but lower than prevalences reported in adults. In the update of June 2021, the ONS survey described that self-reported long COVID was lower in children aged 2 to 16 years than in the adult age group. The prevalence of long-lasting symptoms beyond 12 weeks was 7.4%

(update of April 2021). One of the largest study, at the present time,

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(preprint) was conducted in Russia and reported a prevalence of 24.3%, several months after hospital discharge (median follow-up 256 days).⁷⁹ The most frequently reported symptoms were fatigue, sleep disturbances and sensory problems. Another large study conducted on 1734 positive-tested children aimed at determinig the illness duration.

Only 2.2% of them presented to the emergency department or were admitted to hospital. For 4.4% of children, the disease lasted at least 4 weeks, with fatigue, headache and anosmia as commonest symptoms, while 1.8% of experienced a prolonged illness, for at least 8 weeks.

Negative-tested symptomatic children were matched to positive-tested children. Few children (0.9%) who tested negative reported an illness durartion of 28 days or more.⁸⁰ A study conducted in Switzerland reported lower prevalences in a group of children who were not hospitalised.⁸¹ A comparison was made between 109 children seropositive for SARS-CoV-2 and seronegative ones (various testings phases performed on a randomly selected sample among schools).

Four percents of seropositive children reported persisting symptoms, versus 2% in the seronegative group. The symptoms lasting more that 3 months were fatigue, difficulty of concentrating and increased need for sleep. A cohort study conducted on children in England aimed to describe the phenotype and prevalence of post-COVID physical symptoms (and mental health issues) among 3 065 children with confirmed COVID-19 and 3 739 negative controls. The cohort of SARS-CoV-2 PCR-positive children aged 11-17 years was matched on timing of testing, age, sex and geographical area to PCR negative-controls.

Participants were invited to fill a questionnaire. The study emphasised the importance of having a control test-negative group to objectively interpret the prevalence estimates of symptoms: three months after testing, both groups presented symptoms but the prevalence was higher in the positive tested group (66.5% in positive-tested children versus 53.4% in negative-tested ones). In addition, the prevalence of multiple symptoms (more than 3 symptoms) was higher in the children who got sick with COVID-19 that in control group (30.3% versus 16.2%). The most frequent symptoms were tiredness, headache, loss of smell and shortness of breath.⁸²

• Data aiming at quantifying the burden of long COVID on unemployment, sick-leave or disability leave (See 6.5 Consequences on daily-life) may considerably be influenced by the laws of each country and will have to be interpreted with great caution.

• We did not report the list of excluded studies and we did not analyse whether our conclusion varied from the conclusions of studies with smaller sample sizes.

• The data extraction was not done in duplicate. However a sample of studies was checked by a second researcher (in case of doubt the researcher performing the data extraction asked to cross-check the extraction by a second researcher).

Limitations for the assessment of long COVID prevalence and risk factors

• Variability in the definition of long COVID across studies:

o Symptom pattern variability

o Permanent organ damage as sequelae of the acute phase, or not

o Severity of persistent symptoms and requirement for hospital admission

o Difficulty in knowing to what extent long COVID symptoms are excess symptoms

o Difficulty in accurate diagnosis (overlap with different disease, prexisting symptoms or comorbidities)

• Heterogeneity of targeted populations:

o Severity and level of care of acute infection (ambulatory, hospitalisation, need for ICU admission)

o Characteristics and risk factors of studied populations

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o Sample sizes variability

• Variability of study design: time of inclusion, follow-up duration, number of follow-ups, omission of reporting frequencies of symptoms and large loss to follow-up

• High risk of recall bias (self-reporting; no objective measurement) and lack of control group in most studies

• Underestimation in people who were infected during the first wave of pandemic and were not tested

• Few data on long COVID is available in patients who had asymptomatic infection

7.4 Perspectives

• A proper and appropriate definition of long COVID would guide more efficiently the future research on its diagnosis and the management.

More research on the characterisation and classification of long COVID symptoms is indeed needed. To this end, a distinction should have to be made between long COVID symptoms and post-COVID conditions that refers for the most part to symptoms related to residual organ damage (and post-intensive care syndrome) and, sometimes, not necessarily specific to COVID-19. Picking out what is related to PICS or other overlapping issues would allow a better definition and characterization of subgroups.

• Since there is now evidence that long COVID symptoms fluctuate over time, further studies should always promote assessments at different time points and seek for markers of evolution.

• In order to minimise recall bias, newly conducted studies should assess symptoms during medical visits and by using appropriate and validated tools such as spirometry, cardiac echography or validated measurement scales. This approach could probably reduce the hetereogeneity of reported prevalences. Since long COVID symptoms might overlap with other issues and seeing that it is not uncommon to

present long-lasting symptoms after some infections, a control population should be included in the experimental design.

• Better quality data are needed. Accordingly, determining long COVID prevalences within each level of severity would harmonise the results.

• Addressing the question of the underlying causes of long COVID is a priority to better classify complaints and provide new insights on how to prevent and manage it.

• Even if children seem to be protected from critical form of COVID-19, capturing more data into paediatric long COVID is urgently needed to built appropriate guidelines for management.

• Looking ahead, attention should be paid to the effect of vaccination on long COVID evolution will probably shed light on its pathophysiology.

Also the development of long COVID among vaccinated with breakthough infections has to be further evaluated.⁸³

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CHAPTER 3.

PATHOPHYSIOLOGY

1 DISCLAIMER

The current work is based on the available evidence at the moment of writing the report (09/08/2021). There are still major evidence gaps, as studies are ongoing and science requires time to build up. A part of the available literature is not peer-reviewed and hence not necessarily conforms with the high quality standards for scientific research.

2 KEY POINTS

• The pathophysiology contributing to long COVID symptoms is so far unkown. Since the spectrum of symptoms is very wide, responsible mechanisms are probably numerous and intertwined.

• While many articles elaborate on the putative mechanims involved in the symptomatology, there is little empirical data on the pathophysiology based on measurements among long COVID patients. In addition, the quality of data is limited due to heterogenous timings of inclusion, different initial disease severity and a lack of a comparator group. As such, the reported results need to be interpreted with caution. The current literature is highly hypothetical, cannot be generalised and is subject to change.

• A distinction has to be made between two categories of mechanisms by which persisting symptoms come about:

o Organ injury at the early phase of infection;

o Persisting and/or residual symptoms without evidence of readily measurable markers of organ injury.

• Current literature suggests the following general pathophysiological mechanisms:

o Virus-driven tissue damage

o Dysregulated immune and inflammatory reactions in response to the infection or to an occult viral persistence, giving rise to multiple disorders (microcirculation disorders associated with coagulation and fibrosis pathway activation, autoimmune manifestations and metabolic disturbances)

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3 BACKGROUND