Uta Behrends’s research while affiliated with Technical University of Munich and other places

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Publications (179)


Correction to: Pediatric and adult patients with ME/CFS following COVID-19: A structured approach to diagnosis using the Munich Berlin Symptom Questionnaire (MBSQ)
  • Article
  • Full-text available

April 2025

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18 Reads

European Journal of Pediatrics

Laura-Carlotta Peo

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Katharina Wiehler

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Johannes Paulick

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[...]

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Uta Behrends
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Figure 1 Experimental design. Sera of age-matched female patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) after SARS-CoV-2 (pcME/CFS), or after other infectious triggers (piME/CFS), as well as post-COVID syndrome (PCS) were analyzed in comparison to healthy controls (HC). Peptide cytometric bead array (CBA) for detection of IgG response to peptides of interest (I) Coupling of the beads with 15-mer peptides of interest. (II) Measurement of the serum IgG response against the peptides of interest in a multiplex approach. (III) Measurement of the serum IgG responses in the CytoFlex LX device. (IV) Data analysis of median fluorescence intensity (MFI). Serological multiplex array measurement of serum IgG responses to proteins of interest. (1) Expression vectors for Cterminally His6-tagged proteins of interest were generated using a pcDNA3.1-derived plasmid. (2) Transfection into HEK293T cells. (3) Harvesting and lysing cells after four days. (4) Purification of His6-tagged proteins over to Ni2+-NTA columns. (5) Verification of protein integrity and identity. (6) Addition of the proteins to a nitrocellulose membrane and incubation with an anti His6-tag monoclonal mouse antibody. (7) Detection of bound human and mouse antibodies with secondary antibodies in a near-infrared detection system. (8) Antibody responses to proteins were quantified by normalization of arbitrary fluorescence units (AFU) relative to the amount of spotted protein and a standard. Created in BioRender https://BioRender.com/p19y004
Figure 1 Associations of autoantibodies with symptom severity. IgG reactive to EBV and human peptides (A-C) and to corresponding proteins (D-E) were analyzed by Spearman correlation. Heatmaps presenting the Spearman correlation coefficient r ≥ 0.3 (*p-values < 0.05).
Figure 4 Analysis of IgG reactivity to proteins. Shown are (A-B) the individual serum IgG responses in arbitrary Unit (AFU) and (C-D) the frequency of positive IgG responses in % of the whole patient cohorts (piME/CFS, pcME/CFS, PCS) and the healthy controls (HC). The IgG responses against (A, C) EBNA6 and human proteins, (B, D) EBNA4 and human TSPYL5 proteins were determined. Statistical comparison of the level of specific IgG binding between patients and HC groups was done using the Mann-Whitney-U test (A-B). For the comparisons
Autoantibodies to Arginine-rich Sequences Mimicking Epstein-Barr Virus in Post-COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

December 2024

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100 Reads

Background: Epstein-Barr virus (EBV) infection is a known trigger and risk factor for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-COVID syndrome (PCS). In previous studies, we found enhanced IgG reactivity to EBV EBNA4 and EBNA6 arginine-rich sequences in postinfectious ME/CFS (piME/CFS). Objective: This study aims to investigate IgG responses to arginine-rich (poly-R) EBNA4 and EBNA6 sequences and homologous human sequences in PCS and ME/CFS. Methods: The IgG responses against poly-R EBNA4 and EBNA6 and corresponding homologous human 15-mer peptides and respective full-length proteins were analyzed using a cytometric bead array (CBA) and a multiplex dot-blot assay. Sera of 45 PCS patients diagnosed according to WHO criteria, with 26 patients fulfilling the Canadian Consensus criteria for ME/CFS (pcME/CFS), 36 patients with non-COVID post-infectious ME/CFS (piME/CFS), and 34 healthy controls (HC) were investigated. Results: Autoantibodies to poly-R peptide sequences of the neuronal antigen SRRM3, the ion channel SLC24A3, TGF-β signaling regulator TSPLY2, angiogenic regulator TSPYL5, as well as to full-length α-adrenergic receptor (ADRA) proteins were more frequent in patients. Several autoantibodies were positively associated with key symptoms of autonomic dysfunction, fatigue, cognition, and pain. Conclusion: Collectively, we identified autoantibodies with new antigen specificities with a potential role in PCS and ME/CFS. Clinical Implication: These finding should prompt further studies on the function of these autoantibodies, their exploitation for diagnostic use, and of drugs targeting autoantibodies.


Figure 1. Process of developing the patient education program for affected children and adolescents. ME/CFS: myalgic encephalomyelitis/chronic fatigue syndrome.
Figure 2. Overview of the evaluation of the study. ICF: International Classification of Functioning, Disability and Health; LARES: Large Analysis and Review of European Housing and Health Status; ME/CFS: myalgic encephalomyelitis/chronic fatigue syndrome; SF-36: 36-item Short Form Health Survey; SPQ: Sibling Perception Questionnaire.
Development and Implementation of an Online Patient Education Program for Children and Adolescents With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Their Parents, Siblings, and School Personnel: Protocol for the Prospective BAYNET FOR ME/CFS Study

November 2024

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48 Reads

JMIR Research Protocols

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) presents significant challenges for affected children and adolescents, their social environment, and treating physicians, due to its profound impact on quality of life and the lack of causal therapeutic approaches. One crucial aspect of care that has been missing for these patients is comprehensive education for both them and their social circles.





Potential drivers of PEM include microvascular alterations and mitochondriopathy that can functionally culminate in reduced systemic oxygen extraction and oxidative phosphorylation capacity upon physical activities (a–b). Altered bioenergetics limit the patients’ ability to be physically active and induce the accumulation of lactate, reactive oxygen species and cations (c). Overexertion could manifest as delayed symptom exacerbation and systemic fatigue through subsequent immune activation that might aggravate bioenergetic inflexibilities and modulate CNS functions (d) (Figure created with biorender.com) ATP adenosine triphosphatem, CNS central nervous system, eNOS endothelial nitric oxide synthase, ETC electronic transport chain, FMD flow-mediated dilation, NO nitric oxide, ROS reactive oxygen species, TCA tricarboxylic acid
Potential treatment options targeting proposed drivers of PEM
Towards an understanding of physical activity-induced post-exertional malaise: Insights into microvascular alterations and immunometabolic interactions in post-COVID condition and myalgic encephalomyelitis/chronic fatigue syndrome

September 2024

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420 Reads

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7 Citations

Infection

Background A considerable number of patients who contracted SARS-CoV-2 are affected by persistent multi-systemic symptoms, referred to as Post-COVID Condition (PCC). Post-exertional malaise (PEM) has been recognized as one of the most frequent manifestations of PCC and is a diagnostic criterion of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Yet, its underlying pathomechanisms remain poorly elucidated. Purpose and methods In this review, we describe current evidence indicating that key pathophysiological features of PCC and ME/CFS are involved in physical activity-induced PEM. Results Upon physical activity, affected patients exhibit a reduced systemic oxygen extraction and oxidative phosphorylation capacity. Accumulating evidence suggests that these are mediated by dysfunctions in mitochondrial capacities and microcirculation that are maintained by latent immune activation, conjointly impairing peripheral bioenergetics. Aggravating deficits in tissue perfusion and oxygen utilization during activities cause exertional intolerance that are frequently accompanied by tachycardia, dyspnea, early cessation of activity and elicit downstream metabolic effects. The accumulation of molecules such as lactate, reactive oxygen species or prostaglandins might trigger local and systemic immune activation. Subsequent intensification of bioenergetic inflexibilities, muscular ionic disturbances and modulation of central nervous system functions can lead to an exacerbation of existing pathologies and symptoms.



Total cytokine responses of EBV-reactive CD4+ and CD8+ T cells. Depicted are the frequencies of EBV-reactive CD4+ and CD8+ T cells upon stimulation of PBMC with T-activated EBNA3A and BZLF1 proteins, EBV-like particles (EB-VLP), and a synthetic EBV-derived peptide pool (PP) at visit 1 (v1) (A, B) (grey dots) and visit 2 (v2) (C, D) (brown dots). Total cytokine responses were calculated by adding together the frequencies of EBV-reactive IFN-γ, IL-2, and/or TNF-positive T cells within the CD4+ or CD8+ T-cell populations. Dots represent the patient samples analyzed (n = 20), the horizontal line marks the median, dashed lines the 25th and 75th percentiles. For reasons of clarity, the x-axis was moved to -0.05. v1: 2-14 days after symptom onset; v2: 23-39 days after symptom onset
Individual EBV-specific CD4+ and CD8+ T-cell responses at visits 1 and 2. Stacked bars depict the frequencies of EBV-reactive CD4+ and CD8+ T cells upon stimulation of PBMC from 20 IM patients with T-activated EBNA3A and BZLF1 proteins, EBV-like particles (EB-VLP), and a synthetic EBV-derived peptide pool (PP) at visit 1 (v1) (A, B) and visit 2 (v2) (C, D). Total cytokine responses were calculated by adding together the frequencies of EBV-reactive IFN-γ, IL-2, and/or TNF-positive T cells within the CD4+ or CD8+ T-cell population. v1: 2-14 days after symptom onset; v2: 23-39 days after symptom onset
Functionality of EBV-reactive CD4+ and CD8+ T cells at visit 1 and 2. The colored dots and black lines depict individual frequencies and median frequencies, respectively, of antigen-reactive CD4+ (A) or CD8+ (B) T cells characterized by the indicated combination of cytokines (IFN-γ, IL-2, TNF) at visit 1 (v1) (grey dots) and visit 2 (v2) (brown dots) in samples from 20 patients each. The depicted pies show the average proportion of antigen-reactive mono- (cells producing only one of the cytokines), bi- (cells producing two of the respective cytokines), and tri-functional (cells producing all three cytokines simultaneously) CD4+ (A) and CD8+ (B) T cells at visits 1 and 2. v1: 2-14 days after symptom onset; v2: 23-39 days after symptom onset. * p < 0.05
Functionality of PP-reactive CD8+ T cells at visit 1 and 2. (A) Frequencies of PP-reactive CD8+ T cells in 20 IM patients at visit 1 (v1, grey dots) and visit 2 (v2, brown dots) are depicted for each functional combination of the three cytokines (IFN-γ, IL-2, TNF) analyzed. The colored dots and black lines represent individual frequencies and median frequencies of antigen reactive CD8+ T cells, respectively. The depicted pies show the average proportion of antigen-reactive mono- (cells producing only one of the cytokines), bi- (cells producing two of the respective cytokines), and tri-functional (cells producing all three cytokines simultaneously) CD8+ T cells at visits 1 and 2. * p < 0.05, ** p < 0.01. B Individual proportion of mono-, bi-, and tri-functional PP-reactive CD8+ T cells in the 20 IM patients at v1 and v2
Evaluation of novel Epstein-Barr virus-derived antigen formulations for monitoring virus-specific T cells in pediatric patients with infectious mononucleosis

June 2024

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47 Reads

Virology Journal

Background Infection with the Epstein-Barr virus (EBV) elicits a complex T-cell response against a broad range of viral proteins. Hence, identifying potential differences in the cellular immune response of patients with different EBV-associated diseases or different courses of the same disorder requires interrogation of a maximum number of EBV antigens. Here, we tested three novel EBV-derived antigen formulations for their ability to reactivate virus-specific T cells ex vivo in patients with EBV-associated infectious mononucleosis (IM). Methods We comparatively analyzed EBV-specific CD4+ and CD8+ T-cell responses to three EBV-derived antigen formulations in 20 pediatric patients during the early phase of IM: T-activated EBV proteins (BZLF1, EBNA3A) and EBV-like particles (EB-VLP), both able to induce CD4+ and CD8+ T-cell responses ex vivo, as well as an EBV-derived peptide pool (PP) covering 94 well-characterized CD8+ T-cell epitopes. We assessed the specificity, magnitude, kinetics, and functional characteristics of EBV-specific immune responses at two sequential time points (v1 and v2) within the first six weeks after IM symptom onset (Tonset). Results All three tested EBV-derived antigen formulations enabled the detection of EBV-reactive T cells during the early phase of IM without prior T-cell expansion in vitro. EBV-reactive CD4+ and CD8+ T cells were mainly mono-functional (CD4+: mean 64.92%, range 56.15-71.71%; CD8+: mean 58.55%, range 11.79-85.22%) within the first two weeks after symptom onset (v1) with IFN-γ and TNF-secreting cells representing the majority of mono-functional EBV-reactive T cells. By contrast, PP-reactive CD8+ T cells were primarily bi-functional (>60% at v1 and v2), produced IFN-γ and TNF and had more tri-functional than mono-functional components. We observed a moderate correlation between viral load and EBNA3A, EB-VLP, and PP-reactive CD8+ T cells (rs = 0.345, 0.418, and 0.356, respectively) within the first two weeks after Tonset, but no correlation with the number of detectable EBV-reactive CD4+ T cells. Conclusions All three EBV-derived antigen formulations represent innovative and generic recall antigens suitable for monitoring EBV-specific T-cell responses ex vivo. Their combined use facilitates a thorough analysis of EBV-specific T-cell immunity and allows the identification of functional T-cell signatures linked to disease development and severity.


Age Distribution. Histograms show the age distribution of patients included in the MECFS-R depending on the recruiting center (A) and gender (B). The dotted lines at age 18 indicate the transition from pediatric to adult patients.
Distribution of ME/CFS Triggers. Bar charts display the absolute frequency and relative percentage of reported ME/CFS triggers by age group (A) and gender (B).
Results from the SF-36 questionnaire. Spider diagrams display the results from subdomains of the SF-36 questionnaire for pediatric ME/CFS-R patients (age 11–17 years) (top left), adult ME/CFS-R patients (age 18–61 years) (bottom left), as well as for largely age-matched historic, healthy control populations aged 14 to 20 years (top right) and 17–79 years (bottom right).
Results from Patient-Reported Outcome Measures. Boxplots display the results from the Bell Score, Chalder Fatigue Scale, and COMPASS-31 questionnaire for children and adolescents versus adult patients (A,C,E) and male versus female patients (B,D,F).
The German Multicenter Registry for ME/CFS (MECFS-R)

May 2024

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178 Reads

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1 Citation

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystemic disease characterized by a complex, incompletely understood etiology. Methods: To facilitate future clinical and translational research, a multicenter German ME/CFS registry (MECFS-R) was established to collect comprehensive, longitudinal, clinical, epidemiological, and laboratory data from adults, adolescents, and children in a web-based multilayer-secured database. Results: Here, we present the research protocol and first results of a pilot cohort of 174 ME/CFS patients diagnosed at two specialized tertiary fatigue centers, including 130 (74.7%) adults (mean age 38.4; SD 12.6) and 43 (25.3%) pediatric patients (mean age 15.5; SD 4.2). A viral trigger was identified in 160/174 (92.0%) cases, with SARS-CoV-2 in almost half of them. Patients exhibited severe functional and social impairment, as reflected by a median Bell Score of 30.0 (IQR 30.0 to 40.0) and a poor health-related quality of life assessed with the Short Form-36 health survey, resulting in a mean score of 40.4 (SD 20.6) for physical function and 59.1 (SD 18.8) for mental health. Conclusions: The MECFS-R provides important clinical information on ME/CFS to research and healthcare institutions. Paired with a multicenter biobank, it facilitates research on pathogenesis, diagnostic markers, and treatment options. Trial registration: ClinicalTrials.gov NCT05778006.


Citations (58)


... Although the exact pathophysiology underlying PCS is still unknown, discussed pathways include microvascular alterations and immunometabolic interactions [10] autoimmunology, chronic inflammation, viral persistence, direct organ damage, endothelial dysfunction, or metabolic changes [11]. Female sex, older age, and higher BMI were associated with an increased risk of developing PCS in a recent meta-analysis [12]. ...

Reference:

Possible link between steatotic liver diseases, severe COVID-19 and cognitive impairment in post-COVID-19 syndrome
Towards an understanding of physical activity-induced post-exertional malaise: Insights into microvascular alterations and immunometabolic interactions in post-COVID condition and myalgic encephalomyelitis/chronic fatigue syndrome

Infection

... However, only 15 out of 204 countries attained a 20% reduction in the incidence of TB, and only 17 countries achieved a 35% reduction in TB mortality from 2015 to 2020. It is time for countries to revisit their End TB targets to achieve TB control by 2035 [4]. ...

The German Multicenter Registry for ME/CFS (MECFS-R)

... Neben den akuten Symptomen weisen immer mehr wissenschaftliche Arbeiten darauf hin, dass SARS-CoV-2-Infektionen und COVID bleibende Gesundheitsprobleme verursachen [5,9]. Für die Betroffenen besonders einschneidend sind dabei Long-COVID [6] und ME/CFS [7]. Long-COVID wird bei ca. ...

Interdisziplinäres, kollaboratives D-A-CH Konsensus-Statement zur Diagnostik und Behandlung von Myalgischer Enzephalomyelitis/Chronischem Fatigue-SyndromInterdisciplinary, collaborative D-A-CH (Germany, Austria and Switzerland) consensus statement concerning the diagnostic and treatment of myalgic encephalomyelitis/chronic fatigue syndrome

Wiener klinische Wochenschrift

... There is uncertainty about recommendations for exercise and activity in LC and ME/CFS. Study results show heterogeneous results with a not very robust study situation [36,37]. On the one hand, study results suggest improvement with rehabilitation, but on the other hand, there is also evidence of worsening of symptoms in terms of postexertional malaise in subgroups with overexertion. ...

Practical Recommendations for Exercise Training in Patients with Long COVID with or without Post-exertional Malaise: A Best Practice Proposal

Sports Medicine - Open

... Hematopoietic cell transplantation (HCT) offers curative potential for conditions such as refractory leukemia [1,2], bone marrow failure syndromes [3], immune deficiencies [4,5], and inborn errors of metabolism [6]. However, intensive conditioning regimens and post-transplant immune responses often result in severe, sometimes life-threatening complications, necessitating effective management strategies to improve post-transplant survival. ...

Wiskott-Aldrich Syndrome: A study on 577 patients defining the genotype as a predictive biomarker for disease severity

Blood

... An overview of the items is provided in the supplement (Table S1). The questionnaire has been used in previous studies [7,17,45], where weak to moderate significant correlations between the perceived overall pandemic burden and the specific pandemic-related constraints as well as between the pandemic-related items with parenting stress, child and parental psychopathology were identified [7]. For this study, correlations between the pandemic-related items, separated by group, can be found in the supplement (Table S2). ...

The change of psychosocial stress factors in families with infants and toddlers during the COVID-19 pandemic. A longitudinal perspective on the CoronabaBY study from Germany

... However, studies have shown that the prevalence of MS in patients with IM is three times higher than in the general population, with strong associations in long intervals of more than 5 years [32]. Myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) after EBV-IM is a severely debilitating disease with a delayed clinical diagnosis that has a more significant impact on physical functioning and health-related quality of life in adolescent patients [43]. Eighty per cent of patients with splenic rupture or infarction present with symptoms of IM before 3 weeks of onset [44]. ...

One-year follow-up of young people with ME/CFS following infectious mononucleosis by Epstein-Barr virus

... Additionally, there are a number of criteria catalogs for diagnosing ME/CFS based on the symptoms present; the rather unspecific 1994 Centers for Disease Control and Prevention (CDC) Fukuda criteria (known as CDC or Fukuda criteria) [18] have been replaced by the Canadian Consensus Criteria (CCC), Criteria of the Institute of Medicine (IOM), or the International Consensus Criteria (ICC) [19][20][21][22]. Additionally, a variety of questionnaire tools (e.g., Munich Berlin Symptom Questionnaire (MBSQ) [23], DePaul Symptom Questionnaire (PSQ) [24]) are available for clinical practice. ...

Pediatric and adult patients with ME/CFS following COVID-19: A structured approach to diagnosis using the Munich Berlin Symptom Questionnaire (MBSQ)

European Journal of Pediatrics

... In contrast, the prolonged disruption of normal sleep can contribute to neuroinflammation [168], norepinephrine-stimulated degeneration of the locus coeruleus, and hippocampal amyloid-β 42 accumulation, with the potential to cause memory dysfunction and CD [169]. Unfortunately, the use of benzodiazepines, while sometimes reducing the time to fall asleep and helpful initially [170], frequently causes daytime drowsiness and can exacerbate CD in ME/CFS. Melatonin, however, is more suitable, can encourage the normalisation of sleep chronobiology, and has the ability to scavenge reactive oxygen species that are central to neuroinflammation [171]. ...

Understanding, diagnosing, and treating Myalgic encephalomyelitis/chronic fatigue syndrome – State of the art: Report of the 2nd international meeting at the Charité Fatigue Center

Autoimmunity Reviews