Increased circulating fibronectin, depletion of natural IgM and heightened EBV, HSV-1 reactivation in ME/CFS and long COVID (preprint)

Myalgic Encephalomyelitis/ Chronic Fatigue syndrome (ME/CFS) is a complex, debilitating, long-term illness without a diagnostic biomarker. ME/CFS patients share overlapping symptoms with long COVID patients, an observation which has strengthened the infectious origin hypothesis of ME/CFS. However, the exact sequence of events leading to disease development is largely unknown for both clinical conditions. Here we show antibody response to herpesvirus dUTPases, particularly to that of Epstein-Barr virus (EBV) and HSV-1, increased circulating fibronectin (FN1) levels in serum and depletion of natural IgM against fibronectin ((n)IgM-FN1) are common factors for both severe ME/CFS and long COVID. We provide evidence for herpesvirus dUTPases-mediated alterations in host cell cytoskeleton, mitochondrial dysfunction and OXPHOS. Our data show altered active immune complexes, immunoglobulin-mediated mitochondrial fragmentation as well as adaptive IgM production in ME/CFS patients. Our findings provide mechanistic insight into both ME/CFS and long COVID development. Finding of increased circulating FN1 and depletion of (n)IgM-FN1 as a biomarker for the severity of both ME/CFS and long COVID has an immediate implication in diagnostics and development of treatment modalities.

Estimation of R0 for the spread of SARS-CoV-2 in Germany from Excess Mortality (preprint)

Background: For SARS-CoV-2, R0 calculations in the range of 2-3 dominate the literature, but much higher estimates have also been published. Because capacity for PCR testing increased greatly in the early phase of the Covid-19 pandemic, R0 determinations based on these incidence values are subject to strong bias. We propose to use Covid-19-induced excess mortality to determine R0 regardless of PCR testing capacity. Methods We used data from the Robert Koch Institute (RKI) on the incidence of Covid cases, Covid-related deaths, number of PCR tests performed, and excess mortality calculated from data from the Federal Statistical Office in Germany. We determined R0 using exponential growth estimates with a serial interval of 4.7 days. We used only datasets that were not yet under the influence of policy measures (e.g., lockdowns or school closures). Results The uncorrected R0 value for the spread of SARS-CoV-2 based on PCR incidence data was 2.56 (95% CI 2.52-2.60) for Covid-19 cases and 2.03 (95%CI 1.96-2.10) for Covid-19-related deaths. However, because the number of PCR tests increased by a growth factor of 1.381 during the same period, these R0 values must be corrected accordingly (R0corrected = R0uncorrected/1.381), yielding 1.86 for Covid-19 cases and 1.47 for Covid-19 deaths. The R0 value based on excess deaths was calculated to be 1.34 (95% CI 1.32-1.37). A sine-function-based adjustment for seasonal effects of 40% corresponds to a maximum value of R0 January = 1.68 and a minimum value of R0 July = 1.01. Discussion Our calculations show an R0 that is much lower than previously thought. This relatively low range of R0 fits very well with the observed seasonal pattern of infection across Europe in 2020 and 2021, including the emergence of more contagious escape variants such as delta or omicron. In general, our study shows that excess mortality can be used as a reliable surrogate to determine the R0 in pandemic situations.

Estimation of R0 for the spread of SARS-CoV-2 in Germany from Excess Mortality (preprint)

For SARS-CoV-2, R0 calculations report usually 2-3, biased by PCR testing increases. Covid-19-induced excess mortality is less biased. We used data from Robert Koch Institute on Covid incidence, deaths, and PCR tests and excess mortality to determine early, policy-free R0 estimates with a serial interval of 4.7 days. The PCR-based R0 value was 2.56 (95% CI 2.52-2.60) for Covid-19 cases and 2.03 (95%CI 1.96-2.10) for Covid-19-related deaths. As the number of PCR tests increased, R0 values were corrected accordingly, yielding 1.86 for Covid-19 cases and 1.47 for Covid-19 deaths, excess deaths were 1.34 (95% CI 1.32-1.37). R0 is much lower than previously thought. This fits the observed seasonal pattern of infection across Europe in 2020-2021, including emergence of more contagious escape variants such as delta.