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A subset of patients has long-lasting symptoms after mild to moderate Coronavirus disease 2019 (COVID-19). In a prospective observational cohort study, we analyze clinical and laboratory parameters in 42 post-COVID-19 syndrome patients (29 female/13 male, median age 36.5 years) with persistent moderate to severe fatigue and exertion intolerance six months following COVID-19. Further we evaluate an age- and sex-matched postinfectious non-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome cohort comparatively. Most post-COVID-19 syndrome patients are moderately to severely impaired in daily live. 19 post-COVID-19 syndrome patients fulfill the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome. Disease severity and symptom burden is similar in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome and non-COVID-19/myalgic encephalomyelitis/chronic fatigue syndrome patients. Hand grip strength is diminished in most patients compared to normal values in healthy. Association of hand grip strength with hemoglobin, interleukin 8 and C-reactive protein in post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome and with hemoglobin, N-terminal prohormone of brain natriuretic peptide, bilirubin, and ferritin in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome may indicate low level inflammation and hypoperfusion as potential pathomechanisms.

ImportanceWhile much of the attention on the COVID-19 pandemic was directed at the daily counts of cases and those with serious disease overwhelming health services, increasingly, reports have appeared of people who experience debilitating symptoms after the initial infection. This is popularly known as long COVID.ObjectiveTo estimate by country and territory of the number of patients affected by long COVID in 2020 and 2021, the severity of their symptoms and expected pattern of recoveryDesignWe jointly analyzed ten ongoing cohort studies in ten countries for the occurrence of three major symptom clusters of long COVID among representative COVID cases. The defining symptoms of the three clusters (fatigue, cognitive problems, and shortness of breath) are explicitly mentioned in the WHO clinical case definition. For incidence of long COVID, we adopted the minimum duration after infection of three months from the WHO case definition. We pooled data from the contributing studies, two large medical record databases in the United States, and findings from 44 published studies using a Bayesian meta-regression tool. We separately estimated occurrence and pattern of recovery in patients with milder acute infections and those hospitalized. We estimated the incidence and prevalence of long COVID globally and by country in 2020 and 2021 as well as the severity-weighted prevalence using disability weights from the Global Burden of Disease study.ResultsAnalyses are based on detailed information for 1906 community infections and 10526 hospitalized patients from the ten collaborating cohorts, three of which included children. We added published data on 37262 community infections and 9540 hospitalized patients as well as ICD-coded medical record data concerning 1.3 million infections. Globally, in 2020 and 2021, 144.7 million (95% uncertainty interval [UI] 54.8–312.9) people suffered from any of the three symptom clusters of long COVID. This corresponds to 3.69% (1.38–7.96) of all infections. The fatigue, respiratory, and cognitive clusters occurred in 51.0% (16.9–92.4), 60.4% (18.9–89.1), and 35.4% (9.4–75.1) of long COVID cases, respectively. Those with milder acute COVID-19 cases had a quicker estimated recovery (median duration 3.99 months [IQR 3.84–4.20]) than those admitted for the acute infection (median duration 8.84 months [IQR 8.10–9.78]). At twelve months, 15.1% (10.3–21.1) continued to experience long COVID symptoms.Conclusions and relevanceThe occurrence of debilitating ongoing symptoms of COVID-19 is common. Knowing how many people are affected, and for how long, is important to plan for rehabilitative services and support to return to social activities, places of learning, and the workplace when symptoms start to wane.Key PointsQuestionWhat are the extent and nature of the most common long COVID symptoms by country in 2020 and 2021?FindingsGlobally, 144.7 million people experienced one or more of three symptom clusters (fatigue; cognitive problems; and ongoing respiratory problems) of long COVID three months after infection, in 2020 and 2021. Most cases arose from milder infections. At 12 months after infection, 15.1% of these cases had not yet recovered.MeaningThe substantial number of people with long COVID are in need of rehabilitative care and support to transition back into the workplace or education when symptoms start to wane.

The German government initiated the Network University Medicine (NUM) in early 2020 to improve national research activities on the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic. To this end, 36 German Academic Medical Centers started to collaborate on 13 projects, with the largest being the National Pandemic Cohort Network (NAPKON). The NAPKON’s goal is creating the most comprehensive Coronavirus Disease 2019 (COVID-19) cohort in Germany. Within NAPKON, adult and pediatric patients are observed in three complementary cohort platforms (Cross-Sectoral, High-Resolution and Population-Based) from the initial infection until up to three years of follow-up. Study procedures comprise comprehensive clinical and imaging diagnostics, quality-of-life assessment, patient-reported outcomes and biosampling. The three cohort platforms build on four infrastructure core units (Interaction, Biosampling, Epidemiology, and Integration) and collaborations with NUM projects. Key components of the data capture, regulatory, and data privacy are based on the German Centre for Cardiovascular Research. By December 01, 2021, 34 university and 34 non-university hospitals have enrolled 4,241 patients with local data quality reviews performed on 2,812 (66%). 47% were female, the median age was 53 (IQR: 38-63)) and 3 pediatric cases were included. 30% of patients were hospitalized, 11% admitted to an intensive care unit, and 4% of patients deceased while enrolled. 7,143 visits with biosampling in 3,595 patients were conducted by November 29, 2021. In this overview article, we summarize NAPKON’s design, relevant milestones including first study population characteristics, and outline the potential of NAPKON for German and international research activities.Trial registration:· https://clinicaltrials.gov/ct2/show/NCT04768998· https://clinicaltrials.gov/ct2/show/NCT04747366· https://clinicaltrials.gov/ct2/show/NCT04679584

The German government initiated the Network University Medicine (NUM) in early 2020 to improve national research activities on the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic. To this end, 36 German Academic Medical Centers started to collaborate on 13 projects, with the largest being the National Pandemic Cohort Network (NAPKON). The NAPKON’s goal is creating the most comprehensive Coronavirus Disease 2019 (COVID-19) cohort in Germany. Within NAPKON, adult and pediatric patients are observed in three complementary cohort platforms (Cross-Sectoral, High-Resolution and Population-Based) from the initial infection until up to three years of follow-up. Study procedures comprise comprehensive clinical and imaging diagnostics, quality-of-life assessment, patient-reported outcomes and biosampling. The three cohort platforms build on four infrastructure core units (Interaction, Biosampling, Epidemiology, and Integration) and collaborations with NUM projects. Key components of the data capture, regulatory, and data privacy are based on the German Centre for Cardiovascular Research. By April 01, 2022, 34 university and 40 non-university hospitals have enrolled 5298 patients with local data quality reviews performed on 4727 (89%). 47% were female, the median age was 52 (IQR 36–62-) and 50 pediatric cases were included. 44% of patients were hospitalized, 15% admitted to an intensive care unit, and 12% of patients deceased while enrolled. 8845 visits with biosampling in 4349 patients were conducted by April 03, 2022. In this overview article, we summarize NAPKON’s design, relevant milestones including first study population characteristics, and outline the potential of NAPKON for German and international research activities.Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT04768998.https://clinicaltrials.gov/ct2/show/NCT04747366.https://clinicaltrials.gov/ct2/show/NCT04679584

Glycosylphosphatidylinositols (GPIs) are complex glycolipids present on the surfaces of Plasmodium parasites that may act as toxins during the progression of malaria. GPIs can activate the immune system during infection and induce the formation of anti-GPI antibodies that neutralize their activity. Therefore, an antitoxic vaccine based on GPI glycoconjugates may prevent malaria pathogenesis. To evaluate the role of three key modifications on Plasmodium GPI glycan in the activity of these glycolipids, we synthesized and investigated six structurally distinct GPI fragments from Plasmodium falciparum. The synthetic glycans were conjugated to the CRM197 carrier protein and were tested for immunogenicity and efficacy as antimalarial vaccine candidates in an experimental cerebral malaria model using C57BL/6JRj mice. Protection may be dependent on both the antibody and the cellular immune response to GPIs, and the elicited immune response depends on the orientation of the glycan, the number of mannoses in the structure, and the presence of the phosphoethanolamine and inositol units. This study provides insights into the epitopes in GPIs and contributes to the development of GPI-based antitoxin vaccine candidates against cerebral malaria.

Cardiopulmonary Exercise Testing (CPET) provides a comprehensive assessment of pulmonary, cardiovascular and musculosceletal function. Reduced CPET performance could be an indicator for chronic morbidity after COVID-19.Patients ≥18 years with confirmed PCR positive SARS-CoV-2 infection were offered to participate in a prospective observational study of clinical course and outcomes of COVID-19. 54 patients completed CPET, questionnaires on respiratory quality of life and performed pulmonary function tests 12 months after SARS-CoV-2 infection.At 12 months after SARS-CoV-2 infection, 46.3% of participants had a peak performance and 33.3% a peak oxygen uptake of80% of the predicted values, respectively. Further impairments were observed in diffusion capacity and ventilatory efficiency. Functional limitations were particularly pronounced in patients after invasive mechanical ventilation and extracorporeal membrane oxygenation treatment. Ventilatory capacity was reduced80% of predicted values in 55.6% of participants, independent from initial clinical severity. Patient reported dyspnea and respiratory quality of life after COVID-19 correlated with CPET performance and parameters of gas exchange. Risk factors for reduced CPET performance 12 months after COVID-19 were prior intensive care treatment (OR 5.58, p = 0.004), SGRQ outcome25 points (OR 3.48, p = 0.03) and reduced DFunctional limitations causing chronic morbidity in COVID-19 survivors persist over 12 months after SARS-CoV-2 infection. These limitations were particularly seen in parameters of overall performance and gas exchange resulting from muscular deconditioning and lung parenchymal changes. Patient reported reduced respiratory quality of life was a risk factor for adverse CPET performance.

Introduction Prospective and longitudinal data on pulmonary injury over one year after acute coronavirus disease 2019 (COVID-19) are sparse. We aim to determine reductions in pulmonary function and respiratory related quality of life up to 12 months after acute COVID-19. Methods Patients with acute COVID-19 were enrolled into an ongoing single-centre, prospective observational study and prospectively examined 6 weeks, 3, 6 and 12 months after onset of COVID-19 symptoms. Chest CT-scans, pulmonary function and symptoms assessed by St. Georges Respiratory Questionnaire were used to evaluate respiratory limitations. Patients were stratified according to severity of acute COVID-19. Results Median age of all patients was 57 years, 37.8% were female. Higher age, male sex and higher BMI were associated with acute-COVID-19 severity (p, Graphical abstract Image 1

BackgroundProspective and longitudinal data on pulmonary injury over one year after acute coronavirus disease 2019 (COVID-19) are sparse.Research questionWith this study, we aim to investigate pulmonary outcome following SARS-CoV-2 infection including pulmonary function, computed chest tomography, respiratory symptoms and quality of life over 12 months.Study design and Methods180 patients after acute COVID-19 were enrolled into a single-centre, prospective observational study and examined 6 weeks, 3, 6 and 12 months after onset of COVID-19 symptoms. Chest CT-scans, pulmonary function and symptoms assessed by St. Georges Respiratory Questionnaire were used to evaluate objective and subjective respiratory limitations. Patients were stratified according to acute COVID-19 disease severity.ResultsOf 180 patients enrolled, 42/180 were not hospitalized during acute SARS-CoV-2 infection, 29/180 were hospitalized without need for oxygen, 43/180 with need for low-flow and 24/180 with high-flow oxygen, 26/180 required invasive mechanical ventilation and 16/180 were treated with ECMO. After acute COVID-19, pulmonary restriction and reduced carbon monoxide diffusion capacity was associated with disease severity after the acute phase and improved over 12 months except for those requiring ECMO treatment. Patients with milder disease showed a predominant reduction of ventilated area instead of simple restriction. The CT score of lung involvement in the acute phase increased significantly with COVID-19 severity and was associated with restriction and reduction in diffusion capacity in follow-up. Respiratory symptoms improved for patients in higher severity groups during follow-up, but not for patients with mild initially disease.InterpretationSeverity of respiratory failure during COVID-19 correlates with the degree of pulmonary function impairment and respiratory quality of life in the year after acute infection. Patients with mild vs. severe disease show different patterns of lung involvement and symptom resolution.Clinical Trial RegistrationThe study is registered at the German registry for clinical studies (DRKS00021688)

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.

ObjectiveCharacterization 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).MethodsSetting: Charité Fatigue Center with clinical immunologists and rheumatologist, neurologists and cardiologists at Charité 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 Charité 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.ResultsThe 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 (SF-36) 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 (p=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.ConclusionsChronic 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.

Purpose Over the course of COVID-19 pandemic, evidence has accumulated that SARS-CoV-2 infections may affect multiple organs and have serious clinical sequelae, but on-site clinical examinations with non-hospitalized samples are rare. We, therefore, aimed to systematically assess the long-term health status of samples of hospitalized and non-hospitalized SARS-CoV-2 infected individuals from three regions in Germany. Methods The present paper describes the COVIDOM-study within the population-based cohort platform (POP) which has been established under the auspices of the NAPKON infrastructure (German National Pandemic Cohort Network) of the national Network University Medicine (NUM). Comprehensive health assessments among SARS-CoV-2 infected individuals are conducted at least 6 months after the acute infection at the study sites Kiel, Würzburg and Berlin. Potential participants were identified and contacted via the local public health authorities, irrespective of the severity of the initial infection. A harmonized examination protocol has been implemented, consisting of detailed assessments of medical history, physical examinations, and the collection of multiple biosamples (e.g., serum, plasma, saliva, urine) for future analyses. In addition, patient-reported perception of the impact of local pandemic-related measures and infection on quality-of-life are obtained. Results As of July 2021, in total 6813 individuals infected in 2020 have been invited into the COVIDOM-study. Of these, about 36% wished to participate and 1295 have already been examined at least once. Conclusion NAPKON-POP COVIDOM-study complements other Long COVID studies assessing the long-term consequences of an infection with SARS-CoV-2 by providing detailed health data of population-based samples, including individuals with various degrees of disease severity. Trial registration Registered at the German registry for clinical studies (DRKS00023742).

Objectives Dexamethasone has become the standard of care for severe coronavirus disease 2019 (COVID-19), but its virological impact is poorly understood. The objectives of this work were to characterize the kinetics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) concentration in the upper respiratory tract (URT) and the antibody response in patients with (D+) and without (D–) dexamethasone treatment. Methods Data and biosamples from hospitalized patients with severe COVID-19, enrolled between 4th March and 11th December 2020 in a prospective observational study, were analysed. SARS-CoV-2 virus concentration in serial URT samples was measured using RT-PCR. SARS-CoV-2-specific immunoglobulins A and G (IgA and IgG) were measured in serum samples using S1-ELISA. Results We compared 101 immunocompetent patients who received dexamethasone (according to the inclusion criteria and dosage determined in the RECOVERY trial) to 93 immunocompetent patients with comparable disease severity from the first months of the pandemic, who had not been treated with dexamethasone or other glucocorticoids. We found no inter-group differences in virus concentration kinetics, duration of presence of viral loads >106 viral copies/mL (D+ median 17 days (IQR 13–24), D– 19 days (IQR 13–29)), or time from symptom onset until seroconversion (IgA: D+ median 11.5 days (IQR 11–12), D– 14 days (IQR 11.5–15.75); IgG: D+ 13 days (IQR 12–14.5), D– 12 days (IQR 11–15)). Conclusion Dexamethasone does not appear to lead to a change in virus clearance or a delay in antibody response in immunocompetent patients hospitalized with severe COVID-19.

BackgroundThe major shifts in the global burden of disease over the past decades are well documented, but how these shifts have affected global inequalities in health remains an underexplored topic. We applied comprehensive inequality measures to data from the Global Burden of Disease (GBD) study.MethodsBetween-country relative inequality was measured by the population-weighted Gini Index, between-country absolute inequality was calculated using the population-weighted Slope Inequality Index (SII). Both were applied to country-level GBD data on age-standardised disability-adjusted life years.FindingsAbsolute global health inequality measured by the SII fell notably between 1990 (0.68) and 2017 (0.42), mainly driven by a decrease of disease burden due to communicable, maternal, neonatal and nutritional diseases (CMNN). By contrast, relative inequality remained essentially unchanged from 0.21 to 0.19 (1990–2017), with a peak of 0.23 (2000–2008). The main driver for the increase of relative inequality 1990–2008 was the HIV epidemic in Sub-Saharan Africa. Relative inequality increased 1990–2017 within each of the three main cause groups: CMNNs; non-communicable diseases (NCDs); and injuries.ConclusionsDespite considerable reductions in disease burden in 1990–2017 and absolute health inequality between countries, absolute and relative international health inequality remain high. The limited reduction of relative inequality has been largely due to shifts in disease burden from CMNNs and injuries to NCDs. If progress in the reduction of health inequalities is to be sustained beyond the global epidemiological transition, the fight against CMNNs and injuries must be joined by increased efforts for NCDs.

Background Research on Neglected Tropical Diseases (NTDs) has increased in recent decades, and significant need-gaps in diagnostic and treatment tools remain. Analysing bibliometric data from published research is a powerful method for revealing research efforts, partnerships and expertise. We aim to identify and map NTD research networks in Germany and their partners abroad to enable an informed and transparent evaluation of German contributions to NTD research. Methodology/Principal Findings A SCOPUS database search for articles with German author affiliations that were published between 2002 and 2012 was conducted for kinetoplastid and helminth diseases. Open-access tools were used for data cleaning and scientometrics (OpenRefine), geocoding (OpenStreetMaps) and to create (Table2Net), visualise and analyse co-authorship networks (Gephi). From 26,833 publications from around the world that addressed 11 diseases, we identified 1,187 (4.4%) with at least one German author affiliation, and we processed 972 publications for the five most published-about diseases. Of those, we extracted 4,007 individual authors and 863 research institutions to construct co-author networks. The majority of co-authors outside Germany were from high-income countries and Brazil. Collaborations with partners on the African continent remain scattered. NTD research within Germany was distributed among 220 research institutions. We identified strong performers on an individual level by using classic parameters (number of publications, h-index) and social network analysis parameters (betweenness centrality). The research network characteristics varied strongly between diseases. Conclusions/Significance The share of NTD publications with German affiliations is approximately half of its share in other fields of medical research. This finding underlines the need to identify barriers and expand Germany’s otherwise strong research activities towards NTDs. A geospatial analysis of research collaborations with partners abroad can support decisions to strengthen research capacity, particularly in low- and middle-income countries, which were less involved in collaborations than high-income countries. Identifying knowledge hubs within individual researcher networks complements traditional scientometric indicators that are used to identify opportunities for collaboration. Using free tools to analyse research processes and output could facilitate data-driven health policies. Our findings contribute to the prioritisation of efforts in German NTD research at a time of impending local and global policy decisions., Author Summary Neglected tropical disease research has changed considerably in recent decades, and the German government is committed to addressing its past neglect of NTD research. Our aim was to use an innovative social network analysis of bibliometric data to map neglected tropical disease research networks that are inside of and affiliated with Germany, thereby enabling data-driven health policy decision-making. We created and analysed co-author networks from publications in the SCOPUS database, with a focus on five diseases. We found that Germany's share of global publication output for NTDs is approximately half that of other medical research fields. Furthermore, we identified institutions with prominent NTD research within Germany and strong research collaborations between German institutions and partners abroad, mostly in other high-income countries. This allowed an assessment of strong collaborations for further development, e.g., for research capacity strengthening in low-income-countries, but also for identifying missed opportunities for collaboration within the network. Through co-authorship network analysis of individual researcher networks, we identified strong performers by using classic bibliometric parameters, and we identified academic talent by social network analysis parameters on an individual level.

Background Research and development (R&D) for poverty-related and neglected diseases falls short of their global public health importance. Several major global health initiatives aim to address this shortfall. We analysed the degree to which diseases are related to poverty and whether they are neglected by R&D at present. Methods We measured how diseases were related to poverty with the ratio of disability-adjusted life-years (DALYs) per 100 000 inhabitants in low-income and middle-income countries versus that in high-income countries. We termed this ratio the poverty relation factor (PRF), which we calculated for all 240 causes of death and disability in the Global Burden of Disease Study 2010. We classed each cause as strongly or moderately related to poverty or affluence on the basis of a WHO background report. We measured neglect in R&D by the ratio of disease burden in DALYs (as a percentage of the total global disease burden) versus R&D expenditure (as a percentage of total global health-related R&D expenditure). We termed this ratio the neglect factor, which we assessed for 26 diseases commonly considered neglected and listed in the 2012 G-FINDER report. We estimated total global health-related R&D expenditure from data from official statistical databases and reliable private sources (OECD.stat, UNESCO Institute for Statistics, Eurostat, EP Vantage, Research!America). Research expenditure data for specific diseases were taken from the 2012 G-FINDER report. Findings 28 of 240 (12%) causes of death and disability were strongly related to poverty (PRF >35), 53 (23%) were moderately related (PRF 3–35), 117 (49%) were unrelated to economic development (PRF 0·66–2·99), 27 (11%) were moderately related with affluence (PRF 0·33–0·65), and 16 (7%) were strongly related with affluence (PRF Interpretation A large shortfall exists in global R&D spending for poverty-related and neglected diseases, with huge variations between individual diseases. Funding None.