Elke Wynberg

General introduction 25 1 Key study strengths and limitations Further key details of study design, population and data collection are presented according to an abbreviated version of the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) Checklist in Table 1 of the Appendix to Chapter 1. Whilst reading this thesis, it is important to keep several key strengths and weaknesses of the RECoVERED cohort in mind. Advantages of the study design were its inclusion across a wide spectrum of initial disease severity, collection of a broad and interdisciplinary array of outcomes, frequent (monthly) symptom questionnaires from illness onset onwards, and long follow-up time. These features enabled the RECoVERED cohort to paint a detailed picture of the long-term clinical characteristics of SARS-CoV-2 infection, from illness onset up to two years later, among both non-hospitalised and hospitalised individuals. Importantly, by identifying non-hospitalised individuals from notification data, we overcame possible selection bias resulting from health-seeking behaviour that may be introduced by enrolling persons visiting primary care clinics for their symptoms. However, our cohort also has several limitations, two of which are particularly important to highlight as they have featured prominently in academic discussions in the literature concerning long COVID research over the past three years. Firstly, the RECoVERED cohort did not enroll a SARS-CoV-2-negative control group. We therefore cannot be sure to what extent our outcomes of interest are caused by infection, by public health restrictions, or both. This limitation is particularly important when considering non-specific outcomes such as self-reported fatigue, which may have numerous co-existing causes. Secondly, as the cohort was initiated at the start of the pandemic, we lack pre-COVID-19 data on study participants’ symptoms (for instance, symptoms due to pre-existing comorbidities) and pre-infection biological samples. As such, we were unable to perform any comparative analyses before and after COVID-19 within the same individuals. These two limitations are not unique to the RECoVERED cohort; indeed, only a handful of large prospective cohort studies with pre-COVID-19 measurements and/or SARS-CoV-2-negative controls exist. This serves to highlight the challenges faced in drawing conclusions about long COVID, and will be discussed in further detail in the general discussion (this thesis, Chapter 9). 1.5 AIMS OF THESIS The overarching objective of this thesis is to outline the features of the COVID-19 pandemic in Amsterdam, the Netherlands, from both an epidemiological and clinical perspective. A particular focus is placed on characterising long COVID.

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