Ribavirin’s Daily Dose Growth Determined as the Result of Medicament Testing May Be a Predictor of the Chronic Course of the Disease in Long COVID Syndrome Patients (preprint)

Introduction Long COVID syndrome, a multisystemic condition resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, affects at least 65 million people worldwide. The disease pathogenesis is unclear, and many different assumptions still exist. This study aimed to explore the use of medicament testing to determine the optimal daily dose of ribavirin through the use of electroacupuncture via the Voll (EAV) diagnostic system for acupuncture points. Materials and methods One hundred one patients (aged 16 to 50) with long COVID syndrome were recruited from the Research Institute of Virology and were eligible according to the inclusion criteria. Patients were randomized to the experimental or the placebo groups. The patients were further examined with EAV diagnostics based on the level of electrodermal activity at the acupuncture points, followed by medicament testing with ribavirin (tablets) to determine the daily doses of the drug. Fifty-two participants were randomized to the experimental group and fourty nine to the placebo group and were considered for data analyses. Results The results of this study demonstrated the feasibility of using EAV to identify meridians with decreased levels of electrodermal activity at acupuncture points, followed by medicament testing with ribavirin to restore the decreased electrodermal conductivity at the studied acupuncture points and to measure the daily dose of the drug. Conclusions The measured daily doses of ribavirin in patients with long COVID syndrome may indirectly serve as a prognostic marker of the course of the disease. However, further clinical and instrumental studies are needed to evaluate the clinical application of medicament testing in assessing long-term COVID syndrome.

Immune activation and immune-associated neurotoxicity in Long-COVID: A systematic review and meta-analysis of 82 studies comprising 58 cytokines/chemokines/growth factors. (preprint)

Background: Multiple studies have shown that Long COVID (LC) disease is associated with heightened immune activation, as evidenced by elevated levels of inflammatory mediators. However, there is no comprehensive meta-analysis focusing on activation of the immune inflammatory response system (IRS) and the compensatory immunoregulatory system (CIRS) along with other immune phenotypes in LC patients. Objectives: This meta-analysis is designed to explore the IRS and CIRS profiles in LC patients, the individual cytokines, chemokines, growth factors, along with C-reactive protein (CRP) and immune-associated neurotoxicity. Methods: To gather relevant studies for our research, we conducted a thorough search using databases such as PubMed, Google Scholar, and SciFinder, covering all available literature up to December 20th, 2023. Results: The current meta-analysis encompassed 82 studies that examined multiple immune profiles, C-reactive protein, and 58 cytokines/chemokines/growth factors in 3836 LC patients versus 4537 normal controls (NC). LC patients showed significant increases in IRS/CIRS ratio (standardized mean difference (SMD:0.156, confidence interval (CI): 0.051;0.261), IRS (SMD: 0.345, CI: 0.222;0.468), M1 macrophage (SMD: 0.421, CI: 0.290;0.551), T helper (Th)1 (SMD: 0.353, CI: 0.189;0.517), Th17 (SMD: 0.492, CI: 0.332;0.651) and immune-associated neurotoxicity (SMD: 0.327 CI: 0.205;0.448). In addition, CRP and 19 different cytokines displayed significantly elevated levels in LC patients compared to NC. Conclusion: LC disease is characterized by IRS activation and increased immune-associated neurotoxicity.

Therapeutic challenges of the modern era: QT prolongation management in COVID-19 hospitalised patients (preprint)

Introduction: Hydroxychloroquine, with or without Azithromycin, was used as a treatment strategy for COVID-19 in March and April 2020. The use of Hydroxychloroquine (HCQ), with or without Azithromycin, may increase the risk of QT prolongation. This study was performed to assess the incidence and degree of QT prolongation in hospitalised COVID-19 patients treated with HCQ, and the association with morbidity and mortality. Methods and Results: Single centre retrospective observational study. Baseline corrected QT interval (QTc), peak QTc and change in QTc (∆QTc) were calculated for all patients. Known or suspected risk factors for QT prolongation were assessed. All patients were followed up for QT prolongation, length of stay, incidence of ICU admission and 30 day all-cause mortality. Sixty-two patients were included (mean age 67 years; 33.9% female). QT prolongation occurred in 62.9% of patients given HCQ, with ∆QTc ≥60msec or acquired QTc ≥500msec in 14.5% of patients. The mean ∆QTc was 28.4msec. QT prolongation was associated with increased mortality (OR 11.0; 95% CI 1.3 – 90.9; P=0.03). Conclusions: There was a high incidence of QT prolongation in patients who received HCQ as part of a COVID-19 treatment regimen. We observed an increased risk of death in patients with QT prolongation, as well as an increased incidence of ICU admission and longer length of stay in hospital. We recommend particular attention be paid to the risk of QT prolongation with novel treatment strategies for COVID-19. Further research is warranted on the effect of QT prolongation on clinical outcomes in COVID-19.

Estimating the Repercussions of Covid-19 in Pregnancy and Neonatal Complications (preprint)

The chief goal of this article was to do a literature review on a sensitive topic that has affected many people worldwide. COVID-19 was declared as a pandemic as it crossed all the boundaries. The effects of COVID-19 infection were seen globally, affecting every individual of the society. But here, the main intention was to study the impact of COVID-19 illness in pregnancy since pregnancy is an immune-compromised condition. The effects that had on pregnancy were preterm labor, premature birth, pre-eclampsia, and miscarriages. The other objective was to study the neonatal outcomes, which showed fetal respiratory distress syndrome, Prolonged QT.

Innate Immune Activation and Mitochondrial ROS Invoke Persistent Cardiac Conduction System Dysfunction after COVID-19 (preprint)

BackgroundCardiac risk rises during acute SARS-CoV-2 infection and in long COVID syndrome in humans, but the mechanisms behind COVID-19-linked arrhythmias are unknown. This study explores the acute and long term effects of SARS-CoV-2 on the cardiac conduction system (CCS) in a hamster model of COVID-19. MethodsRadiotelemetry in conscious animals was used to non-invasively record electrocardiograms and subpleural pressures after intranasal SARS-CoV-2 infection. Cardiac cytokines, interferon-stimulated gene expression, and macrophage infiltration of the CCS, were assessed at 4 days and 4 weeks post-infection. A double-stranded RNA mimetic, polyinosinic:polycytidylic acid (PIC), was used in vivo and in vitro to activate viral pattern recognition receptors in the absence of SARS-CoV-2 infection. ResultsCOVID-19 induced pronounced tachypnea and severe cardiac conduction system (CCS) dysfunction, spanning from bradycardia to persistent atrioventricular block, although no viral protein expression was detected in the heart. Arrhythmias developed rapidly, partially reversed, and then redeveloped after the pulmonary infection was resolved, indicating persistent CCS injury. Increased cardiac cytokines, interferon-stimulated gene expression, and macrophage remodeling in the CCS accompanied the electrophysiological abnormalities. Interestingly, the arrhythmia phenotype was reproduced by cardiac injection of PIC in the absence of virus, indicating that innate immune activation was sufficient to drive the response. PIC also strongly induced cytokine secretion and robust interferon signaling in hearts, human iPSC-derived cardiomyocytes (hiPSC-CMs), and engineered heart tissues, accompanied by alterations in electrical and Ca2+ handling properties. Importantly, the pulmonary and cardiac effects of COVID-19 were blunted by in vivo inhibition of JAK/STAT signaling or by a mitochondrially-targeted antioxidant. ConclusionsThe findings indicate that long term dysfunction and immune cell remodeling of the CCS is induced by COVID-19, arising indirectly from oxidative stress and excessive activation of cardiac innate immune responses during infection, with implications for long COVID Syndrome.

Efficacy and Safety of African Medicinal plants in the treatment of mild or moderate COVID-19: a randomized clinical trial using Doubase C ® (preprint)

Introduction At the start of the COVID-19 pandemic, an herbal medicine Doubase C = Uvaria brevistipita + Haroungana madasgascariensis (DBC) had received authorization for clinical trials in DR Congo. We aimed to determine its efficacy and safety compared to hydroxychloroquine-azithromycin (HCQ-AZI), the national standard treatment for COVID-19 at that time. Methods We conducted an open randomized clinical trial between May 2021 and January 2022. Only mild and moderate cases of COVID-19 (WHO classification) were included. Asymptomatic, severe and critical cases were excluded. Each patient's parameters (NEW score, Ordinale scale, viral load, EKG tracing) were evaluated sequentially and the proportion of changes was compared between the two arms on days 7 and 14. Results 376 patients randomized (mean age = 40 years, 14 % ≥ 60 years, 90.7% mild case, 9.3% moderate case). From day 7, 97.6 % of mild case had a marked improvement in their NEW score and Ordinal scale (p=ns). Among patients with moderate case, 5.8% progressed to the severe form of COVID-19 in the HCQ-AZI arm and no patient in the DBC arm (p=ns). The viral load was progressively negative (29.8 % negative viral load on day 7 and 86.7 % on day 14) (p=ns). 4.4 % of patients on HCQ-AZI experienced QTc interval prolongation and none in the DBC arm (p=0.021). We have not recorded any critical cases or deaths. Conclusions In both arms, most patients experienced clinical improvement but DBC offers better cardiac safety. The young age of the patients may have influenced the results.

Symptom experience before vs. after confirmed SARS-CoV-2 infection: a population and case control study using prospectively recorded symptom data. (preprint)

Background: Some individuals experience prolonged illness after acute COVID-19. We assessed whether pre-infection symptoms affected post-COVID illness duration. Methods Survival analysis was performed in adults (n=23,452) with community-managed SARC-CoV-2 infection prospectively self-logging data through the ZOE COVID Symptom Study app, at least weekly, from 8 weeks before to 12 weeks after COVID-19 onset, conditioned on presence vs. absence of baseline symptoms (4-8 weeks before COVID-19). A case-control study was performed in 1350 individuals with long illness ([≥]8 weeks, 906 [67.1%] with illness [≥]12 weeks), matched 1:1 (for age, sex, body mass index, testing week, prior infection, vaccination, smoking, index of multiple deprivation) with 1350 individuals with short illness (<4 weeks). Baseline symptoms were compared between the two groups; and against post-COVID symptoms. Findings: Individuals reporting baseline symptoms had longer post-COVID symptom duration (from 10 to 15 days) with baseline fatigue nearly doubling duration. Two-thirds (910 of 1350 [67.4%]) of individuals with long illness were asymptomatic beforehand. However, 440 (32.6%) had baseline symptoms, vs. 255 (18.9%) of 1350 individuals with short illness (p<0.0001). Baseline symptoms increased the odds ratio for long illness (2.14 [CI: 1.78; 2.57]). Prior comorbidities were more common in individuals with long vs. short illness. In individuals with long illness, baseline symptomatic (vs. asymptomatic) individuals were more likely to be female, younger, and have prior comorbidities; and baseline and post-acute symptoms and symptom burden correlated strongly. Interpretation: Individuals experiencing symptoms before COVID-19 have longer illness duration and increased odds of long illness. However, many individuals with long illness are well before SARS-CoV-2 infection.

Genetic Risk Factors for Severe and Fatigue Dominant Long COVID and Commonalities with ME/CFS Identified by Combinatorial Analysis (preprint)

Background Long COVID is a debilitating chronic condition that has affected over 100 million people globally. It is characterized by a diverse array of symptoms, including fatigue, cognitive dysfunction and respiratory problems. Studies have so far largely failed to identify genetic associations, the mechanisms behind the disease, or any common pathophysiology with other conditions such as ME/CFS that present with similar symptoms. Methods We used a combinatorial analysis approach to identify combinations of genetic variants significantly associated with the development of long COVID and to examine the biological mechanisms underpinning its various symptoms. We compared two subpopulations of long COVID patients from Sano Genetics' Long COVID GOLD study cohort, focusing on patients with severe or fatigue dominant phenotypes. We evaluated the genetic signatures previously identified in an ME/CFS population against this long COVID population to understand similarities with other fatigue disorders that may be triggered by a prior viral infection. Finally, we also compared the output of this long COVID analysis against known genetic associations in other chronic diseases, including a range of metabolic and neurological disorders, to understand the overlap of pathophysiological mechanisms. Results Combinatorial analysis identified 73 genes that were highly associated with at least one of the long COVID populations included in this analysis. Of these, 9 genes have prior associations with acute COVID-19, and 14 were differentially expressed in a transcriptomic analysis of long COVID patients. A pathway enrichment analysis revealed that the biological pathways most significantly associated with the 73 long COVID genes were mainly aligned with neurological and cardiometabolic diseases. Expanded genotype analysis suggests that specific SNX9 genotypes are a significant contributor to the risk of or protection against severe long COVID infection, but that the gene-disease relationship is context dependent and mediated by interactions with KLF15 and RYR3. Comparison of the genes uniquely associated with the Severe and Fatigue Dominant long COVID patients revealed significant differences between the pathways enriched in each subgroup. The genes unique to Severe long COVID patients were associated with immune pathways such as myeloid differentiation and macrophage foam cells. Genes unique to the Fatigue Dominant subgroup were enriched in metabolic pathways such as MAPK/JNK signaling. We also identified overlap in the genes associated with Fatigue Dominant long COVID and ME/CFS, including several involved in circadian rhythm regulation and insulin regulation. Overall, 39 SNPs associated in this study with long COVID can be linked to 9 genes identified in a recent combinatorial analysis of ME/CFS patient from UK Biobank. Among the 73 genes associated with long COVID, 42 are potentially tractable for novel drug discovery approaches, with 13 of these already targeted by drugs in clinical development pipelines. From this analysis for example, we identified TLR4 antagonists as repurposing candidates with potential to protect against long term cognitive impairment pathology caused by SARS-CoV-2. We are currently evaluating the repurposing potential of these drug targets for use in treating long COVID and/or ME/CFS. Conclusion This study demonstrates the power of combinatorial analytics for stratifying heterogeneous populations in complex diseases that do not have simple monogenic etiologies. These results build upon the genetic findings from combinatorial analyses of severe acute COVID-19 patients and an ME/CFS population and we expect that access to additional independent, larger patient datasets will further improve the disease insights and validate potential treatment options in long COVID.

Clinical Characteristics and Short-term Outcomes of Acute Pancreatitis with COVID-19 (preprint)

Introduction: The existing literature on the combination of acute pancreatitis (AP) and COVID-19 is scarce. The objective of our study is to compare the clinical outcomes and occurrence of long COVID syndrome in AP patients with and without COVID-19, while investigating the potential impact of COVID-19 on the severity, mortality rate, and long COVID syndrome in these patients.Materials and methods This retrospective, observational study was conducted at a single center. It included patients aged 18 years and above who were diagnosed with AP during the pandemic. Patients were categorized into two groups based on the results of RT-qPCR testing: the COVID-19 positive group and the COVID-19 negative group. The study aimed to compare the severity of AP, mortality rate, and occurrence of long COVID syndrome between these two groups.Result A retrospective review was conducted on 122 patients diagnosed with acute pancreatitis between December 1, 2022, and January 31, 2023. Out of these patients, 100 were included in the study. The analysis revealed no significant differences in mortality rate, severity, and sequelae between AP patients with COVID-19 and those without COVID-19 (p > 0.005). However, a statistically significant difference was observed in the occurrence of long COVID syndrome, specifically in the presence of cough (P = 0.04).Conclusion This study demonstrates that the presence of COVID-19 in patients with pancreatitis does not lead to an increase in the mortality and severity rate of pancreatitis.

Cardiovascular Safety of Hydroxychloroquine-Azithromycin in 424 COVID-19 Patients.

Background and Objectives: Hydroxychloroquine (HCQ) combined with azithromycin (AZM) has been widely administered to patients with COVID-19 despite scientific controversies. In particular, the potential of prolong cardiac repolarization when using this combination has been discussed. Materials and Methods: We report a pragmatic and simple safety approach which we implemented among the first patients treated for COVID-19 in our center in early 2020. Treatment contraindications were the presence of severe structural or electrical heart disease, baseline corrected QT interval (QTc) > 500 ms, hypokalemia, or other drugs prolonging QTc that could not be interrupted. Electrocardiogram and QTc was evaluated at admission and re-evaluated after 48 h of the initial prescription. Results: Among the 424 consecutive adult patients (mean age 46.3 ± 16.1 years; 216 women), 21.5% patients were followed in conventional wards and 78.5% in a day-care unit. A total of 11 patients (2.6%) had contraindications to the HCQ-AZ combination. In the remaining 413 treated patients, there were no arrhythmic events in any patient during the 10-day treatment regimen. QTc was slightly but statistically significantly prolonged by 3.75 ± 25.4 ms after 2 days of treatment (p = 0.003). QTc prolongation was particularly observed in female outpatients <65 years old without cardiovascular disease. Ten patients (2.4%) developed QTc prolongation > 60 ms, and none had QTc > 500 ms. Conclusions: This report does not aim to contribute to knowledge of the efficacy of treating COVID-19 with HCQ-AZ. However, it shows that a simple initial assessment of patient medical history, electrocardiogram (ECG), and kalemia identifies contraindicated patients and enables the safe treatment of COVID-19 patients with HCQ-AZ. QT-prolonging anti-infective drugs can be used safely in acute life-threatening infections, provided that a strict protocol and close collaboration between infectious disease specialists and rhythmologists are applied.

Improvement of clinical symptoms and cardiac abnormalities detected by cardiac magnetic resonance imaging in patients with long COVID syndrome after guideline-oriented therapy (preprint)

Patients with cardiovascular long COVID syndrome and cardiac magnetic resonance (CMR) scans were included prospectively into the Vienna PostCoV Registry between March 2021 and March 2023 (EC: 1008/2021, clinicaltrials.gov NCT05398952; n=240). Clinical symptoms, age and sex, time between COVID-positivity and vaccination and CMR, as well as CMR findings were recorded. After medical treatment, clinical assessment and CMR was repeated in 67 patients with pathological CMR findings showing myopericarditis, pericardial effusion or cardiac functional abnormalities. Blood pressure and condition-adapted heart failure treatment led to a significant increase in left ventricular ejection fraction. Low-moderate doses of NSAIDs for 3 months significantly reduced pericardial effusion. Clinical symptoms improved markedly with a decrease in CMR abnormalities.  In conclusion, medical treatment of cardiac/cardiovascular long COVID syndrome related to CMR abnormalities led to significant improvement in ejection fraction and decreased pericardial effusion, and were associated with improvements in the cardiovascular long COVID complaints.

Neurodivergence as a risk factor for Post-Covid-19 Syndrome (preprint)

Neurodivergent (ND) individuals (e.g., Autistic people) are more likely to experience health problems that are characterised by central sensitisation'. Recent research suggests that a so-called Long-COVID syndrome might also be explained by a heightened response to internal physiological stimuli, much like in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Using a standardised assessment tool, we examined whether traits associated with Autism would predict long-term COVID-19 symptoms in 267 Healthcare Workers (HCW).. Higher autistic traits predicted COVID-19 symptoms that lasting more than 12 weeks regardless of formal autism diagnosis. A personality measure also showed that negative affect was associated with experiencing COVID-19 symptoms for 4-12 weeks, though the direction of causality in this case is uncertain. Limitations of the present study are 1) the retrospective nature of COVID-19 symptom reporting; 2) likely self-selection bias given the high number of HCWs who reported long-term COVID-19 symptoms; and 3) the gender-bias towards females in our sample.

SARS-CoV-2 spike protein-mediated cardiomyocyte fusion may contribute to increased arrhythmic risk in COVID-19.

BACKGROUND: SARS-CoV-2-mediated COVID-19 may cause sudden cardiac death (SCD). Factors contributing to this increased risk of potentially fatal arrhythmias include thrombosis, exaggerated immune response, and treatment with QT-prolonging drugs. However, the intrinsic arrhythmic potential of direct SARS-CoV-2 infection of the heart remains unknown. OBJECTIVE: To assess the cellular and electrophysiological effects of direct SARS-CoV-2 infection of the heart using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). METHODS: hiPSC-CMs were transfected with recombinant SARS-CoV-2 spike protein (CoV-2 S) or CoV-2 S fused to a modified Emerald fluorescence protein (CoV-2 S-mEm). Cell morphology was visualized using immunofluorescence microscopy. Action potential duration (APD) and cellular arrhythmias were measured by whole cell patch-clamp. Calcium handling was assessed using the Fluo-4 Ca2+ indicator. RESULTS: Transfection of hiPSC-CMs with CoV-2 S-mEm produced multinucleated giant cells (syncytia) displaying increased cellular capacitance (75±7 pF, n = 10 vs. 26±3 pF, n = 10; P<0.0001) consistent with increased cell size. The APD90 was prolonged significantly from 419±26 ms (n = 10) in untransfected hiPSC-CMs to 590±67 ms (n = 10; P<0.05) in CoV-2 S-mEm-transfected hiPSC-CMs. CoV-2 S-induced syncytia displayed delayed afterdepolarizations, erratic beating frequency, and calcium handling abnormalities including calcium sparks, large "tsunami"-like waves, and increased calcium transient amplitude. After furin protease inhibitor treatment or mutating the CoV-2 S furin cleavage site, cell-cell fusion was no longer evident and Ca2+ handling returned to normal. CONCLUSION: The SARS-CoV-2 spike protein can directly perturb both the cardiomyocyte's repolarization reserve and intracellular calcium handling that may confer the intrinsic, mechanistic substrate for the increased risk of SCD observed during this COVID-19 pandemic.

An electrophysiological substrate of COVID-19.

SARS-CoV-2 infection is associated with an increased risk of late cardiovascular (CV) outcomes. However, more data is needed to describe the electrophysiologic (EP) manifestation of post-acute CV sequelae of COVID-19. We compared two cohorts of adult patients with SARS-CoV-2 polymerase chain reaction (PCR) test and an electrocardiogram (ECG) performed between March 1, 2020, and September 13, 2020, in a retrospective double-cohort study, "Cardiovascular Risk Stratification in Covid-19" (CaVaR-Co19; NCT04555187). Patients with positive PCR comprised a COVID-19(+) cohort (n = 41; 61% women; 80% symptomatic), whereas patients with negative tests formed the COVID-19(-) cohort (n = 155; 56% women). In longitudinal analysis, comparing 3 ECGs recorded before, during, and on average 40 days after index COVID-19 episode, after adjustment for demographic and socioeconomic characteristics, baseline CV risk factors and comorbidities, use of prescription medications (including QT-prolonging drugs) before and during index COVID-19 episode, and the longitudinal changes in RR' intervals, heart rhythm, and ventricular conduction type, only in the COVID-19(+) cohort QTc increased by +30.2(95% confidence interval [CI] 0.1-60.3) ms and the spatial ventricular gradient (SVG) elevation increased by +13.5(95%CI 1.2-25.9)°. In contrast, much smaller, statistically nonsignificant changes were observed in the COVID-19(-) cohort. In conclusion, post-acute CV sequelae of SARS-CoV-2 infection manifested on ECG by QTc prolongation and rotation of the SVG vector upward.

Prevalence and Characterization of Long Covid-19 Symptoms in Health Care Professionals- A Need of the Hour (preprint)

Background: With the global advent of Covid-19, Healthcare workers (HCW) were under a lot of physical and psychological pressure. Information on persistent symptoms post Covid-19 Infection in HCWs is lacking.  Objectives: This Study is aimed at assessing the impact of the post Covid-19 syndrome in HCWs.  Materials and Methods: A Questionnaire was prepared as google form and shared with the HCWs through WhatsApp enquiring regarding the health conditions that are still persistent post recovery from Covid-19 infection.  Results: A total of 328 Health Care Professionals participated in the present survey (18-65 yrs). The gender distribution revealed 67.7% were females and 32.3% were males. 60.3% of the participants were infected with COVID-19 before taking the first dose of vaccination which is reduced to 17.5% after vaccination. The post COVID complications observed from the study were hair loss (35.4%), easy fatigability (25%), mood swings (22.9%), anxiety (18.8%), insomnia/sleeplessness (13.9%), depression (12.5%) and joint pains/arthritis (11.8%). The other complications observed were loss of taste (9%), lightheadedness/postural hypotension (8.3%), amnesia/loss of memory and anosmia/loss of smell (7.6%), gastritis (6.3%), palpitations, hypersomnia and pulmonary complications (5.6%) and chest pain (4.9%). Unpaired t-test and One-Way ANNOVA resulted in a significant value (p values of >0.05).  Discussion: Despite the fact that females experienced more post-Covid-19 symptoms (15 out of 17), males experienced more chest pain and anxiety symptoms. According to our findings, 57 of 100 Covid-19 health care workers have post-Covid complications. The participants presented with non-specific symptoms such as easy fatigability, mood swings, light headedness, anxiety but most of the participants quoted more specific symptoms such as depression, pulmonary complications, hair loss, joint pains, gastritis, chest pain, palpitations, loss of taste, amnesia, hyperglycemia, insomnia, hypersomnia and anosmia. However, non-specific symptoms such as fatigue, mood swings, lightheadedness, and anxiety were also mentioned. The symptoms of post-acute COVID-19 syndrome vary greatly. Early detection requires a unified definition of long COVID and characterization of its manifestation. Furthermore, more research should be conducted to identify risk factors and the precise mechanisms that lead to the development of long COVID syndrome. Such knowledge may aid future research aimed at preventing such a complication.

Dynamics of upper respiratory tract infections before, during, and after the COVID-19 pandemic in Germany: a cross-sectional study of 2,167,453 outpatients (preprint)

Background Although the burden of the COVID-19 pandemic on global healthcare systems is declining, long-term sequelae such as long COVID syndrome and other disease dynamics not primarily associated with COVID-19 remain a challenge. Recent data suggest that the incidence of non-COVID upper respiratory tract infections (URTI) is increasing sharply in the post-pandemic period, but there is a lack of real-world data from Germany in this respect.Methods This cross-sectional study evaluated the number of patients with a diagnosis of URTI from the Disease Analyzer database (IQVIA) between January 2019 and December 2022. The number of UTRI diagnoses per practice and the duration of sick leave per patient were compared over time.Results A total of 1,872,935 individuals (1,403,907 patients from general practices (GP) and 469,028 patients from pediatric offices) were included, 48% of whom were female. The number of URTI patients per practice was significantly higher in 2022 than in 2019 (732 vs. 464, 58%, p < 0.001) and this was observed for both women (56%, p < 0.001) and men (60%, p < 0.001). The post-pandemic increase in the number of URTI diagnoses correlated with age and was highest in the age group between 18–30 years (22%, p < 0.001) and lowest in older patients > 70 years (3%). In pediatric patients (< 18 years), the increase was highest in the age group ≤ 5 years (89%). Both the number of patients per practice on sick leave due to URTI (184 vs. 92) and the average duration of sick leave (+ 2 days) increased from 2019 to 2022.Conclusion Our data suggest a dramatic increase in the incidence of URTI among all demographic subgroups in Germany between 2019 and 2022, which was associated with a tremendous impact on socioeconomic variables such as the frequency or duration of sick leave. These data could be of great importance in current pandemic management and the management of future pandemics.

Cardiovascular Safety of Hydroxychloroquine-Azithromycin in 424 COVID-19 Patients (preprint)

Background Hydroxychloroquine (HCQ) combined with azithromycin (AZM) has been widely administered to patients with COVID-19 despite scientific controversies. In particular the potential to prolong cardiac repolarisation by using this combination has been discussed. Materials and methods We report a pragmatic and simple safety approach which we implemented in the first patients treated for COVID-19 in our center early 2020. Treatment contraindications were the presence of severe structural or electrical heart disease, baseline corrected QT interval (QTc) >500 ms, hypokalaemia, or other drugs prolonging QTc that could not be interrupted. Electrocardiogram and QTc was evaluated at admission and re-evaluated after 48 hours of the initial prescription. Results Among 424 consecutive adults (mean age 46.3 ± 16.1 years; 216 women). Patients were followed in conventional wards (21.5%) or in a day-care unit (78.5%). A total of 11 patients (2.6%) had contraindications to HCQ-AZ combination. In the remaining 413 treated patients, there were no arrhythmic events in any patient during the 10-day treatment regimen. QTc was slightly but statistically significantly prolonged by 3.75 ± 25.4 ms after two days (p=0.003). Ten patients (2.4%) developed QTc prolongation >60 ms, and none had QTc >500 ms. Conclusions This report do not aim to contribute to knowledge of the efficacy of treating COVID-19 with HCQ-AZ. However, a simple initial assessment of patient medical history, ECG and kalaemia identifies contraindicated patients and enables the safe treatment by HCQ-AZ of COVID-19 patients. QT-prolonging anti-infective drugs can be used safely in acute life-threatening infections, provided that a strict protocol and close collaboration between infectious disease specialists and rhythmologists are followed.

Interruption of viral interference by anti-SARS-CoV-2 vaccination (preprint)

Epstein-Barr virus (EBV) reactivation may be involved in long-COVID symptoms. Here we evaluated reactivation of parvovirus B19 and several viruses of the herpes family in patients with long-COVID syndrome, how vaccination affected viral interference, and how virus reactivation influenced clinical conditions. Clinical and laboratory data on 252 consecutive patients (97 vaccinated and 155 non-vaccinated) were recorded between April 2021–May 2022 (median 243 days post-COVID-19 infection). Viral IgG and IgM titers were compared between vaccinated or non-vaccinated patients, and age and sex-matched healthy controls. Vaccination was associated with significantly less frequent fatigue and multiorgan symptoms (P < 0.001), significantly less cumulative IgM positivity of the investigated viruses, significantly lower plasma levels of IgG subfractions 2 and 4, and significantly lower quantitative Cytomegalovirus (CMV) IgG, CMV IgM, and EBV IgM titers. These results indicate that anti-SARS-CoV2 vaccination interrupts viral crosstalk in patients with long-COVID syndrome. (ClinicalTrials.gov Identifier: NCT05398952)