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1.
Nat Commun ; 13(1): 153, 2022 01 10.
Article in English | MEDLINE | ID: covidwho-1616980

ABSTRACT

Anti-viral immunity continuously declines over time after SARS-CoV-2 infection. Here, we characterize the dynamics of anti-viral immunity during long-term follow-up and after BNT162b2 mRNA-vaccination in convalescents after asymptomatic or mild SARS-CoV-2 infection. Virus-specific and virus-neutralizing antibody titers rapidly declined in convalescents over 9 months after infection, whereas virus-specific cytokine-producing polyfunctional T cells persisted, among which IL-2-producing T cells correlated with virus-neutralizing antibody titers. Among convalescents, 5% of individuals failed to mount long-lasting immunity after infection and showed a delayed response to vaccination compared to 1% of naïve vaccinees, but successfully responded to prime/boost vaccination. During the follow-up period, 8% of convalescents showed a selective increase in virus-neutralizing antibody titers without accompanying increased frequencies of circulating SARS-CoV-2-specific T cells. The same convalescents, however, responded to vaccination with simultaneous increase in antibody and T cell immunity revealing the strength of mRNA-vaccination to increase virus-specific immunity in convalescents.

2.
Cell Rep ; 37(13): 110169, 2021 12 28.
Article in English | MEDLINE | ID: covidwho-1616407

ABSTRACT

The importance of pre-existing immune responses to seasonal endemic coronaviruses (HCoVs) for the susceptibility to SARS-CoV-2 infection and the course of COVID-19 is the subject of an ongoing scientific debate. Recent studies postulate that immune responses to previous HCoV infections can either have a slightly protective or no effect on SARS-CoV-2 pathogenesis and, consequently, be neglected for COVID-19 risk stratification. Challenging this notion, we provide evidence that pre-existing, anti-nucleocapsid antibodies against endemic α-coronaviruses and S2 domain-specific anti-spike antibodies against ß-coronavirus HCoV-OC43 are elevated in patients with COVID-19 compared to pre-pandemic donors. This finding is particularly pronounced in males and in critically ill patients. Longitudinal evaluation reveals that antibody cross-reactivity or polyclonal stimulation by SARS-CoV-2 infection are unlikely to be confounders. Thus, specific pre-existing immunity to seasonal coronaviruses may increase susceptibility to SARS-CoV-2 and predispose individuals to an adverse COVID-19 outcome, guiding risk management and supporting the development of universal coronavirus vaccines.


Subject(s)
COVID-19/immunology , Coronavirus/immunology , SARS-CoV-2/immunology , Adult , Antibodies/immunology , Antibodies, Viral/immunology , COVID-19/etiology , Coronavirus Infections/immunology , Coronavirus OC43, Human/immunology , Coronavirus OC43, Human/pathogenicity , Cross Reactions/immunology , Female , Germany , Humans , Immunity, Humoral/immunology , Immunoglobulin G/immunology , Longitudinal Studies , Male , Middle Aged , Pandemics , SARS-CoV-2/pathogenicity , Seasons , Severity of Illness Index , Spike Glycoprotein, Coronavirus/immunology
3.
Graefes Arch Clin Exp Ophthalmol ; 2021 Dec 28.
Article in English | MEDLINE | ID: covidwho-1588798

ABSTRACT

PURPOSE: To detect SARS-CoV-2 RNA in post-mortem human eyes. Ocular symptoms are common in patients with COVID-19. In some cases, they can occur before the onset of respiratory and other symptoms. Accordingly, SARS-CoV-2 RNA has been detected in conjunctival samples and tear film of patients suffering from COVID-19. However, the detection and clinical relevance of intravitreal SARS-CoV-2 RNA still remain unclear due to so far contradictory reports in the literature. METHODS: In our study 20 patients with confirmed diagnosis of COVID-19 were evaluated post-mortem to assess the conjunctival and intraocular presence of SARS-CoV-2 RNA using sterile pulmonary and conjunctival swabs as well as intravitreal biopsies (IVB) via needle puncture. SARS-CoV-2 PCR and whole genome sequencing from the samples of the deceased patients were performed. Medical history and comorbidities of all subjects were recorded and analyzed for correlations with viral data. RESULTS: SARS-CoV-2 RNA was detected in 10 conjunctival (50%) and 6 vitreal (30%) samples. SARS-CoV-2 whole genome sequencing showed the distribution of cases largely reflecting the frequency of circulating lineages in the Munich area at the time of examination with no preponderance of specific variants. Especially there was no association between the presence of SARS-CoV-2 RNA in IVBs and infection with the variant of concern (VOC) alpha. Viral load in bronchial samples correlated positively with load in conjunctiva but not the vitreous. CONCLUSION: SARS-CoV-2 RNA can be detected post mortem in conjunctival tissues and IVBs. This is relevant to the planning of ophthalmologic surgical procedures in COVID-19 patients, such as pars plana vitrectomy or corneal transplantation. Furthermore, not only during surgery but also in an outpatient setting it is important to emphasize the need for personal protection in order to avoid infection and spreading of SARS-CoV-2. Prospective studies are needed, especially to determine the clinical relevance of conjunctival and intravitreal SARS-CoV-2 detection concerning intraocular affection in active COVID-19 state and in post-COVID syndrome.

4.
iScience ; 25(1): 103659, 2022 Jan 21.
Article in English | MEDLINE | ID: covidwho-1587464

ABSTRACT

Although some COVID-19 patients maintain SARS-CoV-2-specific serum immunoglobulin G (IgG) for more than 6 months postinfection, others eventually lose IgG levels. We assessed the persistence of SARS-CoV-2-specific B cells in 17 patients, 5 of whom had lost specific IgGs after 5-8 months. Differentiation of blood-derived B cells in vitro revealed persistent SARS-CoV-2-specific IgG B cells in all patients, whereas IgA B cells were maintained in 11. Antibodies derived from cultured B cells blocked binding of viral receptor-binding domain (RBD) to the cellular receptor ACE-2, had neutralizing activity to authentic virus, and recognized the RBD of the variant of concern Alpha similarly to the wild type, whereas reactivity to Beta and Gamma were decreased. Thus, differentiation of memory B cells could be more sensitive for detecting previous infection than measuring serum antibodies. Understanding the persistence of SARS-CoV-2-specific B cells even in the absence of specific serum IgG will help to promote long-term immunity.

5.
Cell reports ; 2021.
Article in English | EuropePMC | ID: covidwho-1565013

ABSTRACT

Wratil et al. find specific antibody responses against seasonal human coronaviruses, which cause the common cold, to be elevated in patients with COVID-19 compared to pre-pandemic blood donors. This specific immunity is likely pre-existing in patients and increases their susceptibility to SARS-CoV-2 and severity of COVID-19.

6.
Euro Surveill ; 26(43)2021 10.
Article in English | MEDLINE | ID: covidwho-1547185

ABSTRACT

BackgroundIn the SARS-CoV-2 pandemic, viral genomes are available at unprecedented speed, but spatio-temporal bias in genome sequence sampling precludes phylogeographical inference without additional contextual data.AimWe applied genomic epidemiology to trace SARS-CoV-2 spread on an international, national and local level, to illustrate how transmission chains can be resolved to the level of a single event and single person using integrated sequence data and spatio-temporal metadata.MethodsWe investigated 289 COVID-19 cases at a university hospital in Munich, Germany, between 29 February and 27 May 2020. Using the ARTIC protocol, we obtained near full-length viral genomes from 174 SARS-CoV-2-positive respiratory samples. Phylogenetic analyses using the Auspice software were employed in combination with anamnestic reporting of travel history, interpersonal interactions and perceived high-risk exposures among patients and healthcare workers to characterise cluster outbreaks and establish likely scenarios and timelines of transmission.ResultsWe identified multiple independent introductions in the Munich Metropolitan Region during the first weeks of the first pandemic wave, mainly by travellers returning from popular skiing areas in the Alps. In these early weeks, the rate of presumable hospital-acquired infections among patients and in particular healthcare workers was high (9.6% and 54%, respectively) and we illustrated how transmission chains can be dissected at high resolution combining virus sequences and spatio-temporal networks of human interactions.ConclusionsEarly spread of SARS-CoV-2 in Europe was catalysed by superspreading events and regional hotspots during the winter holiday season. Genomic epidemiology can be employed to trace viral spread and inform effective containment strategies.


Subject(s)
COVID-19 , Cross Infection , Cross Infection/epidemiology , Genome, Viral , Genomics , Germany/epidemiology , Hospitals , Humans , Phylogeny , SARS-CoV-2
7.
Antiviral Res ; 196: 105197, 2021 12.
Article in English | MEDLINE | ID: covidwho-1509565

ABSTRACT

SARS-CoV-2 enters host cells after binding through its spike glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor. Soluble ACE2 ectodomains bind and neutralize the virus, yet their short in vivo half-live limits their therapeutic use. This limitation can be overcome by fusing the fragment crystallizable (Fc) part of human immunoglobulin G (IgG) to the ACE2 ectodomain, but this bears the risk of Fc-receptor activation and antibody-dependent cellular cytotoxicity. Here, we describe optimized ACE2-IgG4-Fc fusion constructs that avoid Fc-receptor activation, preserve the desired ACE2 enzymatic activity and show promising pharmaceutical properties. The engineered ACE2-IgG4-Fc fusion proteins neutralize the original SARS-CoV, pandemic SARS-CoV-2 as well as the rapidly spreading SARS-CoV-2 alpha, beta and delta variants of concern. Importantly, these variants of concern are inhibited at picomolar concentrations proving that ACE2-IgG4 maintains - in contrast to therapeutic antibodies - its full antiviral potential. Thus, ACE2-IgG4-Fc fusion proteins are promising candidate anti-antivirals to combat the current and future pandemics.

8.
Clin Infect Dis ; 73(9): e3055-e3065, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1501051

ABSTRACT

BACKGROUND: High infection rates among healthcare personnel in an uncontained pandemic can paralyze health systems due to staff shortages. Risk constellations and rates of seroconversion for healthcare workers (HCWs) during the first wave of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic are still largely unclear. METHODS: Healthcare personnel (n = 300) on different organizational units in the LMU Munich University Hospital were included and followed in this prospective longitudinal study from 24 March until 7 July 2020. Participants were monitored in intervals of 2 to 6 weeks using different antibody assays for serological testing and questionnaires to evaluate risk contacts. In a subgroup of infected participants, we obtained nasopharyngeal swabs to perform whole-genome sequencing for outbreak characterization. RESULTS: HCWs involved in patient care on dedicated coronavirus disease 2019 (COVID-19) wards or on regular non-COVID-19 wards showed a higher rate of SARS-CoV-2 seroconversion than staff in the emergency department and non-frontline personnel. The landscape of risk contacts in these units was dynamic, with a decrease in unprotected risk contacts in the emergency department and an increase on non-COVID-19 wards. Both intensity and number of risk contacts were associated with higher rates of seroconversion. On regular wards, staff infections tended to occur in clusters, while infections on COVID-19 wards were less frequent and apparently independent of each other. CONCLUSIONS: Risk of SARS-CoV-2 infection for frontline HCWs was increased during the first pandemic wave in southern Germany. Stringent measures for infection control are essential to protect all patient-facing staff during the ongoing pandemic.


Subject(s)
COVID-19 , SARS-CoV-2 , Germany/epidemiology , Health Personnel , Hospitals, University , Humans , Longitudinal Studies , Pandemics , Prospective Studies
9.
Infection ; 2021 Oct 30.
Article in English | MEDLINE | ID: covidwho-1491465

ABSTRACT

PURPOSE: To investigate the expression of the receptor protein ACE-2 alongside the urinary tract, urinary shedding and urinary stability of SARS-CoV-2 RNA. METHODS: Immunohistochemical staining was performed on tissue from urological surgery of 10 patients. Further, patients treated for coronavirus disease (COVID-19) at specialized care-units of a university hospital were assessed for detection of SARS-CoV-2 RNA in urinary samples via PCR, disease severity (WHO score), inflammatory response of patients. Finally, the stability of SARS-CoV-2 RNA in urine was analyzed. RESULTS: High ACE-2 expression (3/3) was observed in the tubules of the kidney and prostate glands, moderate expression in urothelial cells of the bladder (0-2/3) and no expression in kidney glomeruli, muscularis of the bladder and stroma of the prostate (0/3). SARS-CoV-2 RNA was detected in 5/199 urine samples from 64 patients. Viral RNA was detected in the first urinary sample of sequential samples. Viral RNA load from other specimen as nasopharyngeal swabs (NPS) or endotracheal aspirates revealed higher levels than from urine. Detection of SARS-CoV-2 RNA in urine was not associated with impaired WHO score (median 5, range 3-8 vs median 4, range 1-8, p = 0.314), peak white blood cell count (median 24.1 × 1000/ml, range 5.19-48.1 versus median 11.9 × 1000/ml, range 2.9-60.3, p = 0.307), peak CRP (median 20.7 mg/dl, 4.2-40.2 versus median 11.9 mg/dl, range 0.1-51.9, p = 0.316) or peak IL-6 levels (median: 1442 ng/ml, range 26.7-3918 versus median 140 ng/ml, range 3.0-11,041, p = 0.099). SARS-CoV-2 RNA was stable under different storage conditions and after freeze-thaw cycles. CONCLUSIONS: SARS-CoV-2 RNA in the urine of COVID-19 patients occurs infrequently. The viral RNA load and dynamics of SARS-CoV-2 RNA shedding suggest no relevant route of transmission through the urinary tract.

10.
PLoS Pathog ; 17(10): e1009742, 2021 10.
Article in English | MEDLINE | ID: covidwho-1456098

ABSTRACT

Disease manifestations in COVID-19 range from mild to severe illness associated with a dysregulated innate immune response. Alterations in function and regeneration of dendritic cells (DCs) and monocytes may contribute to immunopathology and influence adaptive immune responses in COVID-19 patients. We analyzed circulating DC and monocyte subsets in 65 hospitalized COVID-19 patients with mild/moderate or severe disease from acute illness to recovery and in healthy controls. Persisting reduction of all DC subpopulations was accompanied by an expansion of proliferating Lineage-HLADR+ cells lacking DC markers. Increased frequency of CD163+ CD14+ cells within the recently discovered DC3 subpopulation in patients with more severe disease was associated with systemic inflammation, activated T follicular helper cells, and antibody-secreting cells. Persistent downregulation of CD86 and upregulation of programmed death-ligand 1 (PD-L1) in conventional DCs (cDC2 and DC3) and classical monocytes associated with a reduced capacity to stimulate naïve CD4+ T cells correlated with disease severity. Long-lasting depletion and functional impairment of DCs and monocytes may have consequences for susceptibility to secondary infections and therapy of COVID-19 patients.


Subject(s)
COVID-19/immunology , Dendritic Cells/immunology , Regeneration/immunology , SARS-CoV-2/immunology , Adult , Antigens, CD/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , COVID-19/pathology , Dendritic Cells/pathology , Female , Humans , Male , Middle Aged , Monocytes/immunology , Monocytes/pathology , Programmed Cell Death 1 Receptor/immunology
11.
Med Microbiol Immunol ; 210(5-6): 263-275, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1366361

ABSTRACT

A versatile portfolio of diagnostic tests is essential for the containment of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic. Besides nucleic acid-based test systems and point-of-care (POCT) antigen (Ag) tests, quantitative, laboratory-based nucleocapsid Ag tests for SARS-CoV-2 have recently been launched. Here, we evaluated four commercial Ag tests on automated platforms and one POCT to detect SARS-CoV-2. We evaluated PCR-positive (n = 107) and PCR-negative (n = 303) respiratory swabs from asymptomatic and symptomatic patients at the end of the second pandemic wave in Germany (February-March 2021) as well as clinical isolates EU1 (B.1.117), variant of concern (VOC) Alpha (B.1.1.7) or Beta (B.1.351), which had been expanded in a biosafety level 3 laboratory. The specificities of automated SARS-CoV-2 Ag tests ranged between 97.0 and 99.7% (Lumipulse G SARS-CoV-2 Ag (Fujirebio): 97.03%, Elecsys SARS-CoV-2 Ag (Roche Diagnostics): 97.69%; LIAISON® SARS-CoV-2 Ag (Diasorin) and SARS-CoV-2 Ag ELISA (Euroimmun): 99.67%). In this study cohort of hospitalized patients, the clinical sensitivities of tests were low, ranging from 17.76 to 52.34%, and analytical sensitivities ranged from 420,000 to 25,000,000 Geq/ml. In comparison, the detection limit of the Roche Rapid Ag Test (RAT) was 9,300,000 Geq/ml, detecting 23.58% of respiratory samples. Receiver-operating-characteristics (ROCs) and Youden's index analyses were performed to further characterize the assays' overall performance and determine optimal assay cutoffs for sensitivity and specificity. VOCs carrying up to four amino acid mutations in nucleocapsid were detected by all five assays with characteristics comparable to non-VOCs. In summary, automated, quantitative SARS-CoV-2 Ag tests show variable performance and are not necessarily superior to a standard POCT. The efficacy of any alternative testing strategies to complement nucleic acid-based assays must be carefully evaluated by independent laboratories prior to widespread implementation.


Subject(s)
Antigens, Viral/analysis , COVID-19 Serological Testing/methods , COVID-19/virology , SARS-CoV-2/isolation & purification , Antigens, Viral/immunology , Automation/economics , Automation/methods , COVID-19/diagnosis , COVID-19 Serological Testing/economics , Cohort Studies , False Negative Reactions , Germany , Humans , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Sensitivity and Specificity
12.
Infection ; 2021 Aug 11.
Article in English | MEDLINE | ID: covidwho-1351389

ABSTRACT

PURPOSE: To determine risk factors for coronavirus disease 2019 (COVID-19) in healthcare workers (HCWs), characterize symptoms, and evaluate preventive measures against SARS-CoV-2 spread in hospitals. METHODS: In a cross-sectional study conducted between May 27 and August 12, 2020, after the first wave of the COVID-19 pandemic, we obtained serological, epidemiological, occupational as well as COVID-19-related data at a quaternary care, multicenter hospital in Munich, Germany. RESULTS: 7554 HCWs participated, 2.2% of whom tested positive for anti-SARS-CoV-2 antibodies. Multivariate analysis revealed increased COVID-19 risk for nurses (3.1% seropositivity, 95% CI 2.5-3.9%, p = 0.012), staff working on COVID-19 units (4.6% seropositivity, 95% CI 3.2-6.5%, p = 0.032), males (2.4% seropositivity, 95% CI 1.8-3.2%, p = 0.019), and HCWs reporting high-risk exposures to infected patients (5.5% seropositivity, 95% CI 4.0-7.5%, p = 0.0022) or outside of work (12.0% seropositivity, 95% CI 8.0-17.4%, p < 0.0001). Smoking was a protective factor (1.1% seropositivity, 95% CI 0.7-1.8% p = 0.00018) and the symptom taste disorder was strongly associated with COVID-19 (29.8% seropositivity, 95% CI 24.3-35.8%, p < 0.0001). An unbiased decision tree identified subgroups with different risk profiles. Working from home as a preventive measure did not protect against SARS-CoV-2 infection. A PCR-testing strategy focused on symptoms and high-risk exposures detected all larger COVID-19 outbreaks. CONCLUSION: Awareness of the identified COVID-19 risk factors and successful surveillance strategies are key to protecting HCWs against SARS-CoV-2, especially in settings with limited vaccination capacities or reduced vaccine efficacy.

13.
Sci Total Environ ; 797: 149031, 2021 Nov 25.
Article in English | MEDLINE | ID: covidwho-1322345

ABSTRACT

Wastewater-based epidemiology (WBE) is a tool now increasingly proposed to monitor the SARS-CoV-2 burden in populations without the need for individual mass testing. It is especially interesting in metropolitan areas where spread can be very fast, and proper sewage systems are available for sampling with short flow times and thus little decay of the virus. We started in March 2020 to set up a once-a-week qualified spot sampling protocol in six different locations in Munich carefully chosen to contain primarily wastewater of permanent residential areas, rather than industry or hospitals. We used RT-PCR and sequencing to track the spread of SARS-CoV-2 in the Munich population with temporo-spatial resolution. The study became fully operational in mid-April 2020 and has been tracking SARS-CoV-2 RNA load weekly for one year. Sequencing of the isolated viral RNA was performed to obtain information about the presence and abundance of variants of concern in the Munich area over time. We demonstrate that the evolution of SARS-CoV-2 RNA loads (between <7.5 and 3874/ml) in these different areas within Munich correlates well with official seven day incidence notification data (between 0.0 and 327 per 100,000) obtained from the authorities within the respective region. Wastewater viral loads predicted the dynamic of SARS-CoV-2 local incidence about 3 weeks in advance of data based on respiratory swab analyses. Aligning with multiple different point-mutations characteristic for certain variants of concern, we could demonstrate the gradual increase of variant of concern B.1.1.7 in the Munich population beginning in January 2021, weeks before it became apparent in sequencing results of swabs samples taken from patients living in Munich. Overall, the study highlights the potential of WBE to monitor the SARS-CoV-2 pandemic, including the introduction of variants of concern in a local population.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , RNA, Viral , Sewage , Waste Water
14.
Blood ; 138(14): 1269-1277, 2021 10 07.
Article in English | MEDLINE | ID: covidwho-1317119

ABSTRACT

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe adverse effect of ChAdOx1 nCoV-19 COVID-19 vaccine (Vaxzevria) and Janssen Ad26.COV2.S COVID-19 vaccine, and it is associated with unusual thrombosis. VITT is caused by anti-platelet factor 4 (PF4) antibodies activating platelets through their FcγRIIa receptors. Antibodies that activate platelets through FcγRIIa receptors have also been identified in patients with COVID-19. These findings raise concern that vaccination-induced antibodies against anti-SARS-CoV-2 spike protein cause thrombosis by cross-reacting with PF4. Immunogenic epitopes of PF4 and SARS-CoV-2 spike protein were compared using in silico prediction tools and 3D modeling. The SARS-CoV-2 spike protein and PF4 share at least 1 similar epitope. Reactivity of purified anti-PF4 antibodies from patients with VITT was tested against recombinant SARS-CoV-2 spike protein. However, none of the affinity-purified anti-PF4 antibodies from 14 patients with VITT cross-reacted with SARS-CoV-2 spike protein. Sera from 222 polymerase chain reaction-confirmed patients with COVID-19 from 5 European centers were tested by PF4-heparin enzyme-linked immunosorbent assays and PF4-dependent platelet activation assays. We found anti-PF4 antibodies in sera from 19 (8.6%) of 222 patients with COVID-19. However, only 4 showed weak to moderate platelet activation in the presence of PF4, and none of those patients developed thrombotic complications. Among 10 (4.5%) of 222 patients who had COVID-19 with thrombosis, none showed PF4-dependent platelet-activating antibodies. In conclusion, antibodies against PF4 induced by vaccination do not cross-react with the SARS-CoV-2 spike protein, indicating that the intended vaccine-induced immune response against SARS-CoV-2 spike protein is not the trigger of VITT. PF4-reactive antibodies found in patients with COVID-19 in this study were not associated with thrombotic complications.


Subject(s)
Antibodies/adverse effects , COVID-19 Vaccines/adverse effects , Cross Reactions/immunology , Platelet Factor 4/immunology , Purpura, Thrombocytopenic, Idiopathic/etiology , Purpura, Thrombocytopenic, Idiopathic/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , Aged , Aged, 80 and over , Blood Platelets/immunology , COVID-19/immunology , Cohort Studies , Epitopes/immunology , Female , Heparin/metabolism , Humans , Immunoglobulin G/immunology , Male , Middle Aged , Protein Binding , Protein Domains , Purpura, Thrombocytopenic, Idiopathic/blood , Spike Glycoprotein, Coronavirus/chemistry , Young Adult
15.
Hemasphere ; 5(7): e603, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1301392

ABSTRACT

The clinical and immunological impact of B-cell depletion in the context of coronavirus disease 2019 (COVID-19) is unclear. We conducted a prospectively planned analysis of COVID-19 in patients who received B-cell depleting anti-CD20 antibodies and chemotherapy for B-cell lymphomas. The control cohort consisted of age- and sex-matched patients without lymphoma who were hospitalized because of COVID-19. We performed detailed clinical analyses, in-depth cellular and molecular immune profiling, and comprehensive virological studies in 12 patients with available biospecimens. B-cell depleted lymphoma patients had more severe and protracted clinical course (median hospitalization 88 versus 17 d). All patients actively receiving immunochemotherapy (n = 5) required ICU support including long-term mechanical ventilation. Neutrophil recovery following granulocyte colony stimulating factor stimulation coincided with hyperinflammation and clinical deterioration in 4 of the 5 patients. Immune cell profiling and gene expression analysis of peripheral blood mononuclear cells revealed early activation of monocytes/macrophages, neutrophils, and the complement system in B-cell depleted lymphoma patients, with subsequent exacerbation of the inflammatory response and dysfunctional interferon signaling at the time of clinical deterioration of COVID-19. Longitudinal immune cell profiling and functional in vitro assays showed SARS-CoV-2-specific CD8+ and CD4+ T-effector cell responses. Finally, we observed long-term detection of SARS-CoV-2 in respiratory specimens (median 84 versus 12 d) and an inability to mount lasting SARS-CoV-2 antibody responses in B-cell depleted lymphoma patients. In summary, we identified clinically relevant particularities of COVID-19 in lymphoma patients receiving B-cell depleting immunochemotherapies.

17.
Eur Respir J ; 58(1)2021 Jul.
Article in English | MEDLINE | ID: covidwho-1105685

ABSTRACT

A fraction of COVID-19 patients progress to a severe disease manifestation with respiratory failure and the necessity of mechanical ventilation. Identifying patients at risk is critical for optimised care and early therapeutic interventions. We investigated the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding relative to disease severity.We analysed nasopharyngeal and tracheal shedding of SARS-CoV-2 in 92 patients with diagnosed COVID-19. Upon admission, standardised nasopharyngeal swab or sputum samples were collected. If patients were mechanically ventilated, endotracheal aspirate samples were additionally obtained. Viral shedding was quantified by real-time PCR detection of SARS-CoV-2 RNA.45% (41 out of 92) of COVID-19 patients had a severe disease course with the need for mechanical ventilation (severe group). At week 1, the initial viral shedding determined from nasopharyngeal swabs showed no significant difference between nonsevere and severe cases. At week 2, a difference could be observed as the viral shedding remained elevated in severely ill patients. A time-course of C-reactive protein, interleukin-6 and procalcitonin revealed an even more protracted inflammatory response following the delayed drop of virus shedding load in severely ill patients. A significant proportion (47.8%) of patients showed evidence of prolonged viral shedding (>17 days), which was associated with severe disease courses (73.2%).We report that viral shedding does not differ significantly between severe and nonsevere COVID-19 cases upon admission to the hospital. Elevated SARS-CoV-2 shedding in the second week of hospitalisation, a systemic inflammatory reaction peaking between the second and third week, and prolonged viral shedding are associated with a more severe disease course.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , RNA, Viral , Respiratory System , Severity of Illness Index , Virus Shedding
18.
Med Microbiol Immunol ; 210(1): 65-72, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1033378

ABSTRACT

Successful containment strategies for the SARS-CoV-2 pandemic will depend on reliable diagnostic assays. Point-of-care antigen tests (POCT) may provide an alternative to time-consuming PCR tests to rapidly screen for acute infections on site. Here, we evaluated two SARS-CoV-2 antigen tests: the STANDARD™ F COVID-19 Ag FIA (FIA) and the SARS-CoV-2 Rapid Antigen Test (RAT). For diagnostic assessment, we used a large set of PCR-positive and PCR-negative respiratory swabs from asymptomatic and symptomatic patients and health care workers in the setting of two University Hospitals in Munich, Germany, i.e. emergency rooms, patient care units or employee test centers. For FIA, overall clinical sensitivity and specificity were 45.4% (n = 381) and 97.8% (n = 360), respectively, and for RAT, 50.3% (n = 445) and 97.7% (n = 386), respectively. For primary diagnosis of asymptomatic and symptomatic individuals, diagnostic sensitivities were 60.9% (FIA) (n = 189) and 64.5% (RAT) (n = 256). This questions these tests' utility for the reliable detection of acute SARS-CoV-2-infected individuals, in particular in high-risk settings. We support the proposal that convincing high-quality outcome data on the impact of false-negative and false-positive antigen test results need to be obtained in a POCT setting. Moreover, the efficacy of alternative testing strategies to complement PCR assays must be evaluated by independent laboratories, prior to widespread implementation in national and international test strategies.


Subject(s)
COVID-19 Serological Testing/methods , COVID-19/diagnosis , COVID-19/immunology , Adult , Antigens, Viral/blood , Child , Child, Preschool , False Negative Reactions , False Positive Reactions , Germany , Humans , Point-of-Care Systems , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Sensitivity and Specificity
19.
J Thromb Haemost ; 19(2): 574-581, 2021 02.
Article in English | MEDLINE | ID: covidwho-939789

ABSTRACT

OBJECTIVE: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to severe pneumonia, but also thrombotic complications and non-pulmonary organ failure. Recent studies suggest intravascular neutrophil activation and subsequent immune cell-triggered immunothrombosis as a central pathomechanism linking the heterogenous clinical picture of coronavirus disease 2019 (COVID-19). We sought to study whether immunothrombosis is a pathognomonic factor in COVID-19 or a general feature of (viral) pneumonia, as well as to better understand its upstream regulation. APPROACH AND RESULTS: By comparing histopathological specimens of SARS-CoV-2 with influenza-affected lungs, we show that vascular neutrophil recruitment, NETosis, and subsequent immunothrombosis are typical features of severe COVID-19, but less prominent in influenza pneumonia. Activated neutrophils were typically found in physical association with monocytes. To explore this further, we combined clinical data of COVID-19 cases with comprehensive immune cell phenotyping and bronchoalveolar lavage fluid scRNA-seq data. We show that a HLADRlow CD9low monocyte population expands in severe COVID-19, which releases neutrophil chemokines in the lungs, and might in turn explain neutrophil expansion and pulmonary recruitment in the late stages of severe COVID-19. CONCLUSIONS: Our data underline an innate immune cell axis causing vascular inflammation and immunothrombosis in severe SARS-CoV-2 infection.


Subject(s)
COVID-19/immunology , Immunity, Innate , Influenza, Human/immunology , Lung/immunology , Neutrophils/immunology , Thrombosis/immunology , Vasculitis/immunology , COVID-19/diagnosis , COVID-19/virology , Diagnosis, Differential , Host-Pathogen Interactions , Humans , Influenza, Human/diagnosis , Influenza, Human/virology , Lung/pathology , Lung/virology , Neutrophils/virology , Predictive Value of Tests , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Thrombosis/virology , Vasculitis/virology
20.
J Pediatric Infect Dis Soc ; 9(3): 362-365, 2020 Jul 13.
Article in English | MEDLINE | ID: covidwho-684002

ABSTRACT

In a family experiencing coronavirus disease 2019, the parents and 2 children aged 2 and 5 years became infected but the youngest child was not infected. Both children initially shed infectious virus, but cleared the virus after 5 to 6 days in the nasopharynx. However, viral RNA was continuously detected in the children's stool for more than 4 weeks.


Subject(s)
Betacoronavirus , Coronavirus Infections/pathology , Family , Pneumonia, Viral/pathology , Adult , COVID-19 , Child, Preschool , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Female , Germany/epidemiology , Humans , Infant , Infectious Disease Incubation Period , Male , Nasopharynx/virology , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , SARS-CoV-2 , Viral Load , Virus Shedding
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