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1.
Science ; : eabq2679, 2022 Jul 12.
Article in English | MEDLINE | ID: covidwho-1949931

ABSTRACT

The coronavirus spike (S) glycoprotein attaches to host receptors and mediates viral fusion. Using a broad screening approach, we isolated from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune donors seven monoclonal antibodies (mAbs) that bind to all human-infecting coronavirus S proteins. This class of mAbs recognize the fusion peptide and acquire affinity and breadth through somatic mutations. Despite targeting a conserved motif, only some mAbs show broad neutralizing activity in vitro against alpha- and beta-coronaviruses, including animal coronavirus WIV-1 and PDF-2180. Two selected mAbs also neutralize Omicron BA.1 and BA.2 authentic viruses and reduce viral burden and pathology in vivo. Structural and functional analyses show that the fusion peptide-specific mAbs bind with different modalities to a cryptic epitope, which is hidden in prefusion stabilized S, and becomes exposed upon binding of angiotensin-converting enzyme 2 (ACE2) or ACE2-mimicking mAbs.

2.
PLoS One ; 17(2): e0263328, 2022.
Article in English | MEDLINE | ID: covidwho-1883630

ABSTRACT

Patients on dialysis are at risk of severe course of SARS-CoV-2 infection. Understanding the neutralizing activity and coverage of SARS-CoV-2 variants of vaccine-elicited antibodies is required to guide prophylactic and therapeutic COVID-19 interventions in this frail population. By analyzing plasma samples from 130 hemodialysis and 13 peritoneal dialysis patients after two doses of BNT162b2 or mRNA-1273 vaccines, we found that 35% of the patients had low-level or undetectable IgG antibodies to SARS-CoV-2 Spike (S). Neutralizing antibodies against the vaccine-matched SARS-CoV-2 and Delta variant were low or undetectable in 49% and 77% of patients, respectively, and were further reduced against other emerging variants. The fraction of non-responding patients was higher in SARS-CoV-2-naïve hemodialysis patients immunized with BNT162b2 (66%) than those immunized with mRNA-1273 (23%). The reduced neutralizing activity correlated with low antibody avidity. Patients followed up to 7 months after vaccination showed a rapid decay of the antibody response with an average 21- and 10-fold reduction of neutralizing antibodies to vaccine-matched SARS-CoV-2 and Delta variant, which increased the fraction of non-responders to 84% and 90%, respectively. These data indicate that dialysis patients should be prioritized for additional vaccination boosts. Nevertheless, their antibody response to SARS-CoV-2 must be continuously monitored to adopt the best prophylactic and therapeutic strategy.


Subject(s)
Antibodies, Neutralizing/immunology , Neutralization Tests , Renal Dialysis , SARS-CoV-2/immunology , Vaccination , Animals , Antibodies, Neutralizing/blood , Antibody Affinity , CHO Cells , COVID-19 Vaccines/immunology , Case-Control Studies , Cricetulus , Dose-Response Relationship, Immunologic , Follow-Up Studies , HEK293 Cells , Humans , Immunoglobulin G/blood , Risk Factors , /immunology
3.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-336851

ABSTRACT

SARS-CoV-2 Omicron sublineages carry distinct spike mutations and represent an antigenic shift resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters result in potent plasma neutralizing activity against Omicron BA.1 and BA.2 and that breakthrough infections, but not vaccination-only, induce neutralizing activity in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1 and BA.2 receptor-binding domains whereas Omicron primary infections elicit B cells of narrow specificity. While most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant antibody, that is unaffected by any Omicron lineage spike mutations and is a strong candidate for clinical development.

4.
Int J Audiol ; : 1-5, 2022 May 05.
Article in English | MEDLINE | ID: covidwho-1819728

ABSTRACT

OBJECTIVE: To gain medical insight into the clinical course and safety of otolaryngologic disorders following immunisation with severe acute respiratory coronavirus (SARS-CoV-2) mRNA-based vaccines. DESIGN: Case description. STUDY SAMPLE: We report four cases of transient audio-vestibular symptoms, which occurred shortly after inoculation of two BNT162b2 (Pfizer-BioNTech®) and mRNA-1273 (Moderna®) vaccines. RESULTS: Hearing loss was unilateral in all cases and recovered at least partially: it was associated with persistent gait instability in two cases, after 1 and 7 months. Trigger mechanisms underpinning audio-vestibular impairment remain uncertain. Immune tolerance mechanisms with off-target innate activation of T-lymphocytes may be involved in vestibulocochlear nerve disorders, as for other cranial nerves involvement. CONCLUSIONS: The occurrence of audio-vestibular manifestations following mRNA-based vaccines needs ENT monitoring to support their causality in such rare vaccine-related adverse events. Audio-vestibular disorders appeared of transitory nature, including hearing loss, and should not deter further efforts in large-scale vaccination campaigns against SARS-CoV-2.

5.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-331576

ABSTRACT

Coronaviruses use diverse Spike (S) glycoproteins to attach to host receptors and fuse with target cells. Using a broad screening approach, we isolated from SARS-CoV-2 immune donors seven monoclonal antibodies (mAbs) that bind to all human alpha and beta coronavirus S proteins. These mAbs recognize the fusion peptide and acquire high affinity and breadth through somatic mutations. Despite targeting a conserved motif, only some mAbs show broad neutralizing activity in vitro against alpha and beta coronaviruses, including Omicron BA.1 variant and bat WIV-1, and reduce viral titers and pathology in vivo. Structural and functional analyses show that the fusion peptide-specific mAbs bind with different modalities to a cryptic epitope which is concealed by prefusion-stabilizing 2P mutations and becomes exposed upon binding of ACE2 or ACE2-mimicking mAbs. This study identifies a new class of pan-coronavirus neutralizing mAbs and reveals a receptor-induced conformational change in the S protein that exposes the fusion peptide region.

7.
Nature ; 602(7898): 664-670, 2022 02.
Article in English | MEDLINE | ID: covidwho-1616991

ABSTRACT

The recently emerged SARS-CoV-2 Omicron variant encodes 37 amino acid substitutions in the spike protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody-based therapeutics. Here we show that the Omicron RBD binds to human ACE2 with enhanced affinity, relative to the Wuhan-Hu-1 RBD, and binds to mouse ACE2. Marked reductions in neutralizing activity were observed against Omicron compared to the ancestral pseudovirus in plasma from convalescent individuals and from individuals who had been vaccinated against SARS-CoV-2, but this loss was less pronounced after a third dose of vaccine. Most monoclonal antibodies that are directed against the receptor-binding motif lost in vitro neutralizing activity against Omicron, with only 3 out of 29 monoclonal antibodies retaining unaltered potency, including the ACE2-mimicking S2K146 antibody1. Furthermore, a fraction of broadly neutralizing sarbecovirus monoclonal antibodies neutralized Omicron through recognition of antigenic sites outside the receptor-binding motif, including sotrovimab2, S2X2593 and S2H974. The magnitude of Omicron-mediated immune evasion marks a major antigenic shift in SARS-CoV-2. Broadly neutralizing monoclonal antibodies that recognize RBD epitopes that are conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/immunology , Neutralization Tests , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , COVID-19 Vaccines/immunology , Cell Line , Convalescence , Epitopes, B-Lymphocyte/immunology , Humans , Immune Evasion , Mice , SARS-CoV-2/chemistry , SARS-CoV-2/classification , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Vesiculovirus/genetics
8.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-296575

ABSTRACT

The recently emerged SARS-CoV-2 Omicron variant harbors 37 amino acid substitutions in the spike (S) protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody therapeutics. Here, we show that the Omicron RBD binds to human ACE2 with enhanced affinity relative to the Wuhan-Hu-1 RBD and acquires binding to mouse ACE2. Severe reductions of plasma neutralizing activity were observed against Omicron compared to the ancestral pseudovirus for vaccinated and convalescent individuals. Most (26 out of 29) receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only three mAbs, including the ACE2-mimicking S2K146 mAb, retaining unaltered potency. Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs recognizing antigenic sites outside the RBM, including sotrovimab, S2X259 and S2H97, neutralized Omicron. The magnitude of Omicron-mediated immune evasion and the acquisition of binding to mouse ACE2 mark a major SARS-CoV-2 mutational shift. Broadly neutralizing sarbecovirus mAbs recognizing epitopes conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.

9.
Vaccines (Basel) ; 9(9)2021 Sep 14.
Article in English | MEDLINE | ID: covidwho-1411064

ABSTRACT

Since marketing authorization, cases of neuralgic amyotrophy (NA), facial paralysis/Bell's palsy (FP/BP), and Guillain-Barré syndrome (GBS) were reported with COVID-19 vaccines of different technologies. This study aimed to assess whether NA, FP/BP, and GBS were more frequently reported in VigiBase with COVID-19 vaccines (of any technologies) than with other viral vaccines, over the full database and across potential risk groups by sex and age. The reporting odds ratio (ROR) with 95% confidence interval (95% CI) was used as the measure of disproportionality and subgroup disproportionality analyses were performed by sex and age. Out of 808,906 safety reports with COVID-19 vaccines, 57 (0.01%) reported NA, 3320 (0.4%) FP/BP, and 632 (0.1%) GBS. There were not signals of disproportionate reporting for NA and GBS with COVID-19 vaccines against other viral vaccines. FP/BP was disproportionately more frequently reported with COVID-19 vaccines than with other viral vaccines over the full database (ROR 1.12, 95%CI 1.07-1.17), in males (ROR 1.65, 95%CI 1.54-1.78) and in age subgroups 65-74 years (ROR 1.21, 95%CI 1.05-1.39) and ≥75 years (ROR 1.84, 95%CI 1.52-2.22). Albeit not proving causation, these findings might support clinicians in decision-making for patients potentially at risk for developing an acute inflammatory neuropathy with COVID-19 vaccines.

10.
Science ; 373(6559): 1109-1116, 2021 Sep 03.
Article in English | MEDLINE | ID: covidwho-1341301

ABSTRACT

The spillovers of betacoronaviruses in humans and the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlight the need for broad coronavirus countermeasures. We describe five monoclonal antibodies (mAbs) cross-reacting with the stem helix of multiple betacoronavirus spike glycoproteins isolated from COVID-19 convalescent individuals. Using structural and functional studies, we show that the mAb with the greatest breadth (S2P6) neutralizes pseudotyped viruses from three different subgenera through the inhibition of membrane fusion, and we delineate the molecular basis for its cross-reactivity. S2P6 reduces viral burden in hamsters challenged with SARS-CoV-2 through viral neutralization and Fc-mediated effector functions. Stem helix antibodies are rare, oftentimes of narrow specificity, and can acquire neutralization breadth through somatic mutations. These data provide a framework for structure-guided design of pan-betacoronavirus vaccines eliciting broad protection.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Betacoronavirus/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Viral Vaccines/immunology , Virus Internalization , Animals , Antibodies, Monoclonal/isolation & purification , Antibodies, Neutralizing/isolation & purification , Convalescence , Cricetinae , Cross Reactions , Humans , Immunoglobulin Fab Fragments/immunology , Immunoglobulin Fc Fragments/immunology , Jurkat Cells , Lung/immunology , Membrane Fusion/immunology , Neutralization Tests , Peptide Mapping , Protein Conformation, alpha-Helical , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Viral Load/immunology
12.
Science ; 372(6548): 1336-1341, 2021 06 18.
Article in English | MEDLINE | ID: covidwho-1234278

ABSTRACT

The identification of CD4+ T cell epitopes is instrumental for the design of subunit vaccines for broad protection against coronaviruses. Here, we demonstrate in COVID-19-recovered individuals a robust CD4+ T cell response to naturally processed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein and nucleoprotein (N), including effector, helper, and memory T cells. By characterizing 2943 S-reactive T cell clones from 34 individuals, we found that the receptor-binding domain (RBD) is highly immunogenic and that 33% of RBD-reactive clones and 94% of individuals recognized a conserved immunodominant S346-S365 region comprising nested human leukocyte antigen DR (HLA-DR)- and HLA-DP-restricted epitopes. Using pre- and post-COVID-19 samples and S proteins from endemic coronaviruses, we identified cross-reactive T cells targeting multiple S protein sites. The immunodominant and cross-reactive epitopes identified can inform vaccination strategies to counteract emerging SARS-CoV-2 variants.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , Immunodominant Epitopes , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Coronavirus/immunology , Cross Reactions , Epitopes, T-Lymphocyte/immunology , Genes, T-Cell Receptor beta , HLA-DP Antigens/immunology , HLA-DR Antigens/immunology , Humans , Immunologic Memory , Nucleocapsid Proteins/immunology , Protein Domains , Receptors, Antigen, T-Cell, alpha-beta/immunology , Spike Glycoprotein, Coronavirus/chemistry , T Follicular Helper Cells/immunology , T-Lymphocyte Subsets/immunology
13.
Proc Natl Acad Sci U S A ; 118(1)2021 01 07.
Article in English | MEDLINE | ID: covidwho-1066040

ABSTRACT

As the COVID-19 pandemic is spreading around the world, increasing evidence highlights the role of cardiometabolic risk factors in determining the susceptibility to the disease. The fragmented data collected during the initial emergency limited the possibility of investigating the effect of highly correlated covariates and of modeling the interplay between risk factors and medication. The present study is based on comprehensive monitoring of 576 COVID-19 patients. Different statistical approaches were applied to gain a comprehensive insight in terms of both the identification of risk factors and the analysis of dependency structure among clinical and demographic characteristics. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells by binding to the angiotensin-converting enzyme 2 (ACE2), but whether or not renin-angiotensin-aldosterone system inhibitors (RAASi) would be beneficial to COVID-19 cases remains controversial. The survival tree approach was applied to define a multilayer risk stratification and better profile patient survival with respect to drug regimens, showing a significant protective effect of RAASi with a reduced risk of in-hospital death. Bayesian networks were estimated, to uncover complex interrelationships and confounding effects. The results confirmed the role of RAASi in reducing the risk of death in COVID-19 patients. De novo treatment with RAASi in patients hospitalized with COVID-19 should be prospectively investigated in a randomized controlled trial to ascertain the extent of risk reduction for in-hospital death in COVID-19.


Subject(s)
Antiviral Agents , COVID-19 , SARS-CoV-2 , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme Inhibitors , COVID-19/drug therapy , COVID-19/mortality , COVID-19/physiopathology , COVID-19/virology , Female , Hospitalization , Humans , Male , Middle Aged , Pandemics , Protective Agents , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Risk Factors , Survival Analysis
14.
Cell ; 184(5): 1171-1187.e20, 2021 03 04.
Article in English | MEDLINE | ID: covidwho-1051523

ABSTRACT

SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the US Food and Drug Administration (FDA), and reduces the activity of some polyclonal sera from persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics.


Subject(s)
COVID-19/immunology , Genetic Fitness , Immune Evasion , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2/chemistry , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/virology , Humans , Mutation , Phylogeny , SARS-CoV-2/chemistry , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Virulence
15.
Lancet Reg Health Eur ; 1: 100013, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-988714

ABSTRACT

BACKGROUND: Hospital healthcare workers (HCW), in particular those involved in the clinical care of COVID-19 cases, are presumably exposed to a higher risk of acquiring the disease than the general population. METHODS: Between April 16 and 30, 2020 we conducted a prospective, SARS-CoV-2 seroprevalence study in HCWs in Southern Switzerland. Participants were hospital personnel with varying COVID-19 exposure risk depending on job function and working site. They provided personal information (including age, sex, occupation, and medical history) and self-reported COVID-19 symptoms. Odds ratio (OR) of seropositivity to IgG antibodies was estimated by univariate and multivariate logistic regressions. FINDINGS: Among 4726 participants, IgG antibodies to SARS-CoV-2 were detected in 9.6% of the HCWs. Seropositivity was higher among HCWs working on COVID-19 wards (14.1% (11.9-16.5)) compared to other hospital areas at medium (10.7% (7.6-14.6)) or low risk exposure (7.3% (6.4-8.3)). OR for high vs. medium wards risk exposure was 1.42 (0.91-2.22), P = 0.119, and 1.98 (1.55-2.53), P<0.001 for high vs. low wards risk exposure. The same was for true for doctors and nurses (10.1% (9.0-11.3)) compared to other employees at medium (7.1% (4.8-10.0)) or low risk exposure (6.6% (5.0-8.4)). OR for high vs. medium profession risk exposure was 1.37 (0.89-2.11), P = 0.149, and 1.75 (1.28-2.40), P = 0.001 for high vs. low profession risk exposure. Moreover, seropositivity was higher among HCWs who had household exposure to COVID-19 cases compared to those without (18.7% (15.3-22.5) vs. 7.7% (6.9-8.6), OR 2.80 (2.14-3.67), P<0.001). INTERPRETATION: SARS-CoV-2 antibodies are detectable in up to 10% of HCWs from acute care hospitals in a region with high incidence of COVID-19 in the weeks preceding the study. HCWs with exposure to COVID-19 patients have only a slightly higher absolute risk of seropositivity compared to those without, suggesting that the use of PPE and other measures aiming at reducing nosocomial viral transmission are effective. Household contact with known COVID-19 cases represents the highest risk of seropositivity. FUNDING: Henry Krenter Foundation, Ente Ospedaliero Cantonale and Vir Biotechnology.

16.
Proc Natl Acad Sci U S A ; 118(1)2021 01 07.
Article in English | MEDLINE | ID: covidwho-972264

ABSTRACT

As the COVID-19 pandemic is spreading around the world, increasing evidence highlights the role of cardiometabolic risk factors in determining the susceptibility to the disease. The fragmented data collected during the initial emergency limited the possibility of investigating the effect of highly correlated covariates and of modeling the interplay between risk factors and medication. The present study is based on comprehensive monitoring of 576 COVID-19 patients. Different statistical approaches were applied to gain a comprehensive insight in terms of both the identification of risk factors and the analysis of dependency structure among clinical and demographic characteristics. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells by binding to the angiotensin-converting enzyme 2 (ACE2), but whether or not renin-angiotensin-aldosterone system inhibitors (RAASi) would be beneficial to COVID-19 cases remains controversial. The survival tree approach was applied to define a multilayer risk stratification and better profile patient survival with respect to drug regimens, showing a significant protective effect of RAASi with a reduced risk of in-hospital death. Bayesian networks were estimated, to uncover complex interrelationships and confounding effects. The results confirmed the role of RAASi in reducing the risk of death in COVID-19 patients. De novo treatment with RAASi in patients hospitalized with COVID-19 should be prospectively investigated in a randomized controlled trial to ascertain the extent of risk reduction for in-hospital death in COVID-19.


Subject(s)
Antiviral Agents , COVID-19 , SARS-CoV-2 , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme Inhibitors , COVID-19/drug therapy , COVID-19/mortality , COVID-19/physiopathology , COVID-19/virology , Female , Hospitalization , Humans , Male , Middle Aged , Pandemics , Protective Agents , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Risk Factors , Survival Analysis
17.
Cell ; 183(4): 1024-1042.e21, 2020 11 12.
Article in English | MEDLINE | ID: covidwho-773817

ABSTRACT

Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. In a cohort of 647 SARS-CoV-2-infected subjects, we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics.


Subject(s)
Antibodies, Neutralizing/immunology , Epitope Mapping/methods , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2 , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/chemistry , Antibodies, Viral/blood , Antibodies, Viral/chemistry , Antibodies, Viral/immunology , Antigen-Antibody Reactions , Betacoronavirus/immunology , Betacoronavirus/isolation & purification , Betacoronavirus/metabolism , Binding Sites , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/virology , Epitopes/chemistry , Epitopes/immunology , Humans , Immunoglobulin A/blood , Immunoglobulin A/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunoglobulin M/blood , Immunoglobulin M/immunology , Kinetics , Molecular Dynamics Simulation , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Protein Binding , Protein Domains/immunology , Protein Structure, Quaternary , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
18.
Endocrine ; 70(3): 454-460, 2020 12.
Article in English | MEDLINE | ID: covidwho-737716

ABSTRACT

PURPOSE: The length of time a critically ill coronavirus disease 2019 (COVID-19) patient remains infectious and should therefore be isolated remains unknown. This prospective study was undertaken in critically ill patients to evaluate the reliability of single negative real-time polymerase chain reaction (RT-PCR) in lower tracheal aspirates (LTA) in predicting a second negative test and to analyze clinical factors potentially influencing the viral shedding. METHODS: From April 9, 2020 onwards, intubated COVID-19 patients treated in the intensive care unit were systematically evaluated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by RT-PCR of nasopharyngeal swabs and LTA. The time to negativity was defined as the time between the onset of symptoms and the viral clearance in LTA. In order to identify risk factors for prolonged viral shedding, we used univariate and multivariate Cox proportional hazards models. RESULTS: Forty-eight intubated SARS-CoV-2 patients were enrolled. Overall, we observed that the association of the first negative RT-PCR with a second negative result was 96.7%. Median viral shedding was 25 (IQR: 21.5-28) days since symptoms' onset. In the univariate Cox model analysis, type 2 diabetes mellitus was associated with a prolonged viral RNA shedding (hazard ratio [HR]: 0.41, 95% CI: 0.06-3.11, p = 0.04). In the multivariate Cox model analysis, type 2 diabetes was associated with a prolonged viral RNA shedding (HR: 0.31, 95% CI: 0.11-0.89, p = 0.029). CONCLUSION: Intubated patients with type 2 diabetes mellitus may have prolonged SARS-CoV-2 shedding. In critically ill COVID-19 patients, one negative LTA should be sufficient to assess and exclude infectivity.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/virology , Critical Illness , Diabetes Mellitus, Type 2/virology , Pneumonia, Viral/virology , Respiratory System/virology , Virus Shedding , Aged , Betacoronavirus/genetics , COVID-19 , COVID-19 Testing , COVID-19 Vaccines , Clinical Laboratory Techniques/methods , Clinical Laboratory Techniques/standards , Comorbidity , Coronavirus Infections/complications , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/epidemiology , Disease Progression , Female , Humans , Intensive Care Units , Italy/epidemiology , Male , Middle Aged , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Predictive Value of Tests , Prognosis , Prospective Studies , Reproducibility of Results , Respiratory System/pathology , Reverse Transcriptase Polymerase Chain Reaction/methods , Reverse Transcriptase Polymerase Chain Reaction/standards , Risk Factors , SARS-CoV-2 , Specimen Handling/methods , Specimen Handling/standards , Switzerland/epidemiology , Time Factors
19.
Clin Res Hepatol Gastroenterol ; 44(6): e141-e144, 2020 11.
Article in English | MEDLINE | ID: covidwho-592385

ABSTRACT

We present here the case of a 62-year-old man, who was referred to the emergency department with fever and cough for 3 days. He underwent liver transplantation 4 years earlier due to HCV and NASH-related cirrhosis with hepatocellular carcinoma. At admission he was in reduced general conditions. Nasopharyngeal smear specimen resulted positive for SARS-CoV-2 infection. Pulmonary low-dose CT-scan revealed bilateral subpleural ground-glass infiltrates. O2 saturation was 93%. A treatment with lopinavir/ritonavir and hydroxychloroquine twice daily was started. The patient received also cefepime and remained in isolation. Seven days later imaging showed a progression of the pulmonary infiltrates. Cefepime was replaced by meropenem. During the following 3 days the fever resolved, and the general conditions of the patient significantly improved. Consequently, treatment with lopinavir/ritonavir and hydroxychloroquine was stopped. The evolution of SARS-CoV-2 interstitial pneumonia in this immunosuppressed patient was moderate to severe and liver injury was not clinically significant. Despite its limitations, this case report confirm that the liver may be only mildly affected during SARS-CoV-2 infection, also in liver transplanted patients. Further studies are needed to assess whether the outcome of SARS-CoV-2 infection is worse in immunosuppressed patients than in the general population.


Subject(s)
COVID-19/drug therapy , Liver Transplantation , SARS-CoV-2 , Antiviral Agents/administration & dosage , COVID-19/epidemiology , COVID-19/pathology , Comorbidity , Humans , Hydroxychloroquine/administration & dosage , Liver Diseases/epidemiology , Liver Diseases/surgery , Lopinavir/administration & dosage , Lung/pathology , Male , Meropenem/administration & dosage , Middle Aged , Ritonavir/administration & dosage
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