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Dexamethasone is a life-saving treatment for severe COVID-19, yet its mechanism of action is unknown, and many patients deteriorate or die despite timely treatment initiation. Here, we identify dexamethasone treatment-induced cellular and molecular changes associated with improved survival in COVID-19 patients. We observed a reversal of transcriptional hallmark signatures in monocytes associated with severe COVID-19 and the induction of a monocyte substate characterized by the expression of glucocorticoid-response genes. These molecular responses to dexamethasone were detected in circulating and pulmonary monocytes, and they were directly linked to survival. Monocyte single-cell RNA sequencing (scRNA-seq)-derived signatures were enriched in whole blood transcriptomes of patients with fatal outcome in two independent cohorts, highlighting the potential for identifying non-responders refractory to dexamethasone. Our findings link the effects of dexamethasone to specific immunomodulation and reversal of monocyte dysregulation, and they highlight the potential of single-cell omics for monitoring in vivo target engagement of immunomodulatory drugs and for patient stratification for precision medicine approaches.
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Dexametasona , Monocitos , SARS-CoV-2 , Análisis de la Célula Individual , Humanos , Dexametasona/farmacología , Dexametasona/uso terapéutico , Monocitos/metabolismo , Monocitos/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , Masculino , Femenino , Transcriptoma , Persona de Mediana Edad , Anciano , Glucocorticoides/uso terapéutico , Glucocorticoides/farmacología , Pulmón/patología , AdultoRESUMEN
COVID-19-induced "acute respiratory distress syndrome" (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyze pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single-cell genomics, immunohistology, and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.
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COVID-19/patología , COVID-19/virología , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/virología , Macrófagos/patología , Macrófagos/virología , SARS-CoV-2/fisiología , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , COVID-19/diagnóstico por imagen , Comunicación Celular , Estudios de Cohortes , Fibroblastos/patología , Regulación de la Expresión Génica , Humanos , Fibrosis Pulmonar Idiopática/diagnóstico por imagen , Fibrosis Pulmonar Idiopática/genética , Células Madre Mesenquimatosas/patología , Fenotipo , Proteoma/metabolismo , Receptores de Superficie Celular/metabolismo , Síndrome de Dificultad Respiratoria/diagnóstico por imagen , Síndrome de Dificultad Respiratoria/patología , Síndrome de Dificultad Respiratoria/virología , Tomografía Computarizada por Rayos X , Transcripción GenéticaRESUMEN
Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRhiCD11chi inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DRlo monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.
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Infecciones por Coronavirus/inmunología , Células Mieloides/inmunología , Mielopoyesis , Neumonía Viral/inmunología , Adulto , Anciano , Antígenos CD11/genética , Antígenos CD11/metabolismo , COVID-19 , Células Cultivadas , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/patología , Femenino , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Células Mieloides/citología , Pandemias , Neumonía Viral/sangre , Neumonía Viral/patología , Proteoma/genética , Proteoma/metabolismo , Proteómica , Análisis de la Célula IndividualRESUMEN
Diverse autoantibodies were suggested to contribute to severe outcomes of COVID-19, but their functional implications are largely unclear. ACE2, the SARS-CoV-2 receptor and a key regulator of blood pressure, was described to be one of many targets of autoantibodies in COVID-19. ACE2 in its soluble form (sACE2) is highly elevated in the blood of critically ill patients, raising the question of whether sACE2:spike complexes induce ACE2 reactivity. Screening 247 COVID-19 patients, we observed elevated sACE2 and anti-ACE2 IgG that were poorly correlated. Interestingly, levels of IgGs recognizing ACE2, IFNα2, and CD26 strongly correlated in severe COVID-19, with 15% of sera showing polyreactivity versus 4.1% exhibiting target-directed autoimmunity. Promiscuous autoantibodies failed to impair the activity of ACE2 and IFNα2, while only specific anti-IFNα2 IgG compromised cytokine function. Our study suggests that the detection of autoantibodies in COVID-19 is often attributed to a promiscuous reactivity, potentially misinterpreted as target-specific autoimmunity with functional impact.
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COVID-19 , Humanos , SARS-CoV-2 , Autoanticuerpos , Peptidil-Dipeptidasa A , Inmunoglobulina GRESUMEN
INTRODUCTION: Despite growing awareness of post-coronavirus disease 2019 (COVID-19) cholangiopathy as one of the most serious long-term gastrointestinal consequences of COVID-19, the endoscopic features of this disease are still poorly characterized. This study aimed to more precisely define its endoscopic features and to outline the role of endoscopic retrograde cholangiopancreatography (ERCP) in the management of this entity. METHODS: In this observational study, 46 patients with confirmed post-COVID-19 cholangiopathy were included. RESULTS: Based on the endoscopic features observed in 141 ERCP procedures, post-COVID-19 cholangiopathy can be classified as a variant of secondary sclerosing cholangitis in critically ill patients. It appeared early in the course of intensive care treatment of patients with COVID-19 (cholestasis onset 4.5 days after intubation, median). This form of cholangiopathy was more destructive than stricturing in nature and caused irreversible damage to the bile ducts. A centripetal pattern of intrahepatic bile duct destruction, the phenomenon of vanishing bile ducts, the absence of extrahepatic involvement, and the presence of intraductal biliary casts (85% of patients) were typical cholangiographic features of post-COVID-19 cholangiopathy. This cholangiopathy was often complicated by small peribiliary liver abscesses with isolation of Enterococcus faecium and Candida spp. in bile culture. The prognosis was dismal, with a 1-year liver transplantation-free survival rate of 44%. In particular, patients with peribiliary liver abscesses or destruction of the central bile ducts tended to have a poor prognosis (n.s.). As shown by multivariate analysis, bilirubin levels (on intensive care unit day 25-36) negatively correlated with liver transplantation-free survival (hazard ratio 1.08, P < 0.001). Interventional endoscopy with cast removal had a positive effect on cholestasis parameters (gamma-glutamyl transpeptidase, alkaline phosphatase, and bilirubin); approximately 60% of all individual values decreased. DISCUSSION: Gastrointestinal endoscopy makes an important contribution to the management of post-COVID-19 cholangiopathy. ERCP is not only of great diagnostic and prognostic value but also has therapeutic value and therefore remains indispensable.
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COVID-19 , Colestasis , Absceso Hepático , Hepatopatías , Humanos , Colangiopancreatografia Retrógrada Endoscópica , BilirrubinaRESUMEN
BACKGROUND: The severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) pandemic causes a high burden of acute and long-term morbidity and mortality worldwide despite global efforts in containment, prophylaxis, and therapy. With unprecedented speed, the global scientific community has generated pivotal insights into the pathogen and the host response evoked by the infection. However, deeper characterization of the pathophysiology and pathology remains a high priority to reduce morbidity and mortality of coronavirus disease 2019 (COVID-19). METHODS: NAPKON-HAP is a multi-centered prospective observational study with a long-term follow-up phase of up to 36 months post-SARS-CoV-2 infection. It constitutes a central platform for harmonized data and biospecimen for interdisciplinary characterization of acute SARS-CoV-2 infection and long-term outcomes of diverging disease severities of hospitalized patients. RESULTS: Primary outcome measures include clinical scores and quality of life assessment captured during hospitalization and at outpatient follow-up visits to assess acute and chronic morbidity. Secondary measures include results of biomolecular and immunological investigations and assessment of organ-specific involvement during and post-COVID-19 infection. NAPKON-HAP constitutes a national platform to provide accessibility and usability of the comprehensive data and biospecimen collection to global research. CONCLUSION: NAPKON-HAP establishes a platform with standardized high-resolution data and biospecimen collection of hospitalized COVID-19 patients of different disease severities in Germany. With this study, we will add significant scientific insights and provide high-quality data to aid researchers to investigate COVID-19 pathophysiology, pathology, and chronic morbidity.
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COVID-19 , Humanos , COVID-19/epidemiología , SARS-CoV-2 , Pandemias/prevención & control , Calidad de Vida , Alemania/epidemiología , Estudios Observacionales como AsuntoRESUMEN
PURPOSE: Six to 19% of critically ill COVID-19 patients display circulating auto-antibodies against type I interferons (IFN-AABs). Here, we establish a clinically applicable strategy for early identification of IFN-AAB-positive patients for potential subsequent clinical interventions. METHODS: We analyzed sera of 430 COVID-19 patients from four hospitals for presence of IFN-AABs by ELISA. Binding specificity and neutralizing activity were evaluated via competition assay and virus-infection-based neutralization assay. We defined clinical parameters associated with IFN-AAB positivity. In a subgroup of critically ill patients, we analyzed effects of therapeutic plasma exchange (TPE) on the levels of IFN-AABs, SARS-CoV-2 antibodies and clinical outcome. RESULTS: The prevalence of neutralizing AABs to IFN-α and IFN-ω in COVID-19 patients from all cohorts was 4.2% (18/430), while being undetectable in an uninfected control cohort. Neutralizing IFN-AABs were detectable exclusively in critically affected (max. WHO score 6-8), predominantly male (83%) patients (7.6%, 18/237 for IFN-α-AABs and 4.6%, 11/237 for IFN-ω-AABs in 237 patients with critical COVID-19). IFN-AABs were present early post-symptom onset and at the peak of disease. Fever and oxygen requirement at hospital admission co-presented with neutralizing IFN-AAB positivity. IFN-AABs were associated with lower probability of survival (7.7% versus 80.9% in patients without IFN-AABs). TPE reduced levels of IFN-AABs in three of five patients and may increase survival of IFN-AAB-positive patients compared to those not undergoing TPE. CONCLUSION: IFN-AABs may serve as early biomarker for the development of severe COVID-19. We propose to implement routine screening of hospitalized COVID-19 patients for rapid identification of patients with IFN-AABs who most likely benefit from specific therapies.
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COVID-19 , Interferón Tipo I , Anticuerpos Neutralizantes , Autoanticuerpos , COVID-19/diagnóstico , Enfermedad Crítica , Femenino , Humanos , Interferón-alfa/uso terapéutico , Masculino , Oxígeno , SARS-CoV-2RESUMEN
PURPOSE: To investigate antimicrobial use and primary and nosocomial infections in hospitalized COVID-19 patients to provide data for guidance of antimicrobial therapy. METHODS: Prospective observational cohort study conducted at Charité-Universitätsmedizin Berlin, including patients hospitalized with SARS-CoV-2-infection between March and November 2020. RESULTS: 309 patients were included, 231 directly admitted and 78 transferred from other centres. Antimicrobial therapy was initiated in 62/231 (26.8%) of directly admitted and in 44/78 (56.4%) of transferred patients. The rate of microbiologically confirmed primary co-infections was 4.8% (11/231). Although elevated in most COVID-19 patients, C-reactive protein and procalcitonin levels were higher in patients with primary co-infections than in those without (median CRP 110 mg/l, IQR 51-222 vs. 36, IQR 11-101, respectively; p < 0.0001). Nosocomial bloodstream and respiratory infections occurred in 47/309 (15.2%) and 91/309 (29.4%) of patients, respectively, and were associated with need for invasive mechanical ventilation (OR 45.6 95%CI 13.7-151.8 and 104.6 95%CI 41.5-263.5, respectively), extracorporeal membrane oxygenation (OR 14.3 95%CI 6.5-31.5 and 16.5 95%CI 6.5-41.6, respectively), and haemodialysis (OR 31.4 95%CI 13.9-71.2 and OR 22.3 95%CI 11.2-44.2, respectively). The event of any nosocomial infection was significantly associated with in-hospital death (33/99 (33.3%) with nosocomial infection vs. 23/210 (10.9%) without, OR 4.1 95%CI 2.2-7.3). CONCLUSIONS: Primary co-infections are rare, yet antimicrobial use was frequent, mostly based on clinical worsening and elevated inflammation markers without clear evidence for co-infection. More reliable diagnostic prospects may help to reduce overtreatment. Rates of nosocomial infections are substantial in severely ill patients on organ support and associated with worse patient outcome.
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Antiinfecciosos , Tratamiento Farmacológico de COVID-19 , COVID-19 , Coinfección , Infección Hospitalaria , Humanos , COVID-19/epidemiología , Coinfección/tratamiento farmacológico , Coinfección/epidemiología , SARS-CoV-2 , Mortalidad Hospitalaria , Estudios Prospectivos , Antiinfecciosos/uso terapéutico , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/epidemiologíaRESUMEN
One week after second vaccinations were administered, an outbreak of B.1.1.7 lineage severe acute respiratory syndrome coronavirus 2 infections occurred in a long-term care facility in Berlin, Germany, affecting 16/20 vaccinated and 4/4 unvaccinated residents. Despite considerable viral loads, vaccinated residents experienced mild symptoms and faster time to negative test results.
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COVID-19 , SARS-CoV-2 , Berlin , Brotes de Enfermedades , Alemania/epidemiología , Humanos , Cuidados a Largo Plazo , VacunaciónRESUMEN
We detected delayed and reduced antibody and T-cell responses after BNT162b2 vaccination in 71 elderly persons (median age 81 years) compared with 123 healthcare workers (median age 34 years) in Germany. These data emphasize that nonpharmaceutical interventions for coronavirus disease remain crucial and that additional immunizations for the elderly might become necessary.
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COVID-19 , Adulto , Anciano , Anciano de 80 o más Años , Vacuna BNT162 , Vacunas contra la COVID-19 , Alemania/epidemiología , Humanos , SARS-CoV-2 , Linfocitos T , VacunaciónRESUMEN
PURPOSE: Adequate patient allocation is pivotal for optimal resource management in strained healthcare systems, and requires detailed knowledge of clinical and virological disease trajectories. The purpose of this work was to identify risk factors associated with need for invasive mechanical ventilation (IMV), to analyse viral kinetics in patients with and without IMV and to provide a comprehensive description of clinical course. METHODS: A cohort of 168 hospitalised adult COVID-19 patients enrolled in a prospective observational study at a large European tertiary care centre was analysed. RESULTS: Forty-four per cent (71/161) of patients required invasive mechanical ventilation (IMV). Shorter duration of symptoms before admission (aOR 1.22 per day less, 95% CI 1.10-1.37, p < 0.01) and history of hypertension (aOR 5.55, 95% CI 2.00-16.82, p < 0.01) were associated with need for IMV. Patients on IMV had higher maximal concentrations, slower decline rates, and longer shedding of SARS-CoV-2 than non-IMV patients (33 days, IQR 26-46.75, vs 18 days, IQR 16-46.75, respectively, p < 0.01). Median duration of hospitalisation was 9 days (IQR 6-15.5) for non-IMV and 49.5 days (IQR 36.8-82.5) for IMV patients. CONCLUSIONS: Our results indicate a short duration of symptoms before admission as a risk factor for severe disease that merits further investigation and different viral load kinetics in severely affected patients. Median duration of hospitalisation of IMV patients was longer than described for acute respiratory distress syndrome unrelated to COVID-19.
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COVID-19/epidemiología , COVID-19/virología , SARS-CoV-2/fisiología , COVID-19/terapia , Estudios de Cohortes , Alemania/epidemiología , Hospitalización , Humanos , Hipertensión/complicaciones , Cinética , Estudios Prospectivos , Respiración Artificial , Factores de Riesgo , Centros de Atención Terciaria , Factores de Tiempo , Carga Viral , Esparcimiento de VirusRESUMEN
PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing a global health emergency. Pa-COVID-19 aims to provide comprehensive data on clinical course, pathophysiology, immunology and outcome of COVID-19, to identify prognostic biomarkers, clinical scores, and therapeutic targets for improved clinical management and preventive interventions. METHODS: Pa-COVID-19 is a prospective observational cohort study of patients with confirmed SARS-CoV-2 infection treated at Charité - Universitätsmedizin Berlin. We collect data on epidemiology, demography, medical history, symptoms, clinical course, and pathogen testing and treatment. Systematic, serial blood sampling will allow deep molecular and immunological phenotyping, transcriptomic profiling, and comprehensive biobanking. Longitudinal data and sample collection during hospitalization will be supplemented by long-term follow-up. RESULTS: Outcome measures include the WHO clinical ordinal scale on day 15 and clinical, functional, and health-related quality-of-life assessments at discharge and during follow-up. We developed a scalable dataset to (i) suit national standards of care, (ii) facilitate comprehensive data collection in medical care facilities with varying resources, and (iii) allow for rapid implementation of interventional trials based on the standardized study design and data collection. We propose this scalable protocol as blueprint for harmonized data collection and deep phenotyping in COVID-19 in Germany. CONCLUSION: We established a basic platform for harmonized, scalable data collection, pathophysiological analysis, and deep phenotyping of COVID-19, which enables rapid generation of evidence for improved medical care and identification of candidate therapeutic and preventive strategies. The electronic database accredited for interventional trials allows fast trial implementation for candidate therapeutic agents. TRIAL REGISTRATION: Registered at the German registry for clinical studies (DRKS00021688).
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Infecciones por Coronavirus/fisiopatología , Neumonía Viral/fisiopatología , Sistema de Registros , Berlin/epidemiología , Betacoronavirus , Bancos de Muestras Biológicas , COVID-19 , Infecciones por Coronavirus/epidemiología , Manejo de la Enfermedad , Humanos , Estudios Observacionales como Asunto , Pandemias , Fenotipo , Neumonía Viral/epidemiología , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , SARS-CoV-2 , Factores de Tiempo , Resultado del Tratamiento , Organización Mundial de la SaludRESUMEN
Identifying immune modulators that impact neutralizing antibody responses against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is of great relevance. We postulated that high serum concentrations of soluble angiotensin-converting enzyme 2 (sACE2) might mask the spike and interfere with antibody maturation toward the SARS-CoV-2-receptor-binding motif (RBM). We tested 717 longitudinal samples from 295 COVID-19 patients and showed a 2- to 10-fold increase of enzymatically active sACE2 (a-sACE2), with up to 1 µg/mL total sACE2 in moderate and severe patients. Fifty percent of COVID-19 sera inhibited ACE2 activity, in contrast to 1.3% of healthy donors and 4% of non-COVID-19 pneumonia patients. A mild inverse correlation of a-sACE2 with RBM-directed serum antibodies was observed. In silico, we show that sACE2 concentrations measured in COVID-19 sera can disrupt germinal center formation and inhibit timely production of high-affinity antibodies. We suggest that sACE2 is a biomarker for COVID-19 and that soluble receptors may contribute to immune suppression informing vaccine design.
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The clinical course of COVID-19 is variable and often unpredictable. To test the hypothesis that disease progression and inflammatory responses associate with alterations in the microbiome and metabolome, we analyzed metagenome, metabolome, cytokine, and transcriptome profiles of repeated samples from hospitalized COVID-19 patients and uninfected controls, and leveraged clinical information and post-hoc confounder analysis. Severe COVID-19 was associated with a depletion of beneficial intestinal microbes, whereas oropharyngeal microbiota disturbance was mainly linked to antibiotic use. COVID-19 severity was also associated with enhanced plasma concentrations of kynurenine and reduced levels of several other tryptophan metabolites, lysophosphatidylcholines, and secondary bile acids. Moreover, reduced concentrations of various tryptophan metabolites were associated with depletion of Faecalibacterium, and tryptophan decrease and kynurenine increase were linked to enhanced production of inflammatory cytokines. Collectively, our study identifies correlated microbiome and metabolome alterations as a potential contributor to inflammatory dysregulation in severe COVID-19.
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COVID-19 , Citocinas , Disbiosis , Microbioma Gastrointestinal , SARS-CoV-2 , Triptófano , Humanos , COVID-19/microbiología , COVID-19/inmunología , Triptófano/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Citocinas/sangre , Citocinas/metabolismo , Metaboloma , Inflamación , Quinurenina/metabolismo , Quinurenina/sangre , Anciano , AdultoRESUMEN
OBJECTIVES: C-C-chemokine receptors (CCRs) are expressed on a variety of immune cells and play an important role in many immune processes, particularly leukocyte migration. Comprehensive preclinical research demonstrated CCR2/CCR5-dependent pathways as pivotal for the pathophysiology of severe COVID-19. Here we report human data on use of a chemokine receptor inhibitor in patients with COVID-19. METHODS: Interim results of a 2:1 randomised, placebo-controlled, investigator-initiated trial on the CCR2/CCR5-inhibitor Cenicriviroc (CVC) 150 mg BID orally for 28 d in hospitalised patients with moderate to severe COVID-19 are reported. The primary endpoint is the subject's responder status defined by achieving grade 1 or 2 on the 7-point ordinal scale of clinical improvement on day 15. RESULTS: Of the 30 patients randomised, 18 were assigned to receive CVC and 12 to placebo. Efficient CCR2- and CCR5 inhibition was demonstrated through CCL2 and CCL4 elevation in CVC-treated patients (485% and 80% increase on day 3 compared to the baseline, respectively). In the modified intention-to-treat population, 82.4% of patients (14/17) in the CVC group met the primary endpoint, as did 91.7% (11/12) in the placebo group (OR = 0.5, 95% CI = 0.04-3.41). One patient treated with CVC died of progressive acute respiratory distress syndrome, and the remaining had a favourable outcome. Overall, treatment with CVC was well tolerated, with most adverse events being grade I or II and resolving spontaneously. CONCLUSIONS: Our interim analysis provides proof-of-concept data on CVC for COVID-19 patients as an intervention to inhibit CCR2/CCR5. Further studies are warranted to assess its clinical efficacy.
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COVID-19 , Humanos , SARS-CoV-2 , Imidazoles , SulfóxidosRESUMEN
BACKGROUNDAfter its introduction as standard-of-care for severe COVID-19, dexamethasone has been administered to a large number of patients globally. Detailed knowledge of its impact on the cellular and humoral immune response to SARS-CoV-2 remains scarce.METHODSWe included immunocompetent individuals with (a) mild COVID-19, (b) severe COVID-19 before introduction of dexamethasone treatment, and (c) severe COVID-19 infection treated with dexamethasone from prospective observational cohort studies at Charité-Universitätsmedizin Berlin, Germany. We analyzed SARS-CoV-2 spike-reactive T cells, spike-specific IgG titers, and serum neutralizing activity against B.1.1.7 and B.1.617.2 in samples ranging from 2 weeks to 6 months after infection. We also analyzed BA.2 neutralization in sera after booster immunization.RESULTSPatients with severe COVID-19 and dexamethasone treatment had lower T cell and antibody responses to SARS-CoV-2 compared with patients without dexamethasone treatment in the early phase of disease, which converged in both groups before 6 months after infection and also after immunization. Patients with mild COVID-19 had comparatively lower T cell and antibody responses than patients with severe disease, including a lower response to booster immunization during convalescence.CONCLUSIONDexamethasone treatment was associated with a short-term reduction in T cell and antibody responses in severe COVID-19 when compared with the nontreated group, but this difference evened out 6 months after infection. We confirm higher cellular and humoral immune responses in patients after severe versus mild COVID-19 and the concept of improved hybrid immunity upon immunization.FUNDINGBerlin Institute of Health, German Federal Ministry of Education, and German Federal Institute for Drugs and Medical Devices.
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Formación de Anticuerpos , COVID-19 , Humanos , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19 , Linfocitos T , Inmunización Secundaria , Dexametasona/uso terapéuticoRESUMEN
BACKGROUND: Increasing evidence suggests that secondary sclerosing cholangitis (SSC), which can lead to cirrhosis or liver failure, may be a hepatobiliary long-term complication of COVID-19. The aim of this study was to estimate the frequency and outcome of this COVID-19 sequela and to identify possible risk factors. METHODS: This observational study, conducted at University Hospital Charité Berlin and Unfallkrankenhaus Berlin, Germany, involved hospitalized patients with COVID-19 pneumonia, including 1082 ventilated COVID-19 patients. We compared COVID-19 patients who developed SSC with a COVID-19 control group by univariate and multivariate analyses. RESULTS: SSC occurrence after COVID-19 was observed exclusively in critically ill patients with invasive ventilation, albeit with extreme clustering among them. One in every 43 invasively ventilated COVID-19 patients developed this complication. Risk factors preceding the development of secondary sclerosing cholangitis in critically ill COVID-19 patients (SSC-CIP) were signs of systemic reduced blood oxygen supply (e.g., low PaO2/FiO2, ischemic organ infarctions), multi-organ failure (high SOFA score) at admission, high fibrinogen levels and intravenous ketamine use. Multivariate analysis confirmed fibrinogen and increased plasma lactate dehydrogenase as independent risk factors associated with cholangiopathy onset. The 1-year transplant-free survival rate of COVID-19-associated SSC-CIP was 40%. CONCLUSIONS: COVID-19 causes SSC-CIP in a substantial proportion of critically ill patients. SSC-CIP most likely develops due to severe tissue hypoxia and fibrinogen-associated circulatory disturbances. A significant increase of patients with SSC-CIP is to be expected in the post-COVID era.
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COVID-19 , Colangitis Esclerosante , Humanos , Colangitis Esclerosante/complicaciones , Colangitis Esclerosante/terapia , Enfermedad Crítica , COVID-19/complicaciones , Cirrosis Hepática/complicaciones , FibrinógenoRESUMEN
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 < 0.0001, 0.001 and 0.004 respectively). Also, pulmonary restriction and reduced carbon monoxide diffusion capacity was associated with disease severity. In patients with restriction and impaired diffusion capacity, FVC improved over 12 months from 61.32 to 71.82, TLC from 68.92 to 76.95, DLCO from 60.18 to 68.98 and KCO from 81.28 to 87.80 (percent predicted values; p = 0.002, 0.045, 0.0002 and 0.0005). The CT-score of lung involvement in the acute phase 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 initially mild disease. CONCLUSION: Severity 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.
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COVID-19/complicaciones , COVID-19/fisiopatología , Pulmón/fisiopatología , Calidad de Vida , Insuficiencia Respiratoria/fisiopatología , Adulto , Anciano , COVID-19/diagnóstico por imagen , COVID-19/terapia , Oxigenación por Membrana Extracorpórea , Femenino , Volumen Espiratorio Forzado/fisiología , Hospitalización , Humanos , Estudios Longitudinales , Pulmón/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Terapia por Inhalación de Oxígeno , Capacidad de Difusión Pulmonar/fisiología , Recuperación de la Función , Respiración Artificial , Pruebas de Función Respiratoria , Insuficiencia Respiratoria/diagnóstico por imagen , Insuficiencia Respiratoria/terapia , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Tomografía Computarizada por Rayos X , Capacidad Pulmonar Total/fisiología , Capacidad Vital/fisiología , Síndrome Post Agudo de COVID-19RESUMEN
Anonymization has the potential to foster the sharing of medical data. State-of-the-art methods use mathematical models to modify data to reduce privacy risks. However, the degree of protection must be balanced against the impact on statistical properties. We studied an extreme case of this trade-off: the statistical validity of an open medical dataset based on the German National Pandemic Cohort Network (NAPKON), which was prepared for publication using a strong anonymization procedure. Descriptive statistics and results of regression analyses were compared before and after anonymization of multiple variants of the original dataset. Despite significant differences in value distributions, the statistical bias was found to be small in all cases. In the regression analyses, the median absolute deviations of the estimated adjusted odds ratios for different sample sizes ranged from 0.01 [minimum = 0, maximum = 0.58] to 0.52 [minimum = 0.25, maximum = 0.91]. Disproportionate impact on the statistical properties of data is a common argument against the use of anonymization. Our analysis demonstrates that anonymization can actually preserve validity of statistical results in relatively low-dimensional data.
Asunto(s)
COVID-19 , Humanos , Sesgo , Anonimización de la Información , Modelos Teóricos , Privacidad , Interpretación Estadística de Datos , Conjuntos de Datos como AsuntoRESUMEN
BACKGROUND: 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. METHODS: 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. RESULTS: At 12 months after SARS-CoV-2 infection, 46.3% of participants had a peak performance and 33.3% a peak oxygen uptake of <80% 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 reduced <80% 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 outcome >25 points (OR 3.48, p = 0.03) and reduced DLCO (OR 3.01, p = 0.054). CONCLUSIONS: Functional 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.