Symptom persistence and biomarkers in post-COVID-19/chronic fatigue syndrome - results from a prospective observational cohort (preprint)

IntroductionPost-COVID-19 syndrome (PCS) is characterized by a wide range of symptoms, predominantly fatigue and exertional intolerance. While disease courses during the first year post infection have been repeatedly described, little is known about long-term health consequences. MethodsWe assessed symptom severity and various biomarkers at three time points post infection (3-8 months (mo), 9-16mo, 17-20mo) in 106 PCS patients with moderate to severe fatigue and exertional intolerance. A subset of patients fulfilled diagnostic criteria of myalgic encephalomyelitis/chronic fatigue syndrome (PCS-ME/CFS) based on the Canadian Consensus Criteria. ResultsWhile PCS-ME/CFS patients showed persisting symptom severity and disability up to 20mo post infection, PCS patients reported an overall health improvement. Inflammatory biomarkers equally decreased in both groups. Lower hand grip force at onset correlated with symptom persistence especially in PCS-ME/CFS. DiscussionDebilitating PCS may persist beyond 20mo post infection, particularly in patients fulfilling diagnostic criteria for ME/CFS.

Post-COVID syndrome is associated with capillary alterations, macrophage infiltration and distinct transcriptomic signatures in skeletal muscles (preprint)

The SARS-CoV-2 pandemic not only resulted in millions of acute infections worldwide, but also caused innumerable cases of post-infectious syndromes, colloquially referred to as long COVID. Due to the heterogeneous nature of symptoms and scarcity of available tissue samples, little is known about the underlying mechanisms. We present an in-depth analysis of skeletal muscle biopsies obtained from eleven patients suffering from enduring fatigue and post-exertional malaise after an infection with SARS-CoV-2. Compared to two independent historical control cohorts, patients with post-COVID exertion intolerance had fewer capillaries, thicker capillary basement membranes and increased numbers of CD169+ macrophages. SARS-CoV-2 RNA could not be detected in the muscle tissues, but transcriptomic analysis revealed distinct gene signatures compared to the two control cohorts, indicating immune dysregulations and altered metabolic pathways. We hypothesize that the initial viral infection may have caused immune-mediated structural changes of the microvasculature, potentially explaining the exercise-dependent fatigue and muscle pain.

SARS-CoV-2 mRNA vaccination fails to elicit humoral and cellular immune responses in multiple sclerosis patients receiving fingolimod (preprint)

SARS-CoV-2 mRNA vaccination of healthy individuals is highly immunogenic and protective against severe COVID-19. However, there are limited data on how disease-modifying therapies (DMTs) alter SARS-CoV-2 mRNA vaccine immunogenicity in patients with autoimmune diseases. Here we investigated the induction and stability of vaccine-specific antibodies, B cells, and T cells in multiple sclerosis (MS) patients on different DMTs in a prospective cohort study up to 6 months after homologous prime-boost mRNA vaccination. We analysed 103 MS patients of which 86 received anti-CD20-based B cell depletion (aCD20-BCD), fingolimod, interferon-β, dimethyl fumarate, glatiramer acetate, teriflunomide or natalizumab, and compared them to 17 untreated MS patients. In contrast to all other DMTs and untreated patients, treatment with aCD20-BCD or fingolimod significantly reduced anti-S1 IgG, serum neutralizing activity, and RBD- and S2-specific B cells. MS patients receiving fingolimod additionally lacked S1- and S2-reactive CD4 + T cell responses. The duration of fingolimod treatment, rather than peripheral blood B and T cell counts prior to vaccination, determined whether patients successfully developed humoral immune responses. Fingolimod blocks the ability of immune cells to recirculate and migrate within secondary lymphoid organs demonstrating that functional immune responses require not only immune cells themselves but also access of these cells to the site of inoculation and their unimpeded movement. The absence of humoral and T cell responses in fingolimod-treated MS patients suggests that these patients are at risk for severe SARS-CoV-2 infections despite vaccination, which is highly relevant for clinical decision-making and adapted protective measures, particularly in light of additional recently approved S1P receptor antagonists for MS treatment.

Serum but not mucosal antibody responses are associated with pre-existing SARS-CoV-2 spike cross-reactive CD4+ T cells following BNT162b2 vaccination in the elderly (preprint)

Advanced age is a main risk factor for severe COVID-19. However, low vaccination efficacy and accelerated waning immunity have been reported in this age group. To elucidate age-related differences in immunogenicity, we analysed human cellular, serological and salivary SARS-CoV-2 spike glycoprotein-specific immune responses to BNT162b2 COVID-19 vaccine in old (69-92 years) and middle-aged (24-57 years) vaccinees compared to natural infection (COVID-19 convalescents, 21-55 years). Serological humoral responses to vaccination exceeded those of convalescents but salivary anti-spike subunit 1 (S1) IgA and neutralizing capacity were less durable in vaccinees. In old vaccinees, we observed that pre-existing spike-specific CD4 + T cells are associated with efficient induction of anti-S1 IgG and neutralizing capacity in serum but not saliva. Our results suggest pre-existing SARS-CoV-2 cross-reactive CD4 + T cells as predictor of an efficient COVID-19 vaccine-induced humoral immune response in old individuals.

Post Vaccination Optic Neuritis: Observations From the SARS-CoV-2 Pandemic (preprint)

Background: Vaccination against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first approved on the 8th of December 2020. Though safe and effective, very rare side effects continue to be identified as global vaccination advances. They do not necessarily leave “a signal” in public registries if the incidence remains below previously reported total incidence levels. Optic neuritis (ON) is a rare but recognised adverse event after immunisation. The risk of post-vaccination ON and visual outcome in the context of global vaccination efforts against SARS-CoV-2 are not known. Methods: A global report on 73 deep-phenotyped individuals with post-SARS-CoV-2 vaccination ON observed in 15 of 55 countries with designated experts between 14 February to 18 July 2021. Statistical analyses were performed on type of vaccine, number of jabs, time to onset of ON, demographics, clinical features and treatment. Paraclinical data included immunological testing for autoantibodies against myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4, magnetic resonance imaging (MRI) of the brain and orbits, retinal optical coherence tomography (OCT). The primary outcome was the visual acuity (VA). Findings: The characteristics of the 69 individuals included, differed from pre-COVID whole population-based incidence studies in frequency of bilateral presentation, age distribution and radiological features more commonly found in immune-mediated ON. Most events (67%) occurred after vaccination with AstraZeneca, followed by Pfizer-BioNTech (26%) and Sinovac (7%). In 56 this was after the first and in 13 after the second jab with the same vaccine. Autoantibodies against MOG were present in 15 and not detected for aquaporin-4. The condition was steroid responsive in most (58/62), requiring plasma exchange in a few (5) with spontaneous recovery in the remainder (7). The incidence was highest in the UK (0.036 per 100,000 persons) where vaccination commenced earliest. Importantly, the pattern of presentation in time lagged about 1-5 weeks behind the pattern of national age group vaccination. The median VA at presentation was logMAR 1.0 and recovered to 0.0. Interpretation: Post-SARS-CoV-2 vaccination ON is an extremely rare adverse event with generally good outcome of visual function. The global incidence of post-vaccination ON (0.0017 per 100,000 persons) is lower than for ON (3.74 per 100,000 persons in the UK). A causal relationship is plausible, but the overall risk benefit balance is in favour of SARS-CoV-2 vaccination.Funding Information: None.Declaration of Interests: None. Ethics Approval Statement: Reporting of patients was approved by the Institutional Research Board at Moorfields Eye Hospital (study number CaRS_24).

Chronic COVID-19 / Chronic Fatigue Syndrome (ME/CFS) following the first pandemic wave in Germany and biomarkers associated with symptom severity (preprint)

A subset of patients has long-lasting symptoms after mild to moderate COVID-19. In a prospective observational cohort study we analysed clinical and laboratory parameters in 42 patients (29 female/13 male, median age 36.5 years) with persistent moderate to severe fatigue and exertion intolerance six months following COVID-19 referred to as Chronic COVID-19 Syndrome (CCS). Most patients were moderately to severely impaired in daily live. 19 patients fulfilled the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome referred to as CFS/CCS. Hand grip strength (HGS) was diminished in most patients. Association of several biomarker with key symptoms of physical and mental fatigue and post exertional malaise indicate low level inflammation and hypoperfusion as potential pathomechanisms.

Cross-reactive CD4+ T cells enhance SARS-CoV-2 immune responses upon infection and vaccination (preprint)

While evidence for pre-existing SARS-CoV-2-cross-reactive CD4+ T cells in unexposed individuals is increasing, their functional significance remains unclear. Here, we comprehensively determined SARS-CoV-2-cross-reactivity and human coronavirus-reactivity in unexposed individuals. SARS-CoV-2-cross-reactive CD4+ T cells were ubiquitous, but their presence decreased with age. Within the spike glycoprotein fusion domain, we identified a universal immunodominant coronavirus-specific peptide epitope (iCope). Pre-existing spike- and iCope-reactive memory T cells were efficiently recruited into mild SARS-CoV-2 infections and their abundance correlated with higher IgG titers. Importantly, the cells were also reactivated after primary BNT162b2 COVID-19 mRNA vaccination in which their kinetics resembled that of secondary immune responses. Our results highlight the functional importance of pre-existing spike-cross-reactive T cells in SARS-CoV-2 infection and vaccination. Abundant spike-specific cross-immunity may be responsible for the unexpectedly high efficacy of current vaccines even with single doses and the high rate of asymptomatic/mild infection courses.

Chronic COVID-19 Syndrome and Chronic Fatigue Syndrome (ME/CFS) following the first pandemic wave in Germany: a first analysis of a prospective observational study (preprint)

Objective: Characterization of the clinical features of patients with persistent symptoms after mild to moderate COVID-19 infection and exploration of factors associated with the development of Chronic COVID-19 Syndrome (CCS). Methods: Setting: Charite Fatigue Center with clinical immunologists and rheumatologist, neurologists and cardiologists at Charite University hospital. Participants: 42 patients who presented with persistent moderate to severe fatigue six months following a mostly mild SARS-CoV-2 infection at the Charite Fatigue Center from July to November 2020. Main outcome measures: The primary outcomes were clinical and paraclinical data and meeting diagnostic criteria for Chronic Fatigue Syndrome (ME/CFS). Relevant neurological and cardiopulmonary morbidity was excluded. Results: The median age was 36.5, range 22-62, 29 patients were female and 13 male. At six months post acute COVID-19 all patients had fatigue (Chalder Fatigue Score median 25 of 33, range 14-32), the most frequent other symptoms were post exertional malaise (n=41), cognitive symptoms (n=40), headache (n=38), and muscle pain (n=35). Most patients were moderately to severely impaired in daily live with a median Bell disability score of 50 (range 15-90) of 100 (healthy) and Short Form 36 (SF36) physical function score of 63 (range 15-80) of 100. 19 of 42 patients fulfilled the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These patients reported more fatigue in the Chalder Fatigue Score (p=0.006), more stress intolerance (p=0.042) and more frequent and longer post exertional malaise (PEM) (p= 0.003), and hypersensitivity to noise (p=0.029), light (p=0.0143) and temperature (0.024) compared to patients not meeting ME/CFS criteria. Handgrip force was diminished in most patients compared to healthy control values, and lower in CCS/CFS compared to non-CFS CCS (Fmax1 p=0.085, Fmax2, p=0.050, Fmean1 p=0.043, Fmean2 p=0.034, mean of 10 repeat handgrips, 29 female patients). Mannose-binding lectin (MBL) deficiency was observed frequently (22% of all patients) and elevated IL-8 levels were found in 43% of patients. Conclusions: Chronic COVID-19 Syndrome at months 6 is a multisymptomatic frequently debilitating disease fulfilling diagnostic criteria of ME/CFS in about half of the patients in our study. Research in mechanisms and clinical trials are urgently needed.

Covid-19 -- A simple statistical model for predicting ICU load in early phases of the disease (preprint)

One major bottleneck in the ongoing COVID-19 pandemic is the limited number of critical care beds. Due to the dynamic development of infections and the time lag between when patients are infected and when a proportion of them enters an intensive care unit (ICU), the need for future intensive care can easily be underestimated. To infer future ICU load from reported infections, we suggest a simple statistical model that (1) accounts for time lags and (2) allows for making predictions depending on different future growth of infections. We have evaluated our model for three regions, namely Berlin (Germany), Lombardy (Italy), and Madrid (Spain). Before extensive containment measures made an impact, we first estimate the region-specific model parameters. Whereas for Berlin, an ICU rate of 6%, a time lag of 6 days, and an average stay of 12 days in ICU provide the best fit of the data, for Lombardy and Madrid the ICU rate was higher (18% and 15%) and the time lag (0 and 3 days) and the average stay (4 and 8 days) in ICU shorter. The region-specific models are then used to predict future ICU load assuming either a continued exponential phase with varying growth rates (0-15%) or linear growth. Thus, the model can help to predict a potential exceedance of ICU capacity. Although our predictions are based on small data sets and disregard non-stationary dynamics, our model is simple, robust, and can be used in early phases of the disease when data are scarce.