General discussion 9 281 COVID-19 or long COVID. Indeed, it has been demonstrated that harmful stereotypes of women being more often seen as “fragile and overemotional”[79] drives conditions such as long COVID to be perceived as psychosomatic disorders rather than an organic disease. Finally, several studies have aimed to expose the prevalence of long COVID among minority ethnic groups[80] and low-income countries[81, 82]. However, there remains a paucity in data on long COVID among marginalised groups and from lowresource settings. As prospective cohort studies to generate high-quality data on long COVID are costly, it is essential that there is a political and academic mandate to invest in ensuring equity in long COVID research globally. What are the underlying causes of long COVID? In the search for objective diagnostic criteria and possible therapeutic targets, a flurry of research initiatives has attempted to isolate specific biomarkers for long COVID. In the RECoVERED cohort, we explored whether long COVID was associated with specific features in both innate and adaptive immunity. As outlined in Chapter 7, an abundant amount of evidence linked hyperinflammation to severe COVID-19, but the role of immune dysregulation in long COVID pathogenesis has been less consistent. In Chapter 7, we conducted two cross-sectional analyses to explore differences in cytokine levels measured at 9-12 and 21-24 weeks after illness onset, between RECoVERED participants with and without long COVID. In multivariable regression models, long COVID was significantly associated with higher levels of CRP at 21-24 weeks after illness onset (this thesis, Chapter 7). A recent meta-analysis also found upregulation of CRP to be indicative of a wide spectrum of long COVID symptoms[83]. The precise reasons for upregulation of this acute phase reactant warrant further exploration. This meta-analysis[83] and other studies[84] also found other inflammatory markers such as TNF-α and IL-6 to be associated with persistent symptoms. Interestingly, when we defined long COVID according to abnormal lung function (specifically, impaired diffusion capacity), we found an associated with numerous pro-inflammatory cytokines including TNF-α and IL-6 but also IL10, IL17, and IP10 at 6 months after illness onset. This suggests, firstly, that confirming long COVID status with an objective outcome may reduce misclassification bias and thereby reveal important associations. Secondly, the association between impaired pulmonary function and pro-inflammatory cytokines implies that ongoing pulmonary sequelae, specifically, may be a result of a persistent proinflammatory state. We additionally wished to identify possible early biomarkers for long COVID. Raised levels of IL-1β measured early (0-4 week) after acute illness were highly
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